NCCN临床实践指南：Merkel细胞癌（2026.V1）

指南综合与多学科· 未分类与其他 · 2026

NCCN Categories of Preference:

All recommendations are considered appropriate.

See NCCN Categories of Preference.

The NCCN Guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.©2025.

NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

Version 1.2026, 09/02/2025 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

MCC-1

• Additional Workup:

New bullet added: If diagnosis was made only with a core biopsy, consider collecting additional tumor tissue (required for tissue-informed circulating

tumor DNA [ctDNA] testing) prior to immunotherapy or radiation therapy (RT).

Seventh bullet revised: Consider genetics consultation genetic counseling to evaluate for heritable germline mutations in cancer-associated genes in

patients <50 y.

MCC-2

• Significant revisions made to this page.

MCC-2A

• New footnotes added:

Footnote l: With the goal of clear or microscopically positive margins versus grossly positive margins.

Footnote q: Ma KL, et al. Ann Surg Oncol 2023;30:4345-4355.

• Footnotes revised:

Footnote k: Adverse risk factors for local recurrence include: larger primary tumor (>1 cm); chronic T-cell immunosuppression, HIV, chronic

lymphocytic leukemia (CLL), solid organ transplant; head/neck primary site; lymphovascular invasion (LVI) present lymphovascular invasion (LVI),

immunosuppression, primary tumor >1 cm, close or pathologically positive margins, positive SLNB, or head/neck site.

Footnote m: Imaging via whole-body FDG-PET/CT (preferred at initial workup) or CT with contrast of chest, abdomen, pelvis, and neck if primary on

head/neck (and MRI of the brain with and without contrast if clinical suspicion of brain metastases or direct extension). (Also page MCC-4)

MCC-3

• Primary Treatment:

Following first bullet, 2 new pathways added:

◊ Adequate response on neoadjuvant Nivolumab.

◊ Progression on neoadjuvant Nivolumab.

Second bullet revised: For nonsurgical candidates, due to comorbidities, or tumor characteristics, or progression on neoadjuvant Nivolumab, discuss

RT for durable local control versus systemic therapy.

• Additional Treatment:

Following Adequate response on neoadjuvant Nivolumab, column removed: Excision with 1- to 2-cm margins or Mohs or other forms of PDEMA in

certain circumstances and SLNB with appropriate immunopanel.

Following Progression on neoadjuvant Nivolumab, new column added: Discuss RT or surgery for local control versus systemic therapy.

• Footnote removed: Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV Nivolumab. Nivolumab and hyaluronidasenvhy has different dosing and administration instructions compared to IV Nivolumab.

Updates in Version 1.2026 of the NCCN Guidelines for Merkel Cell Carcinoma from Version 2.2025 include:

NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

NCCN Guidelines Index Table of Contents Discussion

MCC-4

• Clinical N+ Disease, new bullet added: Multidisciplinary consultation recommended at center with specialized expertise.

• Additional Treatment:

Top pathway, bullet removed: Multidisciplinary consultation.

Bottom pathway:

◊ New bullet added: Systemic therapy

◊ Last bullet revised: Systemic therapy Additional local considerations if curative surgery and/or RT are not feasible.

◊ Bullet removed: Multidisciplinary consultation recommended at center with specialized expertise.

MCC-6

• Footnote w revised: Risk factors for recurrence include immunosuppression, advancing age, advancing stage of disease (stage II–IV), individuals

assigned male at birth, non-SLN metastases, Merkel Cell polyomavirus negative status, as well as additional factors as determined by the treating

physicians. . .

MCC-B

• Significant changes made to Principles of Radiation Therapy section.

MCC-D 3 of 5

• Primary regional (if curative surgery and curative RT not feasible), Recurrent regional disease N+ (if curative surgery and curative RT not feasible), and In-transit disease moved to this page from MCC-D 4 of 5.

Other Recommended, option added: Ipilimumab + Nivolumab.

Useful in Certain Circumstances:

◊ Option removed: Ipilimumab + Nivolumab.

◊ Last sub-bullet revised: T-VEC (Intralesional Talimogene Laherparepvec) for palliation of injectable sites.

• Link at bottom of page removed: Primary and Regional Disease (if curative surgery and curative RT not feasible) on MCC-D 3 of 4.

• New footnote f added: Ipilimumab + Nivolumab is particularly indicated for disease that is refractory to PD-1 therapy. (Also page MCC-D 3 of 4)

MCC-D 4 of 5

• Table header revised: Primary and Recurrent Regional Disease (if curative surgery and curative RT not feasible) Disseminated Disease M1.

• Other Recommended, option added: Ipilimumab + Nivolumab.

• Useful in Certain Circumstances:

Option removed: Ipilimumab + Nivolumab.

Sub-bullets revised:

◊ Second sub-bullet: Carboplatin/Etoposide (Recurrent regional or M1 only).

◊ Fourth sub-bullet: Cisplatin/Etoposide (Recurrent regional or M1 only).

◊ Eighth sub-bullet: Octreotide long-acting release (LAR) (Somatostatin analog therapy if somatostatin receptor testing is positive) (category 2B for M1).

◊ Ninth sub-bullet: Pazopanib (category 2B for M1).

◊ Last sub-bullet: T-VEC (Intralesional Talimogene Laherparepvec) for palliation of injectable sites (category 2B for M1).

• New footnote g added: In the Stage IV setting, NGS of the tumor sometimes reveals relevant and actionable therapeutic targets.

UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for Merkel Cell Carcinoma from Version 2.2025 include:

Continued

NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

NCCN Guidelines Index Table of Contents Discussion

MCC-D 5 of 5

• New references added:

Reference 22: Kim S, Wuthrick E, Blakaj D, et al. Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for

advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial. Lancet 2022;400:1008-1019.

Reference 23: Brazel D, Kumar P, Doan H, et al. Genomic alterations and tumor mutation burden in Merkel cell carcinoma. JAMA Netw Open

2023;6:e2249674.

Updates in Version 1.2026 of the NCCN Guidelines for Merkel Cell Carcinoma from Version 2.2025 include:

UPDATES

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

NCCN Guidelines Index Table of Contents Discussion

|CLINICAL PRESENTATION|PRELIMINARY WORKUP|DIAGNOSIS|ADDITIONAL WORKUP|CLINICAL FINDINGS|TREATMENT| |---|---|---|---|---|---| |Lesion suspicious for skin cancer|·H&P·Biopsya Hematoxylin and eosin(H&E) Immunopanel|Merkel cell (MCC)|●Complete skin and lymph node (LN) examination ●Multidisciplinary consultation recommended at center with specialized expertise ●Imaging studiesb ● Laboratory studies as clinically indicated,c , the diagnosis as clinically indicated,c , its diagnosis was made only with a core biopsy, consider collecting additional tumor tissue (required for tissue-informed circulating tumor DNA [ctDNA] testing) prior to immunotherapy or radiation therapy (RT) ●For patients who are immunocompromised, consider modification or reduction of immunosuppression as appropriate ●Consider genetic counseling to evaluate for germline mutations in cancer-associated genes in patients<50yf|Clinical N0 →MCC-2 and MCC-3 Clinical N+ →MCC-4 Clinical M1 → MCC-5||

a Principles of Pathology(MCC-A).

bImaging is encouraged for staging of most cases of MCC, because occult metastatic disease resulting in upstaging has been detected in 12%-20% of patients presenting without suspicious H&P findings(Singh N, et al. J Am Acad Dermatol 2021;84:330-339). Several studies indicate whole-body FDG-PET with fused axial imaging is more sensitive for detecting occult metastatic disease at baseline; however, CT with contrast of chest/abdomen/pelvis and neck if primary tumor on head/neck (and MRI of the brain with and without contrast if clinical suspicion of brain metastases) is an acceptable alternative. Imaging may also be useful to evaluate for the possibility of a skin metastasis from a noncutaneous primary neuroendocrine carcinoma (eg, small cell lung cancer), especially in cases where CK20 is negative and/or TTF-1 is positive. The most reliable staging tool to identify subclinical nodal disease is sentinel lymph node biopsy (SLNB) (George A, et al. Nucl Med Commun.452:35:282-290; Hawryluk EB, et al. J Am Acad Dermatol 2013;68:592-599; Siva S, et al. J Nucl Med 2013;54:1223-1229).

c Quantitation of serum Merkel cell polyomavirus(MCPYv) oncoprotein antibodies may be considered as part of initial workup; patients who test seronegative have a higher risk of recurrence; in patients who test seropositive, a rising titer may be an early indicator of recurrence; baseline testing should be performed within 3 months of treatment because titers are expected to decrease significantly after clinically evident disease is eliminated. For surveillance, this test is often obtained every 3 months. Miller D, et al. Cancer 2024;130:2670-2682; Paulson KG, et al. Cancer 2017;123:1464-1474.

d ctDNA can assess disease burden in both virus-positive and virus-negative MCC and typically becomes positive prior to or at the time of a clinically evident recurrence.For surveillance, this test is often obtained every 3 months. Akaike T,et al.J Clin Oncol 2024;42:3151-3161.

eAs immunosuppression in MCC is a risk factor for poor outcomes, immunosuppressive treatments should be minimized as clinically feasible in consultation with the relevant managing physician. As patients who are immunocompromised are at high risk for recurrence, more frequent follow-up may be indicated.

integrated managing physician. As patients who are immunocompromised are at high risk for recurrence, more frequent follow-up may be indicated.

Note:All recommendations are category 2A unless otherwise indicated.

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National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

NCCN Guidelines Index Table of Contents Discussion

CLINICAL NO DISEASE, LOCAL MCC ONLY, SURGICALLY RESECTABLE

![Clinical NO (local MCC only, surgically recommended) & 34 forward RT, PRaper RT\nin{rm}{n}\\{in}{n}\\{PCNN0N(local)) & \nSurally\n\n\n\n| Multi-disciplinary conclusions with a 24th Annual\n](2/aj0YEe4oUhYkBdfpda0fYP/figurebd42f32d9c9f4c7a954c88c3a5e8de9b_0_6.png) Note:All recommendations are category 2A unless otherwise indicated.

Footnotes on MCC-2A

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NCCN Guidelines Index Table of Contents Discussion

a Principles of Pathology (MCC-A).g Criteria for "Local MCC only" are disease limited to the primary tumor, with no evidence of in-transit, nodal, or distant disease.h SLNB is an important staging tool. This procedure and subsequent treatment impacts regional control for patients with positive SLNs. It is recommended, regardless of surgical approach, that every effort is made to coordinate surgical management such that SLNB is performed prior to or at the time of definitive excision. See MCC-C.

i Surgical margins should be balanced with morbidity of surgery, with surgical goal of primary tissue closure to avoid undue delay to adjuvant RT. (If needed, adjuvant RT should be performed as soon as wound healing permits, as delay has been associated with worse outcomes). See Principles of Surgery (MCC-C).

j Mohs or other forms of PDEMA may be appropriate. See NCCN Guidelines for Squamous Cell Skin Cancer - Principles of PDEMA Technique for description of

PDEMA.

k Adverse risk factors for local recurrence include: lymphovascular invasion (LVI), immunosuppression, primary tumor >1 cm, close or pathologically positive margins,

positive SLNB, or head/neck site.

l With the goal of clear or microscopically positive margins versus grossly positive margins.m Imaging via whole-body FDG-PET/CT (preferred at initial workup) or CT with contrast of chest, abdomen, pelvis, and neck if primary on head/neck (and MRI of the

brain with and without contrast if clinical suspicion of brain metastases or direct extension).

n Principles of Radiation Therapy (MCC-B).o Appropriateness of RT should be determined together with a radiation oncologist.p Consider empiric RT to the nodal basin when: 1) the accuracy or reliability of SLNB may have been compromised (eg, prior surgery, extensive chronic lymphocytic

leukemia [CLL] within the nodes, history of prior LN excision); 2) the risk of false-negative SLNB is high due to aberrant LN drainage and presence of multiple SLN

basins (such as in head/neck or midline trunk MCC); or 3) patient presents with profound immunosuppression.

q Ma KL, et al. Ann Surg Oncol 2023;30:4345-4355.

FOOTNOTES

Note: All recommendations are category 2A unless otherwise indicated.

MCC-2A

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

NCCN Guidelines Index Table of Contents Discussion

![CLINICAL NO DISEASE, LOCALLY ADVANCED MCC\nPRIMARY TREATMENT\nADDITIONAL TREATMENT\nDequate response on neoadjuvant Nivolumab\nNivolumab\nmay be considered in-patients who are surgical candidates\n·Neoadjuvant Nivolumab\nProgression on neoadjuvant Nivolumab\nDiscussion\nNivolumab\nADDITIONal Therapy\nPrimary and Additional Treatment(MCC-2)\nTreatment\n(MCC-6)\nFollow-up(MCC-6)\n](2/aj0YEe4oUhYkBdfpda0fYP/figurea0810de0d9a046229b75f7b52088b8a8_0_5.png) "Principles of Systemic Therapy(MCC-B).

Note: All recommendations are category 2A unless otherwise indicated.

![NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figure2e097552abda41c1880ec933dce7dfd0_0_1.png) National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

NCCN Guidelines Index Table of Contents Discussion

![CLINICAL N+ DISEASE\nWORKUP\nTREATMENT\nONALIC FININDINGS\nADDITIONAL FINDINGS\nMO\nNode dissection + RT,n o(preferred)• Node dissection or RT,n o (C-Clinical trial preferred if available• Consider systemic therapy\nMO\n Positive\nMANAGEMENT\nFINDINGS\nM1\nMCC-5\nG=-93\nNGerelts BainS\nNODAL BASIN\n● Fine-needle aspiration\nor core biopsy\nNegative\nLagnetic\nRadiographic surveillance\nFollow-up approach way\nInFocus\nMCC-3\nMANAGEMENT OF THE DRAINING NODAL BASIN\n● Fine-needle aspiration(FNA) or core biopsy\nNegative\nClinical trial\nSurgery or RT,n o\nSystemic therapy\n● Additional correlation if curative surgery and/or RT,n are not feasible:\n● T-VEC (Intralesional Talimogene laerparepvec)(Useful in Certain Circumstances)\nHyperthermic isolated limb infusion/perfusionnt'(Useful in Certain Circumstances)\n](2/aj0YEe4oUhYkBdfpda0fYP/figuref88f2dbae335448bb4180241093673fa_0_5.png) a Principles of Pathology(MCC-A).

mImaging via whole-body FDG-PET/CT(preferred at initial workup) or CT with contrast of chest, abdomen, pelvis, and neck if primary on head/neck(and MRI of the brain with and without contrast if clinical suspicion of brain metastases or direct extension).

^n Principles of Radiation Therapy (MCC-B).

○Appropriateness of RT should be determined together with a radiation oncologist.

r Principles of Systemic Therapy(MCC-D).

s An excisional biopsy may be considered to confirm a negative initial RNA or core LN biopsy if clinical suspicion remains high.

t Thiels CA,et al.J Surg Oncol 2016;114:187-192.

Note:All recommendations are category 2A unless otherwise indicated.

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National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

NCCN Guidelines Index Table of Contents Discussion

METASTATIC M1 DISEASE

TREATMENT OF M1 DISEASE

FOLLOW-UP

![M1 Disseminated MCC→\n Multidisciplinary\nCallian\nor\nConsider any of the following therapies or combinations of:(\nSystemic therapy^{\n\&}\nRT^n,\n●Surgery^u\nor\nBest,\n(See NCCN Guidelines for Palliative Care)\n\n](2/aj0YEe4oUhYkBdfpda0fYP/figure6d9d327c7567416da61305e755e243d8_0_8.png) eAs immunosuppression in MCC is a risk factor for poor outcomes, immunosuppressive treatments should be minimized as clinically feasible in consultation with the relevant managing physician. As patients who are immunocompromised are at high risk for recurrence, more frequent follow-up may be indicated.

oAppropriateness of RT should be determined together with a radiation oncologist.

r Principles of Systemic Therapy (MCC-D).

Under highly selective circumstances, in the context of multidisciplinary consultation, resection of limited metastases can be considered.

Note:All recommendations are category 2A unless otherwise indicated.

![NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figureb0a1efdb8a2d4852b29f0be752739075_0_1.png) National Comprehensive Cancer Network®

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NCCN Guidelines Index Table of Contents Discussion

![FOLLOW-UP\n\nRecurrence\n\nLocal, Locally advanced, and/or Regional\n\n▶■or\n\nEvery 3-6 mo for 3 y\n/→ ECCurence 12023\n\nMerkel Cell Carcinoma\n\nIn-transit disease\nMCC-4\nDisseminated\n→ Treatment of M1 Disease (MCC-5)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure9a3b5132c2de476499d5653baebfae32_0_5.png) cQuantitation of serum MCPyV oncoprotein antibodies may be considered as part of initial workup; patients who test seronegative have a higher risk of recurrence; in patients who test seropositive, a rising titer may be an early indicator of recurrence; baseline testing should be performed within 3 months of treatment because it are expected to decrease significantly after clinically evident disease is eliminated. For surveillance, this test is often obtained every 3 months. Miller D, et al. Cancer 2024;130:2670-2682; Paulson KG,et al. Cancer 2017;123:1464-1474.

oAppropriateness of RT should be determined together with a radiation oncologist.

r Principles of Systemic Therapy(MCC-D).

uUnder highly selective circumstances, in the context of multidisciplinary consultation, resection of limited metastases can be considered.

Whole-body FD-PET/CT may be indicated to evaluate for in-transit metastases if the primary lesion is on the extremity.

w Risk factors for recurrence include immunosuppression, advancing age, advancing stage of disease(stage II-IV), non-SLN metastases, Merkel Cell polyomavirus negative status, as well as additional factors as determined by the treating physicians. McEvoy AM, et al. J Am Acad Dermatol 2024;90:569-576.

Note:All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

MCC-A

• Pathologists should be experienced in distinguishing MCC from cutaneous simulants and metastatic tumors.

• Synoptic reporting is preferred.

• Minimal elements to be reported include largest tumor diameter (cm), peripheral and deep margin status, lymphovascular invasion (LVI), and extracutaneous extension (ie, bone, muscle, fascia, cartilage).

• Strongly encourage reporting of these additional clinically relevant factors (compatible with the American Joint Committee on Cancer [AJCC]and the College of American Pathologists [CAP] recommendations):

Thickness (Breslow, in mm)

Tumor-infiltrating lymphocytes (not identified, brisk, non-brisk)

Tumor growth pattern (nodular or infiltrative)

Presence of a second malignancy within the pathologic specimen itself (ie, concurrent squamous cell carcinoma [SCC])

• Immunohistochemistry (IHC) should be used for confirmation on all newly diagnosed MCC to exclude possible mimickers such as metastatic small cell carcinoma. Staining with CK20 (membranous and/or paranuclear dot-like) and negativity for thyroid transcription factor 1 (TTF1)

are usually sufficient. If an atypical staining pattern is present, AE1/3 keratin (dot-like), or at least one neuroendocrine marker (such as

synaptophysin, neurofilament, INSM1 [insulinoma-associated protein 1],1 chromogranin, CD56, or neuron-specific enolase [NSE]), and/or

Merkel cell polyomavirus (MCPyV) T antigen (CM2B4) stains may be used.

• SLNB evaluation for metastatic MCC requires microscopic evaluation of the entire SLN(s). Before determining SLNB negativity, multiple

levels (recommend at least 2) including H&E and at least one IHC stain should be used to help evaluate for metastatic disease. SLNB

reporting should also include the number of LN(s) involved, size of largest metastatic deposit (mm), and the presence/absence of ENE.

PRINCIPLES OF PATHOLOGY

1 Lilo MT, Chen Y, LeBlanc RE. INSM1 is more sensitive and interpretable than conventional immunohistochemical stains used to diagnose Merkel cell carcinoma. Am J Surg Pathol 2018;42:1541-1548.

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General Principles1,2

• Expeditious initiation of adjuvant RT after surgery is preferred as soon as wound healing permits, as delay >7 to 8 weeks has been

associated with worse outcomes.3

• There is limited evidence supporting dosing recommendations for MCC. Dose ranges provided are based on clinical practice at NCCN

Member Institutions and clinical evidence from studies of other types of skin cancer.

• Recommendations for external beam RT (EBRT) apply to both photons and electrons.

Image-guided radiation therapy (IGRT) is considered best practice when treating with intensity-modulated radiation therapy (IMRT),

proton beam radiotherapy, or 3D conformal radiation. The use of IGRT for other types of radiotherapy to treat skin cancer is considered

unnecessary.

• Application of bolus over the primary tumor should be considered to ensure full dose to the surface. Use of surface dosimeters should be considered to verify delivered dose.

• Radiation treatments should be given by a practicing radiation oncologist with radiation physics support to meet established qualityassurance and dosimetric constraints.

PRINCIPLES OF RADIATION THERAPY

Primary Tumor and Palliative RT Dosing Table on MCC-C (2 of 6)

Regional Nodes and Palliative RT Dosing Table on MCC-C (4 of 6)

Note: All recommendations are category 2A unless otherwise indicated.

MCC-B 1 OF 6 References on MCC-B 6 of 6

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NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF RADIATION THERAPY PRIMARY TUMOR SITE

General Treatment Information-Primary MCC Tumor Site

●Wide margins (5 cm) should be used around the primary site, when clinically feasible with consideration given to anatomic constraints(margins may need to be diminished around critical structures [eg, eye, mouth]).

●If electron beam is used, an energy and prescription isodose should be chosen that will deliver adequate dose to the lateral and deep margins.

|Primary Tumor|RT Dosing| |---|---| |Adjustant RT|| |●Patients with 1 or more risk factors for local recurrence should be considered for adjuvant RT.Risk factors include: LVI, immunosuppression, primary tumor>1 cm, close or pathologically positive margins, positive SLNB, or head/neck site.|| |●Conventional fractionationa,4(1.8-2 Gy/fraction) ●Negative resection margins ● Microscopically positive resection margins|50-56 Gy 56-60 Gy 60 Gy| |Grossly positive resection margins and further resection not possible|2.2-2.5 Gy x 20 fractions 3-3.5 Gy x 10 fractions 8 Gy x 1 fractiond,5| |Definitive RT to Clinically Evident Tumor|| |●Conventional fractionationa,4(1.8-2 Gy/fraction) Unresectable|56-60 Gy 56-60 Gy| |Surgery refused by patient|56-60 Gy 56-60 Gy| |Surgery would result in significant morbidity|56-60 Gy| |●Hypofractionationb|2.5 Gy x 20 fractions 3 Gy x 15-17 fractions 4 Gy x 10 fractions 6-7 Gy x 5 fractions( non-consecutive days) 8 Gy x 3 fractions( non-consecutive days)| |Palliative Regimens|Palliative Regimens| |●Hypofractionationb|3 Gy x 10 fractions 4 Gyx 5 fractions 8 Gy x 1-3 fractions,f|

Footnotes on MCC-B 3 of 6

Note: All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Index Table of Contents Discussion

a In subsets of patients at high risk, such as with chronic or profound immune suppression, an RT dose up to 66 Gy may be considered.b In patients at higher risk (eg, immunosuppression), avoid hypofractionated RT where there is limited data. c Consider dose-painting higher dose/fraction to a subvolume incorporating areas of concerning margins.d May consider a single postoperative fraction of RT (8 Gy) if patient is not a candidate for conventional fractionated radiation due to multiple comorbidities or if surgical margins are negative and risk factors are minimal.

e Caution using multiple fractions >5 Gy/fraction when targets involve cartilage or bone.f Durable palliation is likely to be higher with 8 Gy x 3 fractions.

Note: All recommendations are category 2A unless otherwise indicated.

MCC-B 3 OF 6

PRINCIPLES OF RADIATION THERAPY FOOTNOTES

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PRINCIPLES OF RADIATION THERAPY DRAINING NODAL BASIN

General Treatment Information-Draining Nodal Basin

•Treatment Information:

Irradiation of in-transit lymphatics is recommended only when the primary site is in close proximity to the nodal bed.

Consider empiric RT to the nodal basin when:

The accuracy or reliability of SLNB may have been compromised(eg, prior surgery,extensive chronic lymphocytic leukemia(CLL) within the nodes, history of prior LN excision).

The risk of false-negative SNLB is high due to aberrant LN drainage and presence of multiple SLN basins (such as in head/neck or midline trunk MCC).

□Patient presents with profound immunosuppression.

|Regional Nodes|RT Dosing| |---|---| |Adjuvant RT|| |●Conventional fractionation${}^{a}_{a}$ (1.8-2 Gy/day) SLN without LN dissection $\diamond$ SLN negative- RT not routinely indicated $\diamond$ SLN positive After LN dissection with multiple involved nodes and/or ENE ${}^{g}_{9}$|Observation 50-56 Gy 50-60 Gy| |●Hypofractionation${}^{b,c,h}$|2.2-2.5 Gy x 20 fractions 3-3.5 Gy x 10 fractions 8 Gy x 2 fractions ${}^{e}$| |Definitive RT for Clinically Evident Nodal Disease|| |●Conventional fractionation${}^{a}_{a}$ (1.8-2 Gy/day) No SLN or LN dissection $\diamond$ Clinically evident lymphadenopathy $\diamond$ Clinically node negative, but at risk for subclinical disease|| |●Hypofractionation${}^{b, h}$|2.5 Gy x 20 fractions 3 Gy x 15-17 fractions 6-7 Gy x 5 fractions, 2 treatments per week ${}^{j, 6, 7}$| |Palliative Regimens|| |●Hypofractionation${}^{b, h}$|3 Gy x 10 fractions 4 Gy x 5 fractions 8 Gy x 1-3 fractionse,f|

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a In subsets of patients at high risk, such as with chronic or profound immune suppression, an RT dose up to 66 Gy may be considered.b In patients at higher risk for recurrence (eg, immunosuppression), avoid hypofractionated RT where there is limited data. c Consider dose-painting higher dose/fraction to a subvolume incorporating areas of concerning margins. e Caution using multiple fractions >5 Gy/fraction when targets involve cartilage or bone.f Durable palliation is likely to be higher with 8 Gy x 3 fractions.g Adjuvant RT following LN dissection is more likely indicated for multiple involved nodes, the presence of ENE, or larger nodal size (eg, >1 cm).8h Use caution for patients with existing lymphedema or at high risk for lymphedema (ie, high BMI, groin nodal basin, current smoker).i LN dissection is the recommended initial therapy for clinically evident adenopathy, followed by postoperative RT if indicated. j Generally reserved for patients who are older or unable to come for protracted course.

Note: All recommendations are category 2A unless otherwise indicated.

MCC-B 5 OF 6

PRINCIPLES OF RADIATION THERAPY FOOTNOTES

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1 Rush Z, Fields RC, Lee N, Brownell I. Radiation therapy in the management of Merkel cell carcinoma: current perspectives. Expert Rev Dermatol 2011;6:395-404.2 Rao NG. Review of the role of radiation therapy in the management of Merkel cell carcinoma. Curr Probl Cancer 2010;34:108-117.3 Alexander NA, Schaub SK, Goff PH, et al. Increased risk of recurrence and disease-specific death following delayed postoperative radiation for Merkel cell carcinoma. J Am Acad Dermatol 2024;90:261-268.

4 Liu KX, Milligan MG, Schoenfeld JD, et al. Characterization of clinical outcomes after shorter course hypofractionated and standard-course radiotherapy for stage I–III curatively-treated Merkel cell carcinoma. Radiother Oncol 2022;173:32-40.

5 Dykstra M, Parra CE, Hayman JA, Harms KL. Adjuvant single-fraction radiotherapy to the resected primary tumor site and stage IIIA regional disease results in high

locoregional control in Merkel cell carcinoma in a single-institution retrospective study. J Am Acad Dermatol 2025;92:1438-1439.

6 Veness M. Hypofractionated radiotherapy in older patients with non-melanoma skin cancer: Less is better. Australas J Dermatol 2018;59:124-127.7 Dundar Y, Cannon RB, Hunt JP, et al. Radiotherapy regimens in patients with nonmelanoma head and neck skin cancers. Int J Dermatol 2018;57:441-448.8 Andruska N, Mahapatra L, Brenneman RJ, et al. Regional lymph node irradiation in locally advanced Merkel cell carcinoma reduces regional and distant relapse and improves disease-specific survival. Radiother Oncol 2021;155:246-253.

Note: All recommendations are category 2A unless otherwise indicated.

MCC-B 6 OF 6

PRINCIPLES OF RADIATION THERAPY REFERENCES

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NCCN Guidelines Index Table of Contents Discussion

MCC-C

PRINCIPLES OF SURGERY

Goals:

• Obtain histologically negative margins when clinically feasible.

• Surgical margins should be balanced with morbidity of surgery.

Surgical Approaches:

• It is recommended, regardless of the surgical approach, that every effort be made to coordinate surgical management such that SLNB is

performed prior to or at the time of definitive excision.a Excision options include:

If adjuvant RT is planned, narrow excision margins are likely sufficient (MCC-2).

If adjuvant RT may not be indicated (MCC-2), perform wide excision with 1- to 2-cm margins to investing fascia of muscle or pericranium

when clinically feasible and consistent with reconstruction and radiation goals listed below.

Techniques for more exhaustive histologic margin assessment may be considered (Mohs or other forms of PDEMA),b provided they do not

interfere with SLNB. If SLNB is not performed concurrently, it is recommended that SLNB is performed prior to definitive excision.

Reconstruction:

• It is recommended that any reconstruction involving extensive undermining or tissue movement be delayed until negative histologic margins are verified and SLNB is performed if indicated.

• Since RT is often indicated postoperatively, closure should be chosen to allow for expeditious initiation of RT (eg, primary closure, avoiding extensive tissue movement).

a SLNB is an important staging tool. This procedure and subsequent treatment impact regional control for patients with positive SLNs, but the impact of SLNB on overall survival is unclear.

b When Mohs is being performed and the preoperative biopsy is considered insufficient for providing all the staging information required to properly treat the tumor,

submission of the central specimen for vertical paraffin-embedded permanent sections or documentation of staging parameters in Mohs report is recommended.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPY

Local Disease N0 (MCC-D 2 of 5)

Regional Disease N+ (MCC-D 3 of 5)

Disseminated Disease M1 (MCC-D 4 of 5)

Note: All recommendations are category 2A unless otherwise indicated.

MCC-D 1 OF 5

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NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPYa,b

|Local Disease NO|Local Disease NO|Local Disease NO|Local Disease NO| |---|---|---|---| |●For primary disease, adjuvant systemic therapy is not recommended outside of a clinical trial.|||| ||Preferred|Other Recommended|Useful in Certain Circumstances| |Primary resectable disease|● None|● None|● None| |Primary locally advanced(if curative surgery and curative RT not feasible)|●Avelumab${}^{1,2}$ ●Pembrolizumab${}^{3}$|●Retifanlimab-dlwr${}^{4}$|●Neoadjuvant Nivolumab${}^{5}$| |Recurrent locally advanced(if curative surgery and curative RT not feasible)|●Pembrolizumab${}^{3}$ ●Retifanlimab-dlwr ${}^{4}$|●Avelumab${}^{1,2}$|●None| |Recurrent locally advanced(ii for curative surgery and curative RT not feasible)|●Pembrolizumab${}^{3}$ ●Retifanlimab-dlwr ${}^{4}$|●Avelumab${}^{1,2}$|●None|

a When available and clinically appropriate, enrollment in a clinical trial is recommended.

b Data from non-randomized trials in patients with MCC demonstrate that rates of durable response are improved with PD-1/PD-L1 blockade compared with cytotoxic therapy.The safety profiles for checkpoint immunotherapies are significantly different from cytotoxic therapies. Consult prescribing information for recommendations on detection and management of immune-related adverse events associated with checkpoint immunotherapies. Clinician and patient education is critical for safe administration of checkpoint immunotherapies. See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

c Nivolumab and hyaluronidase-nvyh subcutaneous injection may be substituted for IV Nivolumab. Nivolumab and hyaluronidase-nvyh has different dosing and administration instructions compared to IV Nivolumab.

Note: All recommendations are category 2A unless otherwise indicated.

References on MCC-D 5 of 5

MCC-D 2 OF 5

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NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPYa,b

|Regional Disease N+d|Regional Disease N+d|Regional Disease N+d|Regional Disease N+d| |---|---|---|---| ||Preferred|Other Recommended|Useful in Certain Circumstances| |Primary regional disease|● None|● None|●Neoadjuvant Nivolumabc,5| |Primary regional(if curative surgery and curative RT not feasible) Recurrent regional disease N+(if curative surgery and curative RT not feasible) In-transit disease|●Clinical trial ●Avelumabc-8 ●Nivolumabc,5,9 ●Pembrolizumab3 ●Retifanlimab-dlwr4|●Ipilimumab + Nivolumab,f,10-12|●If anti-PD-L1 or anti-PD-1 therapy is contraindicated or disease has progressed on anti-PD-L1 or anti-PD-1 monotherapy,may consider: Carboplatin(Recurrent regional disease only)13 Carboplatin/Etoposide(Recurrent regional disease only)13|

a When available and clinically appropriate, enrollment in a clinical trial is recommended.

b Data from non-randomized trials in patients with MCC demonstrate that rates of durable response are improved with PD-1/PD-L1 blockade compared with cytotoxic therapy. The safety profiles for checkpoint immunotherapies are significantly different from cytotoxic therapies. Consult prescribing information for recommendations on detection and management of immune-related adverse events associated with checkpoint immunotherapies. Clinician and patient education is critical for safe administration of checkpoint immunotherapies. See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

C Nivolumab and hyaluronidase-nvyh whose chemotherapy is not routinely recommended as survival benefit has not been demonstrated in available retrospective studies but could administration instructions compared to IV Nivolumab.

d For regional disease, adjuvant chemotherapy is not routinely recommended as survival benefit has not been demonstrated in available retrospective studies but could be used on a case-by-case basis if clinical judgement dictates. No data are available to support the adjuvant use of immunotherapy outside of a clinical trial.

e Nivolumab and hyaluronidase-nvhy is not approved for concurrent use with IV Ipilimumab; however, for Nivolumab monotherapy, Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV Nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV Nivolumab.

f Ipilimumab+ Nivolumab is particularly indicated for disease that is refractory to PD-1 therapy.22

References on MCC-D 5 of 5

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NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPYa,b

|Disseminated Disease M1||| |---|---|---| |Preferred|Other Recommended|Useful in Certain Circumstances9| |·Clinical trial|●Ipilimumab + Nivolumabe,f,10-12|●If anti-PD-L1 or anti-PD-1 therapy is contraindicated or disease has progressed on| |·Avelumab6-8||anti-PD-L1 or anti-PD-1 monotherapy,may consider:| |·Nivolumabc,5,9||Carboplatin13| |·Pembrolizumab3||Carboplatin/Etoposide13| |·Retifanlimab-dlwr4||Cisplatin14,15| |||Cisplatin/Etoposide14,15| |||CAV (Cyclophosphamide/Doxorubicin [or Epirubicin]/Vincristine)15,16| |||Ipilimumab17| |||Topotecan20| |||Octroide long-acting release (LAR) (Somatostatin analog therapy if somatostatin receptor testing18 is positive) (category 2B)| |||Pazopanib19 (category 2B)| |||T-VEC (Intralesional Talimogene Laherparepec)21 for palliation of injectable sites (category 2B)|

a When available and clinically appropriate, enrollment in a clinical trial is recommended.

b Data from non-randomized trials in patients with MCC demonstrate that rates of durable response are improved with PD-1/PD-L1 blockade compared with cytotoxic therapy. The safety profiles for checkpoint immunotherapies are significantly different from cytotoxic therapies. Consult prescribing information for recommendations on detection and management of immune-related adverse events associated with checkpoint immunotherapies. Clinician and patient education is critical for safe administration of checkpoint immunotherapies. See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

C Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV Nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV Nivolumab.

f Ipilimumab+ Nivolumab is particularly indicated for disease that is refractory to PD-1 therapy. 22

9 In the Stage IV setting, next generation sequencing (NGS) of the tumor sometimes reveals relevant and actionable trademarks. 23

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NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SYSTEMIC THERAPY REFERENCES

1 Bhatia S,Nghiem P, Veeranki SP,et al. Real-world clinical outcomes among patients with avelumab in patients with advanced Merkel cell carcinoma treated in the USA: a multicenter chart review study. J Immunother Cancer 2022;10:e004904.

2 Cowey LC, Liu FX, Kim R,et al. Real-world clinical outcomes with first-line avelumab in locally advanced/metastatic Merkel cell carcinoma in the USA:SPEAR-Merkel. Future Oncol 2021;17:2339-2350.

3 Nghiem P, Bhatia S, Lipson EJ, et al. Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy. J Clin Oncol 2019;37:693-702.

4 Grignani G, Rutkowski P, Lebbe C, et al. 545 A phase 2 study of retifanlimab in patients with advanced or metastatic merkel cell carcinoma(MCC)(POD1UM-201). J Immunother Cancer 2021;9:A574-A575.

5 Topalian SL, Bhatia S, Amin A, et al. Neoadjuvant nivolumab for patients with resectable Merkel cell carcinoma in the CheckMate 358 Trial. J Clin Oncol 2020;38:2476-2487.

6 Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016;17:1374-1385.

7 Kaufman HL, Russell JS, Hamid O,et al. Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer 2018;6:7.

8 D'Angelo SP, Russell J, Lebbé C, et al. Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial. JAMA Oncol 2018;4:e180077.

9 Topalian SL, Bhatia S, Hollebecque A, et al. Abstract CT074: Non-comparative,open-label, multiple cohort, phase 1/2 study to evaluate nivolumab(NIVO) in patients with virus-associated tumors(CheckMate 358): Efficacy and safety in Merkel cell carcinoma(MCC). Cancer Res 2017;77(13_Supplement):Abstract CT074.

10 LoPiccolo J, Schollenberger MD, Dakhil S, et al. Rescue therapy for patients with anti-PD-1-refractory Merkel cell carcinoma: a multicenter, retrospective case series. J Immunother Cancer 2019;7:170.

11 Glutsch V,Kneitz H,Gesierich A,et al.Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma. Cancer Immunol Immunother 2021;70:2087-2093.

12 Kim S,Wuthrick E,Blakaj D,et al. Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial. Lancet 2022;400:1008-1019.

13 Pectasides D, Pectasides M, Psyri A, et al. Cisplatin-based chemotherapy for merkel cell carcinoma of the skin. Cancer Invest 2006;24:780-785.

14 Satpute SR, Ammakkanavar N, Einhorn LH. Role of platinum-based chemotherapy for Merkel cell tumor in adjuvant and metastatic settings[Abstract].J Clin Oncol 2014;32(Suppl):Abstract 9049.

15 Fenig E, Brenner B, Katz A, et al. The role of radiation therapy and chemotherapy in the treatment of Merkel cell carcinoma. Cancer 1997;80:881-885.

16 Sundstrom S, Bremnes RM, Kaasa S, et al; Norwegian Lung Cancer Study Group. Cisplatin and etoposide regimen is superior to cyclophosphamide,reepirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years' follow-up. J Clin Oncol 2002;20:4665-4672.

17 Akaike T, Jabbour AJ, Goff PH,et al. Merkel cell carcinoma refractory to anti-PD(L)1: utility of adding ipilimumab for salvage therapy. J Immunother Cancer 2024;12:e009396.

18 Akaike T,Qazi J,Anderson A,et al.High somatostatin receptor expression and efficacy of somatostatin analogues in patients with metastatic Merkel cell carcinoma.Br J Dermatol 2021;184:319-327.

19 Tarabadkar ES, Thomas H, Blom A, et al. Clinical benefit from tyrosine kinase inhibitors in metastatic Merkel cell carcinoma: A case series of 5 patients. Am J Case Rep 2018;19:505-511.

20 Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous topoceta as second-line therapy in small-cell lung cancer. J Clin Oncol 2007;25:2086-2092.

21 Singh N, McClure E, Doolittle-Amieva C, et al. Complete resolution of PD-1 refractory, locoregionally advanced Merkel cell carcinoma with talimogene laherparepvec.JAAD Case Rep 2023;36:15-17.

22 Kim S,Wuthrick E,Blakaj D,et al. Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial. Lancet 2022;400:1008-1019.

23 Brazel D, Kumar P, Doan H, et al. Genomic alterations and tumor mutation burden in Merkel cell carcinoma. JAMA Netw Open 2023;6:e2249674.

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NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma Merkel Cell Carcinoma

NCCN Guidelines Index Table of Contents Discussion

American Joint Committee on Cancer (AJCC)

TNM Staging Classification for Merkel Cell Carcinoma(8th ed., 2017)

Table 1. Definitions for T,N,M

T Primary Tumor

TX Primary tumor cannot be assessed (e.g., cureted)

T0 No evidence of primary tumor

Tis In situ primary tumor

T1 Maximum clinical tumor diameter≤2 cm

T2 Maximum clinical tumor diameter>2 but≤5 cm

T3 Maximum clinical tumor diameter>5 cm

T4 Primary tumor invades fascia, muscle, cartilage, or bone

Clinical (N)

N Regional Lymph Nodes

NX Regional lymph nodes cannot be clinically assessed(e.g.,previously removed for another reason, or because of body habitus)

N0 No regional lymph node metastasis detected on clinical and/or radiologic examination

N1 Metastasis in regional lymph node(s)

N2 In-transit metastasis(discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor) without lymph node metastasis

N3 In-transit metastasis(discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor) with lymph node metastasis

Pathological(pN)

pN Regional Lymph Nodes

pNX Regional lymph nodes cannot be assessed (e.g., previously removed for another reason or not removed for pathological evaluation)

pN0 No regional lymph node metastasis detected on pathological evaluation pN1 Metastasis in regional lymph node(s)

pN1a Clinically occult regional lymph node metastasis identified only by sentinel lymph node biopsy

Clinically occult regional lymph node metastasis following lymph node dissection

Clinically and/or radiologically detected regional lymph node metastasis,microscopically confirmed

pN2 In-transit metastasis(discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor)without lymph node metastasis

In-transit metastasis(discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor)with lymph node metastasis

Clinical (M)

M Distant Metastasis

M0 No distant metastasis detected on clinical and/or radiologic examination

M1 Distant metastasis detected on clinical and/or radiologic examination

M1a Metastasis to distant skin, distant subcutaneous tissue, or distant lymph node(s)

M1b Metastasis to lung

M1c Metastasis to all other visceral sites

Pathological(M)

M Distant Metastasis

No distant metastasis detected on clinical and/or radiologic examination

Distant metastasis microscopically confirmed

Metastasis to distant skin, distant subcutaneous tissue, or distant lymph node(s), microscopically confirmed

metastasis to lung, microscopically confirmed

pM1c Metastasis to all other distant sites, microscopically confirmed

©,2021,American College of Surgeons,All Rights Reserved. Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging System.

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NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

American Joint Committee on Cancer (AJCC)AJCC Prognostic Stage Groups for Merkel Cell Carcinoma(8th ed., 2017)

Table 2. AJCC Prognostic Groups

Clinical (cTNM)

T T N M Stage 0 Tis NO MO

Stage I T1 NO MOMO

Stage IIA T2-T3 NO MO MO

Stage IIB T4 N0 MO

Stage III T0-T4 N1-3 MO

Stage IV T0-T4 Any N M1

Pathological (pTNM)

||T|N|M| |---|---|---|---| |Stage 0|Tis|NO|MO| |Stage I|T1|NO|MO| |Stage IIA|T2-T3|NO|MO| |Stage IIB|T4|NO|MO| |Stage IIIA|T1-T4|N1a(sn) or N1a|M0| |Stage IIIB|T1-T4|N1b-3|M0| |Stage IV|T0-T4|Any N|M1|

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NCCN Guidelines Index Table of Contents Discussion

ABBREVIATIONS

|CAP|College of American Pathologists|| |---|---|---| |CLL|chronic lymphocytic leukemia|| |ctDNA|circulating tumor DNA|| |EBRT|external beam radiation therapy|| |ENE|extranodal extension|| |FNA|fine-needle aspiration|| |H&E|hematoxylin and eosin|| |H&P|history and physical|SCC| |IGRT|image-guided radiation therapy|| |IHC|immunohistochemistry|| |IMRT|intensity-modulated radiation therapy|| |LAR|long-acting release|| |LN|lymph node|| |LVI|lymphovascular invasion||

|MCPPy|Merkel cell polymavirus| |---|---| |NGS|next generation sequencing| |NSE|neuron-specific enolase| |PD-1|programmed cell death protein 1| |PDEMA|peripheral and deep en face margin assessment| |PD-L1|programmed death ligand 1| |SCC|squamous cell carcinoma| |SLN|sentinel lymph node| |SLNB|sentinel lymph node biopsy| |TTF1|thyroid transcription factor 1|

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NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

NCCN Guidelines Index Table of Contents Discussion

|NCCN Categories of Evidence and Consensus|| |---|---| |Category 1|Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.| |Category 2A|Based upon lower-level evidence, there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.| |Category 2B|Based upon lower-level evidence, there is NCCN consensus(≥50%, but <85% support of the Panel) that the intervention is appropriate.| |Category 3|Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.|

All recommendations are category 2A unless otherwise indicated.

|NCCN Categories of Preference|| |---|---| |Preferred|Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.| |Other recommended|Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.| |Useful in certain circumstances|Other interventions that may be used for selected patient populations (defined with recommendation).|

All recommendations are considered appropriate.

|National|| |---|---| |Comprehensive Cancer|NCCN Guidelines Version 1.2026| |Network®|Merkel Cell Carcinoma|

Discussion

This discussion corresponds to the NCCN Guidelines for Merkel Cell Carcinoma. Last updated: April 18, 2025.

Overview $\ldots$ MS-2

Follow-up and Recurrence MS-2

Guidelines Update Methodology MS-2

Imaging Surveillance .. MS-20

Literature Search Criteria and Guidelines Update Methodology.... MS-2

Treatment of Recurrence MS-21

Sensitive/inclusive Language .MS-2

References.MS-22

Risk Factors for MCC $\ldots$ MS-3

Preliminary Workup and Diagnosis.MS-3

Pathology Report......MS-3

Additional Workup $\ldots$ MS-5

Characteristics and Differential Diagnosis. $^{\text {MS-7 }}$

Staging and Treatment of the Primary Tumor.

Surgery for Primary Tumor. MS-8

Sentinel Lymph Node Biopsy....MS-9

Definitive Radiation Therapy for Locregional Disease $\ldots$ MS-10

Clinical NO: Local MCC Only, Surgically Resectable..MS-10

Clinical NO: Locally Advanced MCC When Curative Surgery and Adjuvant RT Are not Feasible .MS-11

Nodal Staging and Treatment of Regional Disease

Management of the Primary Tumor for Regional Disease .MS-12

Management of the Draining Nodal Basin. .MS-12

Management of In-transit Disease.MS-13

Surgery Versus Radiation Therapy for Regional Disease $\ldots$ MS-13

Postoperative Radiation for Locregional Disease.MS-14

Treatment of Distant Metastatic Disease. $\ldots$ MS-14

Systemic Therapy for Merkel Cell Carcinoma.MS-15

Immunotherapy $\ldots$ MS-15

Chemotherapy $\ldots$ MS-17

Alternative Therapies. MS-18

NCCN Systemic Therapy Recommendations. MS-19

National Comprehensive Cancer

National Comprehensive NCCN Guidelines Version 1.2026 Cancer Merkel Cell Carcinoma

Overview

Merkel cell carcinoma(MCC) is a rare cutaneous neuroendocrine neoplasia with approximately 2488 individuals affected per year in the United States.1 Despite this, MCC is one of the most aggressive skin cancers, and its incidence is dramatically increasing.1-4 As MCC tumors are frequently misdiagnosed,5-7 the increased incidence may be due to the discovery of biomarkers that improve detection of the disease.8-9 Changes in environmental risk factors, an aging population, as well as improved recognition and diagnosis of MCC lead to an increase in disease incidence.4

MCC can grow rapidly and metastasize early, with 63% of primary lesions having grown rapidly in the 3 months prior to diagnosis.5 Large meta-analyses have shown that at least half of patients with MCC develop lymph node metastases and nearly one third develop distant metastases.10-17 Several studies document the development of locoregional recurrence in up to half of all instances of MCC.6,16-21 MCC has a high mortality rate exceeding melanoma. The 5-year relative or MCC-specific survival rates range from 41% to 77%, depending on stage at presentation.2,6,12,15,20-24

Guidelines Update Methodology

The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.

Literature Search Criteria and Guidelines Update Methodology

Prior to the update of this version of the NCCN Clinical Practice Guidelines(NCCN Guidelines) for Merkel Cell Carcinoma, an electronic search of the PubMed database was performed to obtain key literature using the search term: Merkel cell carcinoma. The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.25

The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types:Clinical Trial, Phase 2; Clinical Trial, Phase 3; Clinical Trial, Phase 4;Guideline; Meta-Analysis; Practice Guideline; Randomized Controlled Trial; Systematic Reviews; and Validation Studies. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the Panel during the Guidelines update have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the Panel's review of lower-level evidence and expert opinion.

Sensitive/Inclusive Language

NCCN Guidelines strive to use language that advances the goals of equity,inclusion,and representation.26 NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, anti-misognist, anti-ageist, anti-ableist, and anti-weight biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently.If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

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NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

Risk Factors for MCC

Sun exposure is believed to be a major risk factor for MCC, based on increased incidence in geographic areas with higher UV(ultraviolet)indices, the tendency to occur on skin areas that are exposed to the sun,and the frequency of MCCs comingled or adjacent to other skin lesions caused by UV exposure.7,27-32 MCC incidence increases with age and is more likely to occur in white individuals compared with people from other ethnicities.4,6,10,15 MCC is disproportionally more common in immunosuppressed individuals, such as those with organ transplants,lymphoproliferative malignancies(such as chronic lymphocytic leukemia[CLL]), or HIV infections.5,33-39 Several studies have reported that MCC-specific survival is worse for those with immunosuppression, 6,38,40-47 although other studies have found no correlation.48-50 Lastly, Merkel cell polyomavirus(MCPYV), a polyomavirus in MCC tumor tissues, is detected in 43% to 100% of tumors.51-56 MCPYV negative-tumors tend to occur more often on the head, neck, or trunk, and have been associated with increased recurrence55 and decreased MCC-specific survival and overall survival(OS) in some studies57-60 but not others.61,62 Genetic analyses have also found a much higher mutational burden in MCPV-negative tumors, and that only the MCPVY-negative group are enriched for cytosine to thymine(C to T) mutations indicative of UV damage.63-65

Preliminary Workup and Diagnosis

Initial workup of a suspicious lesion starts with a complete history and physical(H&P) examination, and biopsy of the primary tumor. Initial diagnosis of MCC in the primary lesion by hematoxylin and eosin(H&E)staining should be confirmed by performing immunohistochemistry(IHC)staining. An appropriate immunopanel should include cytokeratin 20(CK20) and thyroid transcription factor 1(TTF-1). Other IHC neuroendocrine markers such as synaptophysin, neurofilament protein,insulinoma-associated protein 1(NSM1), chromogranin A, CD56, or

neuron-specific enolase(NSE) may be used to exclude other diagnostic considerations.

The goals of histologic evaluation of primary MCC tumors are: 1) to accurately diagnose and distinguish the tumor from cutaneous simulants and metastatic tumors; 2) to provide complete pathologic tumor characteristics for staging according to recommended American Joint Committee on Cancer(AJCC) and College of American Pathologists(CAP) guidelines; and 3) to standardize pathologic data collection to further understand the critical biologic features that impact MCC behavior and prognosis. In accordance with the AJCC, the NCCN Panel agrees that synoptic reporting is preferred. At a minimum, the pathology report should include tumor size, peripheral and deep margin status, lymphovascular invasion(LVI), and extracutaneous extension to the bone, muscle, fascia,or cartilage, as these features may prove to have prognostic value. The NCCN Panel strongly encourages reporting of the following additional primary tumor features: tumor depth(Breslow, in mm), tumor-infiltrating lymphocytes(TILs)(not identified, brisk, or non-brisk), tumor growth pattern(nodular or infiltrative), and the presence of a second malignancy such as concurrent SCC within the pathologic specimen itself.

Pathology Report

The AJCC strongly encourages synoptic reporting for MCC primary tumor specimens, including but not limited to the parameters needed for determining T-stage.66 The College of American Pathologists(CAP) also provides a complete synoptic report protocol for cutaneous MCC.67

Peripheral and Deep Margin Status

Results vary between studies analyzing the prognostic value of margin status, with some studies showing correlations with local control, OS, or disease-specific death(DSD),19,22,23,42,68 but others finding no significant associations with outcome.69-74 The largest study investigating margin

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NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

status in 6901 patients with MCC in the National Cancer Database(NCDB) showed that margin status was significantly associated with survival for MCC with stage I, stage II, or stage III.68 One study of 179 patients found that margin status was correlated with local recurrence in MCC treated with surgery alone, but was far less predictive among patients who received adjuvant radiation therapy (RT).22

Lymphovascular Invasion

Several studies with large sample sizes have found LVI to be predictive of sentinel lymph node (SLN) positivity, recurrence, OS, and DSS.23,72,75-78 A large (N= 500) review of a prospective database supported that LVI in the primary tumor was highly correlated with DSD. Specifically,<1% versus 35% of those who died of MCC were LVI-negative and LVI-positive,respectively.23

Extracutaneous Extension

The 8th edition of the AJCC Cancer Staging Manual includes primary tumor invasion of fascia, muscle, cartilage, or bone as the definition of stage T4 for MCC.14.66 This is supported by results from several studies.12,76,79,80 For example, an analysis of a large database (SEER, N=2104) found that tumor extension beyond the demis was an independent prognostic factor for DSS.79 Another analysis of approximately 5000 patients with MCC from the NCDB found that tumor diameter was reasonably predictive of relative survival among patients with small primary tumors, but resulted in poor separation among patients with larger primary tumors(>2 cm).12

Tumor Size and Tumor Thickness

In addition to the analyses of NCDB data that support T-staging criteria for the AJCC staging guidelines,12,14 many studies have analyzed the relationship between tumor thickness and various outcomes-including lymph node involvement, ability of treatment to achieve local control,probability of distant metastasis, disease-specific survival(DSS), and OS.

Results from smaller studies(N<400) are variable6,19,20,41,42,48,81 but analyses of large databases have all found primary tumor size to be significantly associated with nodal involvement, DSS, and OS.13,15,49,68,79,82 It is important to note that even in these studies, the risk of microscopic lymph node involvement is non-negligible even among patients in the smallest tumor size category.15,49,77,82,83

Multiple institutions have published studies showing correlation between tumor thickness or Breslow depth and SLN positivity, disease-free survival(DFS), DSS, and OS.49,76,83-85 The statistical significance of these correlations varies, perhaps because primary tumor thickness may be correlated with primary tumor size.49 Per the AJCC staging guidelines,tumor thickness should be measured as for Breslow thickness in cutaneous melanoma-as the microscopic distance from the granular layer of the overlying epidermis to the deepest point of tumor invasion-and recorded in mm.66,67

Tumor Infiltrating Lymphocytes

Several studies have found that the presence of TILs in MCC tumors was associated with improved survival outcomes.76,85-91 Notably, a retrospective cohort study(N= 2182) established that subdivision of TIL status into non-brisk and brisk was associated with incrementally improved OS compared with no TILs.86 The prognostic value of TILs seems to depend on the type of immune cells present; however, it is not clear which type of TILs has prognostic value.88-90 The CAP protocol for MCC defines TILs as lymphocytes present at the interface of the tumor and stroma,without specifying any molecular markers.67 The categories for TILs are based on the presence and distribution of lymphocytes in the tumor sample.TILs“not identified” includes samples in which lymphocytes are present but do not infiltrate the tumor."Nonbrisk" should be used when lymphocyte infiltration is focal or not present across the entire base of the vertical growth phase, and“brisk” should be used when lymphocytes

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diffusely infiltrate the entire base of the dermal tumor or the entire invasive component of the tumor. ${}^{67}$

Tumor Growth Pattern

A variety of terms have been used to describe the distinct growth patterns observed in MCC tumors.76,80,83,92-96 In general, growth pattern seems to be prognostic if tumors are grouped into one of two categories: 1)“nodular”(or“circumscribed,”“solid,”“organoid,”“polypoid,” or“multinodular”); or 2)“infiltrative”(or“diffuse” or“trabecular”).76,83 Per the CAP protocol, nodular pattern is defined as tumors with a relatively well-circumscribed interface with the surrounding tissue, typically composed of one or multiple nodules.67 Infiltrative pattern is defined as tumors without a well-circumscribed interface, composed of single cells, rows, or trabeculae strands of cells infiltrating through dermal collagen or deeper soft tissue.Retrospective studies using these categories have found the infiltrative growth pattern to be associated with higher risk of SLN positivity or poor outcomes,76,80,83 possibly due to the difficulty in fully excising tumors that are poorly circumscribed.

Presence of Secondary Malignancy

Patients diagnosed with MCC are at higher risk of developing a second cancer, including squamous cell carcinoma(SCC); basal cell carcinoma(BCC); melanoma; CLL; non-Hodgkin lymphomas(NHLs); lung, breast,and kidney cancers; and vice versa.6,24,35,91,94,97-104 Currently, there appears to be more data showing no significant association between secondary malignancies and the likelihood of MCC SLN positivity, lymph node metastasis, locoregional control(LRC), or survival.23,72,77 In addition, there are numerous reports of other skin lesions or malignancies found within or adjacent to MCC tumors, most commonly SCC, followed by BCC,melanoma, actinic keratoses, and Bowen disease.7,30-32,61,85,92,105-113 It is not known whether the“combined” phenotype is associated with poor outcomes, as there are little comparative data available. One small

retrospective study found that patients with the combined tumors were more likely to have had prior non-melanoma skin cancers(NMSCs),nonhematologic extracutaneous cancers, and immunosuppression/pro-inflammatory comorbidities, and tend to have more metastasis, disease progression, and death from disease.7

Additional Workup

For patients with biopsy-confirmed MCC, additional workup may include complete skin and lymph node examination, imaging studies, and laboratory studies as clinically indicated including MCPyV and MCC circulating tumor(ctDNA) testing. Multidisciplinary consultation is recommended at a center with specialized expertise. As immunosuppression in MCC is a risk factor for poor outcomes,6,38,40-46,49,114 immunosuppressive treatments should be minimized as clinically feasible in consultation with the relevant treating physician. The risk for disease recurrence is higher in patients with immunosuppression43,46,47,114,115;therefore, more frequent follow-up may be indicated. Additionally in patients<50 years diagnosed with MCC, a genetics consultation should be considered to evaluate for heritable mutations in cancer-associated genes as they have been reported in about 20% of patients in this age group.116

Laboratory Testing

Several groups have explored the significance of antibodies to MCPyV in patients with MCC.56,117-119 In one prospective validation study that included 219 patients with newly diagnosed MCC, patients who were oncoprotein antibody seronegative at diagnosis had a significantly higher risk of recurrence, suggesting that they may benefit from more intensive surveillance.55 For patients who were seropositive, the oncoprotein antibody test every 3 months may be a useful component of ongoing surveillance because a rising titer can be an early indicator of recurrence.

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In MCC, circulating tumor DNA (ctDNA) is a promising minimally invasive tool for early stage multi-cancer screening and tumor development monitoring via detection of cell-free DNA fragments.120 Disease burden in both virus-positive and virus-negative MCC can be evaluated by ctDNA testing and surveillance is commonly obtained every 3 months.121 The ctDNA results typically become positive prior to or at the time of a clinically evident recurrence.122 The use of ctDNA in MCC has shown high disease sensitivity and prognostic accuracy for early detection of MCC recurrence.

Imaging Studies

The utility of imaging as part of baseline staging for MCC is an issue of debate in the literature. A number of retrospective analyses have reported data on detection and appearance of MCC tumors using various imaging methods, including conventional x-ray,102,123,124 CT,102,124-128 ultrasound,102,124,127 MRI,123,124,127,129 scintigraphy,130-132 and PET or PET/CT.127,129,133-146 For CT and FDG-PET or FDG-PET/CT, there are reports showing detection of MCC primary tumors, lymph node metastases, and distant metastases in a wide range of anatomic locations.Though the reported sensitivity and specificity of MRI were lower than CT and FDG PET/CT,129 it is still the best imaging tool available for rare cases of MCC brain metastases, 147-149 A number of studies have attempted to determine the utility of specific imaging methodologies for detecting MCC tumors, either in terms of the sensitivity, specificity, and positive/negative predictive value, or in terms of making an impact on disease restaging or management. However, many studies are limited by small sample size(N<30) and did not consistently use pathologic confirmation as a standard of reference for determining positive and negative predictive values.

Imaging is encouraged for staging of most MCC because occult metastatic disease that resulted in upstaging has been detected in 12% to 20% of patients presenting without suspicious H\&P findings. ${}^{150}$ This study by Singh et al indicates that whole-body PET with fused axial imaging is more

sensitive for detecting occult metastatic disease at baseline.150 Acceptable alternative imaging modalities include brain MRI with or without contrast if clinical suspicion of brain metastasis, chest/abdomen/pelvis CT with contrast with neck CT for primary tumor on the head/neck, or whole-body FDG-PET/CT, which might be indicated to evaluate for in-transit metastasis for a primary tumor on an extremity.CT or MRI with contrast may be used if whole-body FDG-PET/CT is not available.The use of brain MRI varies among NCCN Panel members. Some Panel members reserve this test for patients that have an indication of brain metastases or in which widespread systemic disease has been detected.151 Imaging may also be useful to evaluate for the possibility of a skin metastasis from a noncutaneous primary neuroendocrine carcinoma(eg, small cell lung cancer[SCLC]), especially in cases where CK20 is negative and/or TTF-1 is positive. It must be noted that the most reliable staging tool to identify subclinical nodal disease is sentinel lymph node biopsy(SLNB).

Computed Tomography

Only a few studies have evaluated the independent utility of CT for detection of MCC tumors.102,124-129 According to Gupta et al, the calculated sensitivity and specificity of baseline CT imaging for detection of lymph node metastases were 20% and 87%, respectively. Conversely, for the detection of distant metastases, the sensitivity and specificity were 100%and 48%, respectively. For both nodal and distant spread of MCC, true positives oftentimes had disease that were clinically evident at presentation.126 A separate study came to similar conclusions, reporting that the low sensitivity and high specificity of CT scans were 47% and 97%, respectively, in detecting nodal disease. In this study, CT imaging was unable to detect micrometastases as well as larger lymph node metastases, including single node positivity in six patients and multiple positive nodes in five patients.129

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FDG-PET/CT

Compared with CT imaging, there are many more studies with larger sample sizes on the utility of FDG-PET/CT for detecting MCC tumors.127,129,133-146 Overall, FDG-PET/CT has high sensitivity and specificity when compared with subsequent pathologic, clinical, or imaging results, with calculated values of 90% and 98%, respectively, according to a meta-analysis.139 In the only prospective study to date, FDG-PET/CT had a sensitivity of 95% and a specificity of 88%, respectively.146 Small retrospective studies indicate that FDG-PET/CT might not be useful in detecting lymph node metastasis(compared with SLNB),143 as well as primary tumor site in patients with unknown primary MCC.144 A number of studies reported that results from FDG-PET/CT scans at initial presentation impacted baseline staging in 6% to 39% of patients and changed treatment in 6% to 37% of patients.134-138,140-142,145,146 Most of the changes in staging and disease management were due to discovery of more extensive lymph node involvement, distant metastatic disease, or previously undetected secondary cancers, suggesting that FDG-PET imaging may be more useful in patients with clinically advanced disease at presentation.

Some evidence suggests that FDG-PET/CT may be more useful than CT in detecting nodal and distant MCC. In a retrospective analysis, in which CT and FDG-PET results were compared to SLNB results, the calculated sensitivity of FDG-PET was notably better than that for CT(83% vs.47%).129 Furthermore, in some studies, FDG-PET/CT detected positive lymph nodes and distant metastases that were not detectable by CT scans. ${}^{136,137,146}$ In a large retrospective study, patients who underwent PET/CT had disease upstaged more often than those with CT alone(16.8% vs. 6.9%; P=.0006). ${}^{150}$

Characteristics and Differential Diagnosis

MCC is rarely clinically suspected at presentation because the primary tumor lacks distinguishing features and is often asymptomatic. In a study of 195 patients with pathologically confirmed MCC, 88% of MCC tumors were asymptomatic and correct clinical diagnosis was rare(only 1%).5 Based on clinical impression, 56% of MCC tumors were initially presumed to be benign cysts/lesions.5 Other studies confirm that MCCs are frequently clinically misdiagnosed as benign lesions or NMSCs or other rare malignant skin tumors.6,7,152 Midsagnosis is even more prevalent among MCC tumors that are admixed or adjacent to other skin tumors.7,153

MCC tumors visualized by H&E typically contain small round cells with sparse cytoplasm, abundant mitoses, and dense core granules in the cytoplasm.61,93,95,123,154 MCC is similar to a variety of other widely recognized small round cell tumors, including metastatic visceral neuroendocrine carcinomas(eg, neuroblastoma, rhabdomyosarcoma,metastatic carcinoid, SCLC, lymphomas, osteosarcoma).155-160 The most difficult differentiation is often between primary MCC and metastatic SCLC.

HIC has proved useful for distinguishing MCC from other small round cell tumors. In one early study, MCC was correctly diagnosed by light microscopy in 60% of patients, but IHC or electron microscopy was needed to diagnose the remaining patients.102 CK20 and TTF-1 often provide the greatest sensitivity and specificity to exclude SCLC. CK20 is positive in 75% to 100% of primary MCC tumors and rarely positive in SCLC.TTF-1 is never positive in MCC, but is often positive in SCLC(>80%) and other primary pulmonary tumors.8,9,93,159,161-164 Neuroendocrine markers such as INSM1, chromogranin, synaptophysin, CD56, NSE, and neurofilament are found in most MCC tumors.30,75,80,93,95,159,160,165-172 The NCCN Panel recommends that these markers be considered for additional immunostaining. Although the specificity of each of these for MCC is not

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high, when used together they can help identify MCC tumors that are CK20 negative or have other features that make them difficult to diagnose(eg, tumors with squamous components or epidermotropism).96,108-110,112,113,173

Staging and Treatment of the Primary Tumor

Surgery is the primary treatment modality for most MCC and is needed for accurate pathological staging of both the primary lesion and regional disease.The current AJCC staging system(8th edition) is based on an updated analysis of 9387 patients with MCC from the NCDB with a median follow-up of 28.2 months.14 The NCCN staging of MCC largely parallels the AJCC guidelines and divides presentation into surgically resectable local, locally advanced(curative surgery and RT not feasible), regional/in-transit, and disseminated disease.66 Clinical exam, imaging, laboratory studies, a multidisciplinary consultation, immunosuppression assessment,and potentially a genetics consultation are used to make an initial determination of the clinical N-stage and M-stage. Clinical staging determines the recommended approach for evaluating pathologic nodal status.There is evidence that among patients with clinically apparent nodal disease at presentation, those with unknown primary have a better outcome than those with synchronous known primary,14,41,174-177 and these findings are reflected in the AJCC staging system.66 However, the NCCN recommendations for pathologic evaluation of nodal status and management of the nodal basin are the same for both groups of patients.

Surgery for Primary Tumor

Given the potential for rapid growth, surgery has been the most common approach used to treat primary MCC tumors and has been shown to produce superior outcomes compared to nonsurgical primary treatment.42,178 Outcomes for a variety of surgical approaches to remove MCC primary tumors have been reported in the literature, including biopsy approaches, either with or without subsequent re-excision to obtain clear

margins, standard excision,local amputation, and Mohs or other approaches with integrated complete margin assessment.6,22,42,48,179-189 Whereas there are a number of retrospective studies that found that negative margin status was associated with improved local recurrence and survival,22,23,42,68,183,185,190-192 other analyses did not consistently find such associations.19,71-74,136,193-197 There is evidence that margin status has an impact on survival regardless of adjuvant RT receipt.192 Among cases with stage I/II disease treated with surgery only, recurrence rates and OS were better for negative versus positive margins.185 On the other hand, for high-risk local and regional MCC, margin status did not seem to have an impact on recurrence in those who received adjuvant RT.198,199

Mohs is a useful technique for margin control in MCC and has been associated with improved outcomes compared with standard excision for primary MCC lesions.183,184,186 In many studies, Mohs and wide local excision(WLE) resulted in similar rates of recurrence and survival.6,180,184,185,188 There is much debate about the size of surgical excision margins needed to achieve histologically clear margins. Among patients treated with Mohs, the mean margin needed to achieve histologic clearance was 16.7 mm, and 2-cm and 3-cm surgical margins would have resulted in incomplete histologic clearance in 25% and 12% of patients,respectively.187 Among those treated with WLE,2-cm and 3-cm clinical margins resulted in incomplete excision in 50% and 0% of patients,respectively.200 For patients with histologically clear margins, retrospective data suggest a trend toward reduced risk of recurrence for patients with histologic margins>1 cm versus<1 cm.22,181,201 However, those who received adjuvant RT and had margins<1 cm had similar OS to those who did not receive adjuvant RT and had margins>1 cm.201 There are data supporting excision margins>2 cm as being significantly associated with higher OS,201,202 while some studies contend that increasing histologic margin size beyond 1 cm is not associated with additional clinical benefit.69,179,181

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In addition to Mohs, other forms of peripheral and deep en face margin assessment(PDEMA) are appropriate surgical approaches in certain circumstances. PDEMA, or complete margin assessment, is a term used for a subset of surgical techniques for high-quality histologic visualization and interpretation of the margin surface or surgically excised tissue. Mohs micrographic surgery is the most common utilized PDEMA technique.PDEMA is a team procedure that requires the participation of physicians from multiple disciplines while Mohs physicians serve as both surgeon and pathologist requiring highly specialized training. Efforts have been extended to generate consensus recommendations to offer Mohs surgeons guidance and promote standardization to make data aggregate from multicenter clinical trials.203

Sentinel Lymph Node Biopsy

SLNB is an important staging tool for identifying subclinical nodal metastases, which is valuable for accurate staging in addition to impacting subsequent treatment decisions. 6,50,83 Given the benefits of performing SLNB, every effort should be made to perform sentinel lymph node biopsy prior to or at the time of primary tumor excision. This is particularly important in the cases of head and neck MCC given the concern that resection and reconstruction prior to performing a SLNB may impact the accuracy of subsequent nodal basin mapping. 199

Large retrospective analyses(N>100) or meta-analyses of SLNB in patients with clinically node-negative, localized MCC have reported rates of SLN positivity ranging from 30% to 40%.6,46,49,94,126,204,205 As discussed in the elements of pathology report, there are a number of primary tumor characteristics that have been proposed to be predictive of SLN positivity,including primary tumor diameter, thickness, LVI, and TILs.49,77,83,91,206 Some studies showed significant association between SLN negativity and lower risk of recurrence and improved DSS or OS,46,49,50,78,126,206-209 while others did not.77,205,210 Reported rates of regional relapse in patients with

negative SLNB results range from 5% to 12%, with corresponding false-negative rates between 17% and 21%.46,50,204 Some studies have reported complicated drainage patterns for MCCs occurring in the head and neck.211-213 Besides, multiple SLNs have been identified in some patients,suggesting that the inability to identify all relevant SLNs may contribute to the relatively high rates of false-negative SLNs.46,50,204

Another issue of debate is whether the SLNB procedure itself offers some protection against recurrence, progression, or death from disease for patients with clinically node-negative disease. One retrospective study of patients with clinical stage I/II MCC found that those who underwent SLNB had improved 5-year DSS compared with those who did not undergo SLNB, although the actual difference was small(79% vs. 74%).208 Another analysis of a large population database found that compared with patients who had no pathologic nodal evaluation, those with SLNB alone or SLNB plus lymph node dissection(LND) had lower risk of all-cause mortality,and that SLNB plus LND was also associated with improved MCC-specific mortality.41 There is insufficient information to ascertain whether these associations are due to the SLNB procedure itself or due to subsequent disease management choices informed by the results of pathologic nodal evaluation. Other retrospective studies have found that among patients presenting with clinically node-negative MCC, SLNB is not significantly associated with improved LRC or OS,6,42 except for one report of significantly longer OS.181

SLNB Pathology

IHC analysis has been shown to be effective in detecting MCC lymph node metastases not detected by H&E.137,214-216 IHC with CK20 has been included as part of routine screening in multiple studies. ${}^{50,143,181,214,217}$ 217 Other IHC stains for histologic analysis of SLNs have also been reported such as pancytokeratins(AE1/AE3, CAM5.2), or antibodies sometimes used for differential diagnosis of primary MCC lesions, such as

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chromogranin A, neurofilament, MCPYV, and synaptophysin.50,77,83,143,181,215,217

Fine-Needle Aspiration

Several retrospective studies have reported that fine-needle aspiration(FNA) biopsy is an accurate method for diagnosing MCC lesions, including primary tumors and nodal and distant metastases.218-221 One small study compared FNA results with subsequent LND results, and found that the FNA procedure identified all patients with lymph node(LN) metastases that were>6 mm, but did not consistently identify smaller foci. ${}^{219}$ This finding underscores that FNA biopsy is not an appropriate method for detection of clinically occult metastases, but is effective for verifying MCC in palpable nodes. IHC analyses of FNA samples showed that most MCCs were positive for CK20, AE1/AE3, synaptophysin, NSE, and CD56.218,220,221 Chromogranin staining was present in a smaller proportion of patient samples(36%).220,221 Markers for melanoma(ie, S100, HMB45,Melan A, CD45) or lymphoma(leukocyte common antigen) were nearly always negative.218,220,221

Definitive Radiation Therapy for Locregional Disease

Historically, surgery has been the mainstay of treatment for local and regional MCC; as a result, data on the efficacy of definitive RT are extremely limited. There are a large number of retrospective studies that include very small samples of patients(N< 10) who received definitive RT instead of surgery.19,23,42,71,152,174,194,195,197,222-230 Patients whose disease received nonsurgical initial treatment, most often definite RT or RT in conjunction with chemotherapy, tended to have poorer outcomes than those initially treated with surgery.42,178 The largest study(N> 2000)comparing outcomes between definitive RT and surgery showed improved OS with surgery(± adjuvant RT) versus definitive RT, both among patients with stage I/II disease(median OS, 76 vs. 25 months; P<.001) and among those with stage III disease(median OS, 30 vs. 15 months; P<

.001).178 However, the patient population where MCC was treated with surgery was more likely to have factors associated with improved outcomes such as smaller primary tumor size, tumor in the upper extremity, shorter time to diagnosis,treatment at an academic hospital,and no chemotherapy.

For those with local or locregional MCC who are poor surgical candidates or refuse surgery, however, initial treatment that includes definitive RT likely provides good outcomes. One study using SEER data found that among patients who did not receive surgery(N= 746), those who received RT had better OS and DSS than those who did not(DSS at 5 years, 73%vs.54%;P<.0001).15 Retrospective studies of MCC treated with definitive RT to their primary and/or nodal MCC reported in-field recurrence rates of<25%, with median time to in-field recurrence ranging from 4 to 6.3 months.22,231-236 One meta-analysis of 264 patients with locregional MCC treated with definitive RT reported that cumulative in-field recurrence rate was 12% per site, and that in-field recurrence was significantly more likely at regional versus primary irradiated sites(16% vs. 7.6%; P=.02).229 The NCCN Panel generally recommends that RT be initiated as soon as wound healing permits as delays have been associated with poorer outcomes,237,238

Clinical N0: Local MCC Only, Surgically Resectable

The disease management plan for primary MCC tumors that are surgically resectable is dictated by the state of the surgical margins and the presence of adverse risk factors, which include larger primary tumor size(>1 cm), chronic T-cell immunosuppression, HIV,CLL,solid organ transplant, head/neck primary site, and LVI6,23,38,40-47,49,72,75-78,114,239 These are risk factors of particular concern because they are highly associated with poor outcomes. Mohs micrographic surgery (Mohs) and PDEMA are methods for surgical excision of the primary tumor, using margins similar to WLE (See NCCN Guidelines for Squamous Cell Skin Cancer-

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Principles of PDEMA Technique, available at www.NCCN.org). These alternative methods ensure complete tumor removal and clear margins,while sparing surrounding healthy tissue. Regardless of the surgical technique used, the goal should be primary tissue closure to avoid any undue delay in proceeding with RT and allow for initiation of adjuvant RT.238

Primary treatment for patients that are deemed surgically resectable include excision with 1 to 2 cm margins,238 or in certain circumstances Mohs or others forms of PDEMA, as well as SLNB with an appropriate immunopanel. Because of the high historic risk of local recurrence in MCC, there is emphasis on a complete extpiration of tumor at the time of initial resection to achieve histologically clear surgical margins when clinically feasible.68,199,240 If clear margins are achieved, observation is recommended if there are no adverse risk factors; however, if one or more adverse risk factors are detected, adjuvant radiation therapy is recommended as an additional treatment.238 In the case of microscopically positive margins, adjuvant RT is preferred along with or over re-excision.Adjuvant RT is also a treatment option for individuals with narrow postsurgical margins of<1 cm or with adverse risk factors.Additionally, the recommended surgical margin may vary based upon recommendations for adjuvant radiation therapy. To minimize morbidity,narrow excision margins resulting in possible microscopically positive margins are acceptable when followed by adjuvant RT to the primary site.238 Surgical margins should be balanced with morbidity of surgery.

In addition to surgical resection, primary treatment also includes SLNB with an appropriate immunopanel. The preferred additional treatment for patients with negative SLN is continued observation of the nodal basin. RT to the nodal basin may be considered in certain high-risk scenarios, such as a compromised SLNB result, high probability of false-negative SLN due to aberrant lymph node drainage or multiple SLN basins, or profound

immunosuppression. Appropriateness of RT should be determined together with a radiation oncologist. If the SLNB is positive, baseline imaging should be performed, if not previously. Imaging may include whole-body FDG-PET/CT or CT with contrast of chest, abdomen, pelvis,and neck if the primary tumor is on the head/neck. Additionally, MRI of the brain with and without contrast is recommended if there is clinical suspicion of brain metastases or direct extension. Following imaging,additional treatment requires a multidisciplinary consultation at a center with specialized expertise to consider subsequent treatment via RT to the nodal basin or node dissection. If node dissection is performed, the patient can be observed for disease progression or subsequent adjuvant RT can be applied for multiple involved nodes and/or the presence of extranodal extension(ENE).

Clinical NO: Locally Advanced MCC When Curative Surgery and Adjuvant RT Are not Feasible

A multidisciplinary consultation at a specialized center is recommended for locally advanced Merkel cell carcinoma(laMCC) patients for whom curative surgery and curative RT is not feasible prior to deciding on a primary treatment path. After a multidisciplinary discussion, the favored treatment option includes neoadjuvant immunotherapy with an anti-PD-1 agent(see Systemic Therapy for Merkel Cell Carcinoma) for patients who are surgical candidates. If a treatment response is seen and the tumor is amenable to resection, either WLE or more rarely Mohs or other forms of PDEMA can be pursued with consideration for SLNB. After resection, the tumor can be further treated following the resectable local MCC path primary and additional treatment options. Patients that are considered nonsurgical candidates due to comorbidities, tumor characteristics, or progression on neoadjuvant nivolumab, will require a discussion regarding the advantages and disadvantages of treatment with RT for durable local control versus systemic therapy.

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Nodal Staging and Treatment of Regional Disease

Management of the Primary Tumor for Regional Disease

SLNB is recommended for all patients with clinically node-negative disease who are fit for surgery. The NCCN Panel believes that by identifying patients with positive microscopic nodal disease and then performing full LNDs and/or RT, the care of regional disease in this patient population is maximized. SLNB should be performed prior to surgical removal of the primary tumor, with special care taken in the head and neck region where drainage patterns are often complex and can lead to unreliable SLNB results (risk of false negative results241). The primary tumor can be treated as clinical N0 and follow the resectable local MCC or laMCC pathways including SLNB after initial recommended imaging studies to evaluate the extent of lymph node and/or visceral organ involvement. Subsequently, there are separate recommendations for the management of the draining nodal basin and in-transit disease; however,these treatment options can both be considered for appropriate patients.

Management of the Draining Nodal Basin

A clinical N+ diagnosis(palpable lymph nodes) should be confirmed by using FNA or core biopsy of the draining nodal basin with an appropriate immunopanel. An excisional biopsy may be considered to confirm a negative initial FNA or core lymph node biopsy if clinical suspicion remains high. Alternatively, patients with negative results can also continue radiographic surveillance. If initial or subsequent lymph node biopsy results are positive and distant metastasis is detected, disease management should follow the M1 pathway. In case of no detected distant metastases, multidisciplinary consultation, node dissection and RT(preferred), node dissection or RT, clinical trial, and consideration for systemic therapy are recommended treatment options. The node dissection and RT treatment option is preferred and enrollment in a clinical trial for adjuvant therapy is preferred, if available.

IHC analysis should be included in the SLNB evaluation in addition to H&E sections to reduce the risk of false negative results. CK20 immunostaining should be included in the pathologic assessment to facilitate accurate identification of micrometastases. An appropriate immunoplane may also include pancytokeratins(AE1/AE3), depending on the immunostaining pattern of the primary tumor. Some NCCN Member Institutions routinely use both CK20 and pancytokeratin strains to evaluate SLN samples to ensure detection of MCC metastases, because results from these two markers are not always consistent. The pathology report should also include the number of lymph nodes involved, size of largest metastatic deposit(mm), and the presence or absence of ENE.

Empric RT to the nodal basin can be considered in patients with certain high-risk clinical scenarios: 1) the accuracy or reliability of SLNB may have been compromised (eg, prior surgery, extensive CLL within the nodes,history of prior LN excision); 2) the risk of false-negative SLNB is high due to aberrant lymph node drainage and presence of multiple SLN basins(such as in head and neck or midline trunk MCC); or 3) patients present with profound immunosuppression (ie, solid organ transplant recipients).

Patients with positive SLNB results should receive baseline imaging, if not already performed, to screen for and quantify regional and distant metastases. If the tumor burden in the sentinel node is low, the risk of distant disease may also be low. However, it is important to confirm staging, and baseline scans are useful for comparison in the event of a suspected recurrence.

Adjuvant systemic therapy should be considered for certain patients with regional disease as part of a multidisciplinary consultation. For patients with primary or recurrent regional MCC where curative surgery and curative RT is not feasible adjuvant systemic therapy similar to the options available to individuals with disseminated disease is considered, treatment in the context of a clinical trial is preferred, when available.

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Management of In-transit Disease

The AJCC eighth edition staging system defines MCC in-transit lesions as discontinuous from primary tumor, located between the primary tumor and the draining regional nodal basin or distal to the primary tumor site.14,66 The in-transit disease pathway delineates alternative treatment options when compared to regionally nodal positive MCC. For management of in-transit disease, diagnosis confirmation with biopsy is recommended.Following confirmation, treatment options for in-transit disease include multidisciplinary consultation, clinical trials, surgery, radiation treatment, as well as systemic therapy if curative surgery and/or RT are not feasible.While the Panel has made these general treatment recommendations for in-transit disease, it is important to note that due to the rarity of this clinical scenario and the lack of high quality peer-reviewed primary literature,these recommendations are based on expert opinion. ${ }^{242-245}$ This lack of large studies has led to individualized treatment decisions with the input of a multidisciplinary team at a high volume treatment center.

Surgery Versus Radiation Therapy for Regional Disease

Since the presence of MCC in the lymph nodes is associated with poorer prognosis, 14,20,79,183,209,246 the clinical instinct is to aggressively treat the nodal basin in patients with pathologically positive lymph node(s). Indeed,a retrospective study of 82 patients with locoregional MCC found that nodal treatment was associated with improved disease control: LND prolonged the time to first recurrence(median of 11.8-28.5 months; P=.034), as did RT to the nodal basin(median of 11.3-46.2 months; P=.01).193 A meta-analysis that included 39 patients with SLN positivity found that those who received some form of post-SLNB treatment for nodal disease(therapeutic LND[TLND], RT, chemotherapy) had improved 3-year relapse-free survival(51% vs. 0%; P<.01).126

Due to lack of prospective data, however, it is unclear whether surgical approaches or RT are more effective as initial treatment for nodal MCC.For studies with at least 20 patients with MCC lymph node involvement,few reported outcomes for specific nodal treatments.22,68,77,174,178,222,227,247,248 Wright et al showed that surgery(with or without adjuvant RT) was associated with better OS compared with definitive RT (median, 30 vs. 15 months; P <.001).178 In contrast, Bhatia et al found no significant difference in OS for surgery alone compared with RT alone or surgery plus RT.68 Furthermore, while some studies suggest that nodal surgery may improve outcomes, 48,247-249 a few found that patients who received nodal RT alone fared better, 20,22 and others found no clear trends according to nodal treatment. 20,77,174,222,227,250 Perez et al and Lee et al, retrospectively, evaluated outcomes for MCC treated with lymph node dissection versus RT for sentinel lymph node biopsy positive disease and found low rates of regional recurrence for both treatment modalities, suggesting that both treatment modalities may be effective in appropriate patient cohorts.251,252

There are very few data to inform the extent of nodal surgery needed for patients with biopsy-proven regional disease. Results from retrospective analyses suggest that MCC prognosis worsens with increasing nodal involvement (clinically detectable nodal involvement versus microscopic nodal involvement, ${ }^{14,23,49,72}$ increasing number of nodes involved, ${ }^{15,19,68,79,82,195,205,225,236,253,254}$ and the presence of ECE ${ }^{84,205,225}$ ).These findings suggest that the aggressiveness of nodal treatment should perhaps be commensurate with the extent of nodal disease. The type of LN surgery may not be very important if patients are also treated with RT.A pooled analysis of several prospective studies found that the margin status of surgically removed lymph nodes was not associated with locoregional recurrence in patients who received RT to the nodal basin. ${ }^{255}$ One of these prospective studies also found that among patients with locoregional MCC, all of whom were treated with surgery plus RT (with or

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without chemotherapy), nodal involvement was not prognostic for DSS or OS.256

Postoperative Radiation for Locregional Disease

Many studies have found that postoperative RT is associated with lower recurrence and/or improved survival compared with surgery alone.22,68,180,197,199,239,257-261 However, many of these studies reported mixed results, finding that adjuvant RT was significantly associated with improvements in some but not all outcome measures or only in particular subsets of patients. Some studies, on the other hand, found no significant correlations with outcomes.6,19,46,72,262-264 For most of these studies, the results are difficult to interpret because they included a range of MCC stages,a mix of primary and recurrent MCCs,a variety of surgical procedures prior to RT, and a mix of patients who received RT to the primary site only, nodal basin only, or both. For studies that included sub-group analysis, the sample sizes were usually too small for meaningful interpretations.

Overall, studies reporting results specifically for patients with stage I/II disease agree that adjuvant RT to the primary tumor significantly reduced the rate and time to locregional recurrence ${ }^{17,187,260,265-267}$ while many also reported improvements in survival. 68,184,185,197,259,265 Kang et al examined 42 patients with stage I/II MCC and determined that those who had RT to their primary site had significantly higher 2-year local recurrence-free survival compared to those who did not receive RT (89% vs. 36 %; P<.001).265 Of note, three large studies using NCDB data (N > 1000 patients with stage I/II MCC) concluded that surgery plus RT or conformal RT (CRT) led to significantly better survival results compared to surgery alone. 68,184,185 Even though benefit has been noted for low-risk stage I MCC, 260,266 local MCC with high-risk features might have the most to gain from adjuvant RT. 22,239,258,263,268 Particularly, a study of 1858 patients with stage I/II MCC who met indication for RT according to the NCCN

recommendation(positive margin,tumor size≥1 cm,LVI) concluded that 5-year OS advantage was identified for those who received RT when indicated(P<.003). On the other hand, no OS advantage was observed when patients received guideline-discordant RT(P=.478).259

Regarding the clinical benefit of adjuvant RT for patients with node-positive versus node-negative MCC, results vary widely between studies.19,22,46,48,50,68,69,72,73,126,197,239,251,262,269-271 Some studies showed that postoperative RT was associated with improved survival in patients with stage I/ll disease, but not for stage III disease.68,197 In contrast, a retrospective study found that postoperative RT to the primary tumor bed improved LRC and DSS in patients with pathologic or clinically positive nodes, but not in patients with negative nodes.239 In other studies, nodal RT in patients with positive SLNB significantly reduced 3-year relapse-free survival rate (51% vs. 0%;P=.008).272 A large study using NCDB data (N = 447) of patients with SLNB-positive MCC reported that compared with completion lymph node dissection (CLND), observation, or RT alone, CLND and adjuvant RT were associated with better OS. 271 Several studies pointed out that the utility of adjuvant RT might be extended to patients with negative nodes.22,50,69,73,269,272 Specifically, tumor-bed irradiation was significantly associated with prolonged DFS (P=.006) and OS (P=.014)in patients with negative SLNB.50 In another study, RT to regional nodes was associated with improved regional control, irrespective of clinical status (P=.01).73 Overall, studies have both supported 22 and refuted 262 the effectiveness of nodal RT in reducing nodal relapse in node-negative patients.

Treatment of Distant Metastatic Disease

Many retrospective studies have reported the pattern of MCC metastatic spread to distant sites based on large patient databases that include data from various points in the development of the disease. ${}^{18,72,101,102,137,273-275}$

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Based on these analyses, distant metastatic MCC is most likely to arise in distant lymph nodes or skin, bone/bone marrow, lung/pleura, or liver,followed by the pancreas, adrenal glands, brain, kidneys, subcutaneous tissue, or muscle.

The NCCN Panel recommends multidisciplinary consultation for patients with distant metastatic disease (M1) at a center with specialized expertise.Comprehensive imaging is recommended for all patients with any clinically detected and pathologically proven regional or distant metastases. In general, the treatment of distant metastases must be individually tailored.Although the NCCN Panel recognized that MCC is a rare disease that precludes robust randomized studies, enrollment in clinical trials is encouraged whenever available and appropriate. Clinical trials testing therapies shown to be effective against other metastatic cancers (eg,melanoma) should be considered. The multidisciplinary Panel may consider treatment with one or more of the following modalities: systemic therapy,RT,and surgery. Systemic therapy and RT will likely be the primary treatment options to consider (see Systemic Therapy for Merkel Cell Carcinoma section). Surgery may be beneficial in highly selective circumstances for resection of oligometastases or symptomatic lesions. All patients should receive best supportive care, and depending on the extent of the disease and other patient-specific circumstances, palliative care alone may be the most appropriate option for some patients (See NCCN Guidelines for Palliative Care, available at www.NCCN.org).

Systemic Therapy for Merkel Cell Carcinoma

Immunotherapy

Results from clinical trials, case, retrospective, and prospective studies support the use of avelumab, ipilimumab, ipilimumab/nivolumab,nivolumab, pembrolizumab, retifanlimab-dlwr, and talimogene laherparepvec (T-VEC) for the treatment of certain patients with local,regional, or disseminated disease. Although there are no randomized

comparative trials comparing immune checkpoint inhibitors (ICls) and chemotherapy, ICls provide response rates similar to those previously reported for chemotherapy and may provide greater durability of response.

Avelumab

Two retrospective multi-institutional studies assessed treatment outcomes for avelumab in MCC. Advanced stage (IIIB/IV) avelumab-treated MCC was studied in 90 patients in six U.S. academic medical centers.276 A median follow-up of 20.8 months (95% CI, 19.1-24.2) and median duration of treatment of 13.5 months (95% CI, 6.4-30.6) were achieved.Patients treated with avelumab had a 73% (95% CI, 64-83) objective response rate (ORR), 24.4 months (95% CI, 8.31-not estimable [NE])median progression-free survival (PFS), and 30.7 months (95% CI, 11.2-NE) median OS.276

SPEAR-Merkel was an additional retrospective observational study of metastatic MCC(mMCC) and laMCC response to first-line avelumab treatment that included selected patients treated by the US Oncology Network from 2017 to 2019.277 For mMCC (N = 19) median OS was 20.2 months (95% CI, 10.0-not reached [NR]), PFS was 10 months (95% CI,2.8-NR), and 63.2%(95% CI, 38.4%-83.7%) response rate. Median OS and PFS were not reached in the laMCC (N = 9) group; however, a response rate of 66.7%(95% CI, 29.9-92.5) was recorded.277

The JAVELIN Merkel 200 trial, is an open-label multicenter prospective clinical trial testing avelumab in patients with histologically confirmed and measurable stage IV distant MCC.278-284 The cohort of patients in Part A of the trial had mMCC, which progressed after more than 1 prior line of chemotherapy(N= 88), with a median follow-up of 65.1 months(range,60.8-74.1 months), median OS was 12.6 months(95% CI, 7.5-17.1), and with a 5-year OS rate of 26%(95% CI, 17-36).281 The Part B cohort was treated with avelumab as first-line therapy(N= 116), the median follow-up was 21.2 months(range, 14.9-36.6), the ORR was 39.7%(95% CI, 30.7-

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49.2), median PFS was 4.1 months (95% CI, 1.4-6.1), and median OS was 20.3 months (95% CI, 12.4-NE).283 A 2022 update to the part B cohort reported a median follow-up of 54.3 month (range, 48.0-69.7) as well as a 4-year OS rate of 38% (95% CI, 29-47), where programmed death ligand 1 (PD-L1) positive tumor median OS was 38.7 months (N =21; 95% CI, 11.3-NE) and 16.1 months (N = 87; 95% CI, 9.6-42) for PD-L1 negative tumors.284

Ipilimumab± Nivolumab

Ipilimumab, a cytotoxic T lymphocyte antigen-4 (CTLA-4) targeted antibody, has been evaluated as a monotherapy as well as in combination with nivolumab, an anti-programmed cell death protein 1 (PD-1)inhibitor.121 A small retrospective study ( N = 5) conducted in Germany,where systemic therapy in 2021 was limited to avelumab, treated avelumab-refractory disease with combination ipilimumab plus nivolumab.285 Combination therapy was tolerated well with no grade 2 or 3 treatment-related adverse events (TRAEs). Patients with refractory disease experienced a high response rate and durable response in this and other studies.285,286

In a randomized, open label, phase II trial, two cohorts of combined nivolumab plus ipilimumab with or without stereotactic body radiotherapy(SBRT), cohort A and B respectively, were evaluated for ORR.287 Of the 50 patients enrolled in the trial, 24 had not previously taken ICls. Overall patients had a median follow-up of 14.6 months. All of the ICl-naive patients(N=22; 95% CI, 82-100) had an objective response, including a complete response in nine patients(41%; 95% CI, 21-63). Of the 26 patients with previous ICl exposure, eight (31%; 95% CI, 15-52) had an objective response and a complete response in four (15%; 95% CI, 5-36).No significant differences in ORR were observed between both cohorts of patient with or without SBRT (P=0.26). These results indicate that the addition of SBRT did not improve the efficacy of ipilimumab plus

nivolumab. Grade 3 or 4 TRAEs were observed in 10 (40%) cohort A and 8 (32%) of cohort B patients.

Ipilimumab with or without nivolumab was studied in a nonrandomized,open label, multicenter phase l/Il trial for 68 patients with recurrent or metastatic MCC. ${}^{288}$ Patients were treated with nivolumab(N=25) or nivolumab plus ipilimumab(N=43) with an observed ORR and median DOR of 60% and 60.6 months with nivolumab and 58% and 25.9 months with nivolumab plus ipilimumab, respectively. Additionally, the median PFS was 21.3 months for nivolumab and 8.4 months for the combination regimen. The OS for nivolumab and nivolumab plus ipilimumab was 80.7 and 29.8 months, respectively. The TRAE incidence was higher for the combination than the monotherapy (47% vs. 28%).

Nivolumab

Nivolumab in the neoadjuvant setting was studied in the Checkmate 358 phase I/II trial that included 39 patients with resectable MCC stage IIA-IV who had received≥1 doses of nivolumab.289 Among 36 patients who underwent surgery,47.2%(N=17) achieved a pathologic complete response(pCR).In 54.5%(N= 18) of 33 radiographically evaluable patients who underwent surgery,54.5% had tumor reductions of≥30%.The median follow-up for this cohort was 20.3 months(range, 0.5-39.7);however, median recurrence-free survival and OS were not reached in this study.289

In a non-comparative, open label, multicohort phase I/ll trial, the efficacy and safety of nivolumab monotherapy was evaluated(N= 25) where an overall follow-up of 26 weeks was observed.290 Response assessment was completed in 22 patients of which 14 were treatment-naive and eight had treatment with one to two prior systemic therapies. ORR in treatment-naive patients was 71%(95% CI, 42-92) and 63%(95% CI, 25-92) in the group of patients with previously treated disease. The treatment naive group had a higher percentage of patients with a complete response and

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stable disease than the previously treated group (CR, 21% vs. 0%; SD,$21 \%$ vs. 13%). On the other hand, the naïve group had lower partial response and progressive disease (PR, 50% vs. 63%; SD, 7% vs. 25%).This data supports the addition of nivolumab monotherapy as a systemic therapy option for certain patients with advanced MCC.

Pembrolizumab

A phase ll, single-arm multicenter trial tested pembrolizumab in patients with distant metastatic or regocional MCC not amenable to definitive surgery or RT with no prior MCC systemic therapy treatment(N= 50).291-293 After a median follow-up of 31.8 months(range, 0.4-56.9), the ORR was 58%(95% CI, 43.2-71.8) with a 30% complete response(N= 15;95% CI, 17.9-44.6) and 28% partial response(N= 14; 95% CI, 16.2-42.5).293 For this study, the median PFS was 16.8 months(95% CI, 4.6-43.4) and the 3-year estimated PFS was 39.1%.293 While the median OS was not reached, and the OS for all participants at 3-years was 59.4% and 89.5% for patients with responsive disease(complete and partial response).293

Retifanlimab-dwr

POD1UM-201 is an open-label, single-arm, multicenter, phase II trial for patients with unresectable laMCC or mMCC.294 This study tested retifanlimab-dlrw in patients with chemotherapy-naive or chemotherapy-refractory disease and had no prior therapy with anti-PD-1/L1 regimens.Current data is available for the chemotherapy-naive group(N= 87) of which the first 65 patients were assessed with an ORR of 46.2%(N= 30)with 12.3%(N=8) complete response and 33.8%(N=22) partial response. Additionally, the disease control rate for the group assessed was 53.8%(N=35).

Talimogene laherparepvec

T-VEC is a modified oncolytic herpes simplex virus that promotes an antitumor response. Treatment with T-VEC was approved by the U.S.

Food and Drug Administration for treatment of advanced melanoma.295 In a phase III study,intralesional T-VEC injection had superior durable and overall response rates in patients with advanced melanoma.296 The clinical benefit of T-VEC in patients with advanced MCC has been presented in case reports or series.297-299 These patients reported complete response with intralesional T-VEC use with limited toxicities and present a compelling argument in patients with anti-PD-1/L1 refractory MCC or for individuals with contraindications to receiving other immunotherapies

Based on analyses of the trials described toxicity profiles in patients with MCC were similar for avelumab, pembrolizumab, and nivolumab, with treatment-related adverse events (AEs) occurring in 68% to 77% of patients, and grade 3 or 4 AEs occurring in 5% to 21%. Immune-related AEs were seen in <20% of patients receiving avelumab, and were all grade 1 or 2.278-283,289,291-293 The safety profiles for checkpoint immunotherapies are significantly different from cytotoxic therapies, so clinician and patient education is critical for safe administration of checkpoint immunotherapies. For example, patients with well-controlled HIV were not represented in initial trials; however, the infection does appear to respond to PD1 pathway blockade at a rate (two of three patients in one series) that is similar to patients without immune compromise.300 It is important to consult the prescribing information for recommendations regarding contraindications to checkpoint immunotherapy as well as the detection and management of immune-related AEs295 (See NCCN Guidelines for Management of Immunotherapy-Related Toxicities, available at www.NCCN.org).

Chemotherapy

Responses to chemotherapy in patients with MCC have been reported for a variety of regimens, including regimens that contain platinum agents(often in combination with etoposide), cyclophosphamide (often in CAV),cyclophosphamide with methotrexate and 5-fluorouracil (CMF), paclitaxel,

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nab-paclitaxel, docetaxi, ifosfamide, anthracycline, 5-fluouracil,topotecan, gemcitabine, and irinotecan. 231,273,301-305 In analyses with >20 patients, reported ORRs were usually around 40% to 60%. In several studies the response rate appeared to depend on the number of prior chemotherapy regimens, with reports of response rates up to 70% for first-line chemotherapy, and as low as 9% to 20% in patients who received one or more prior lines of chemotherapy.231,273,301-307 Reported responses to chemotherapy were fairly short-lived, with a median duration ranging from approximately 2 to 9 months, 231,273,302-306 Reported rates of toxic death were between 3% and 10%, with patients who are older being at higher risk.231,273,302

High-quality clinical data on adjuvant systemic therapy options are lacking since very few patients receive chemotherapy for MCC. For most of the studies in which some subsets of patients received postoperative chemotherapy, often in combination with adjuvant RT, use of chemotherapy was not associated with reduced risk of recurrence or distant metastasis, or improved survival.41,68,73,183,256,263,302,308,309 Two studies found that adjuvant chemotherapy was associated with worse survival.19,309 Several studies found that postoperative chemoradiation did not improve outcomes compared with postoperative RT.48,183,263 Particularly,results from a prospective trial of chemoradiation(carboplatin plus etoposide) in 40 patients with stage l-III disease compared with historical controls(N=62) treated with postoperative RT did not support the use of adjuvant chemotherapy.256 A large NCDB study(N= 4815)found that, relative to surgery alone, postoperative chemoradiation improved OS but postoperative chemotherapy(without RT) had the opposite effect.183 There was a nonsignificant trend toward improved OS with postoperative chemoradiation compared with postoperative RT alone(P=.08). However, this difference was only significant in patients with positive margins(P=.03) and primary tumor size≥3 cm(P=.02).183 These results suggest that although postoperative chemotherapy alone is

unlikely to improve outcomes, postoperative chemoradiation may have a role in particularly high-risk MCCs in which residual disease is present after surgery.

The most common systemic therapy regimen used for adjuvant treatment of regional disease is cisplatin or carboplatin with or without etoposide 19,48,223,256,263,309; however, information about the agents used was not available from the NCDB analysis that showed that postoperative chemotherapy may provide clinical benefit in certain patients with high-risk disease.183

Alternative Therapies

Hyperthermic Isolated Limb Infusion/Perfusion

While established as a regional therapy in melanoma, hyperthermic isolated limb perfusion(HILP) as a MCC treatment option is not as extensively studied. In a single institution retrospective review of 10 studies over 6 years, an initial group of four patients treated with HILP were identified.310 All patients experienced complete response, however two of the patients developed early metastatic recurrence and the other two had no evidence of disease at the last 36-month follow-up. An additional group of 12 patients treated with HILP were identified through systemic review. Twelve(86%) of the patients with follow-up had a complete response while one had stable disease and another partial response. Within 6 months, four patients presented with locoregional recurrence and a further six had distant metastases. Despite the development of distant metastases, HILP presents a viable treatment option to achieve complete response.

Octreotide

Octreotide is a somatostatin analog(SSA) used as a treatment option in neuroendocrine tumors (NET), such as MCC, that express the somatostatin receptor (SSTR). In a multicenter phase II study(N= 58),

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octroide demonstrated poor tumor regression with a 3% partial response; however, the disease was stabilized for at least 6 months in 47% of patients(N= 27).311 A retrospective study in patients with mMCC included 39 patients whose MCC expressed SSTR and a subset(N= 19)were treated with an SSA.312 From the SSA group, only seven had a target lesion from which a response could be evaluated and 43% (N=3)experienced disease control with a median PFS of 237 days. Of the remaining 12 individuals in the SSA group, 42% (N= 5) also experienced disease control with a median PFS of 429 days. As metastatic MCC commonly expresses SSTRs, octrootide can lead to significant disease control.

Pazopanib

Pazopanib is a tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma and soft tissue sarcoma with prior chemotherapy treatment.295 It is not currently approved by the FDA for use in MCC; however, it does promise as a treatment option for certain patients with advanced MCC in case reports and institutional database analyses.313,314 In a case study(N= 5), patients with mMCC were treated with pazopanib(N= 4) or cabozantinib(N= 1) and one pazopanib recipient had a complete response after 3 months.314 Four patients experienced a 5 month to 3.5 year disease stabilization. Overall patients did not experience any unusual toxicities. These results support the use of pazopanib in certain patients with disseminated disease.

NCCN Systemic Therapy Recommendations

In-transit Disease

After a multidisciplinary consultation at a center with specialized expertise,systemic therapy may be considered if curative surgery and/or RT are not feasible. The NCCN Panel recommendation is that both T-VEC and HILP can be considered and may be useful in certain circumstances.

Local Disease

Adjuvant systemic therapy is not recommended outside of a clinical trial for primary resectable disease. However, systemic therapies are recommended for primary and recurrent locally advanced MCC if curative surgery and curative RT are not feasible. The NCCN Panel considers all regimens for local disease as category 2A where there is uniform NCCN consensus that the intervention is appropriate based on lower-level evidence. For primary laMCC, avelumab and pembrolizumab are preferred regimens, retaniflimab-dlrw is classified as other recommended regimen,and neoadjuvant nivolumab as useful in patients who are surgical candidates. For recurrent laMCC, the preferred regimens are pembrolizumab and retaniflimab-dlrw while avelumab is recommended as other recommended regimen.

Regional and Disseminated Disease

Neoadjuvant nivolumab is a NCCN category 2A regimen recommended in certain circumstances for patients with primary regional MCC disease.Primary and recurrent regional disease where curative surgery and curative RT are not feasible along with metastatic disease have four preferred regimens recommended as treatment options. These preferred category 2A regimens are avelumab, nivolumab, pembrolizumab, and retifanlimab-dlrw. Ipilimumab plus nivolumab is also a category 2A regimen, however it is only recommended under certain circumstances.Reother useful in certain circumstances regimens are recommended for consideration if anti-PD-L1 or anti-PD-1 therapy is contraindicated or the disease has progressed on monotherapy regimens. Topotecan, CAV(cyclophosphamide, doxorubicin [or epirubicin], and vincristine),ipilimumab, octreotide long-acting release(LAR), pazopanib, and T-VEC can be considered under these conditions for primary/recurrent regional and disseminated disease. Octreotide LAR, pazopanib, and T-VEC are considered category 2B regimens for disseminated disease, but all other

Other useful in certain circumstances regimens are recommended for consideration if anti-PD-L1 or anti-PD-1 therapy is contraindicated or the disease has progressed on monotherapy regimens. Topotecan, CAVC(cyclophosphamide, doxorubicin [or epirubicin], and vincristine),ipilimumab, octreotide long-acting release(LAR), pazopanib, and T-VEC are recommended under these conditions for primary/recurrent regional and disseminated disease. Octroide LAR, pazopanib, and T-VEC are considered category 2B regimens for disseminated disease, but all other

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regimens are category 2A for all three settings. Carboplatin or cisplatin with or without etoposide are only recommended regimens for recurrent regional or disseminated disease.

Follow-up and Recurrence

Recurrence and development of lymph node and distant metastases in MCC are not uncommon.6,16-20,84,223,315 Based on data from large retrospective analyses (N > 100), the median time to recurrence in patients with MCC is about 8 to 9 months, with 90% of the recurrences occurring within 24 months. 19,20,48,137 Time to local recurrence is generally shorter than for regional recurrence, and time to distant metastasis is longer.6,18,19,222 Due to the fast-growing nature of the disease, detection of multiple distant metastases at once is not uncommon. 124 As described in Presence of Secondary Malignancy above, patients who have had MCC are also at increased risk for a prior, concurrent, or subsequent second primary malignancy. 24,35,97-100

Multiple retrospective analyses,71,73,93,236,247,308 data from a phase II study, 256 and a few meta-analyses229,316,317 have shown that recurrence of MCC is associated with poor prognosis. Collectively, these studies support that locoregional recurrence is associated with the development of distant metastasis, and that all types of recurrences(local, regional, and distant)may be associated with poorer DSS and OS. A few retrospective studies found no significant association between recurrence and outcome measures including survival.48,194,232,235,236,250

The NCCN Panel recommends close clinical follow-up for patients with MCC starting immediately after diagnosis and treatment. The physical examination should include a complete skin and complete lymph node examination every 3 to 6 months for the first 3 years, then every 6 to 12 months thereafter. The recommended frequency of follow-up visits is purposely broad to allow for an individualized schedule based on the risk

<EndOfPara>of recurrence, stage of disease, and other factors such as patient anxiety and clinician preference. The Panel's recommendation for frequent clinical exams during the first 3 years also reflects the fact that MCC will recur in up to half of patients, and most recurrences occur within the first few years after diagnosis. Education regarding self-examination of the skin is useful for patients with MCC because of their increased risk for other NMSCs.

Imaging and other studies should be performed as clinically indicated,such as in cases of emergent adenopathy or organomegaly, unexplained changes in liver function tests, or development of new suspicious symptoms. As patients with immunosuppression are at higher risk for recurrence, more frequent follow-up may be indicated. To lower the risk of recurrence/progression, immunosuppressive treatments should be minimized as clinically feasible.

As described previously,MCPyV oncoprotein antibody testing performed at initial workup may help guide surveillance.55,117-119 Patients who are oncoprotein antibody seronegative at diagnosis may be at higher risk of recurrence and may benefit from more intensive surveillance.55 For patients who are seropositive at baseline, the MCPyV oncoprotein antibody test may be a useful component of ongoing surveillance because a rising titer can be an early indicator of recurrence.55 Additionally, MCC ctDNA assessment is an option if the treating physician considers it clinically relevant to monitor disease burden with a typical surveillance of every 3 months. 122

Imaging Surveillance

Retrospective studies of follow-up imaging results have reported both local and systemic MCC recurrences detected by a variety of techniques,including MRI, ${}^{124}$ CT, ${}^{124,125,135}$ and FDG-PET/CT. ${}^{127,133-135,137,141,142,145,318}$ Data on the accuracy of imaging techniques for follow-up surveillance are limited, because very few report whether or not the imaging findings were

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histologically confirmed.125,133,134 The yield from different imaging regimens and techniques is also unknown, as most studies did not clarify the frequency of follow-up or whether the patients had no evidence of disease prior to follow-up imaging. One retrospective study of 61 patients with stage III MC who were clinically asymptomatic and underwent surveillance FDG-PET/CT revealed a recurrence rate of 33%, with a median follow-up period of 4.8 years.The sensitivity, specificity, and accuracy were determined to be 92%, 93%, and 93%, respectively.318

For disease features considered of higher risk(eg, stage IIIB or higher,immunosuppression), routine imaging surveillance should be considered.Recommended imaging modality options are the same as for the initial clinical workup in patients for whom regional or distant metastases are suspected. Surveillance imaging is typically via diagnostic CT of chest/abdomen/pelvis with oral and IV contrast; neck CT is often included if the primary lesion was on head/neck. Whole-body FDG-PET/CT may be indicated to evaluate for in-transit metastases if the primary lesion is on the extremity.

Treatment of Recurrence

Although patients with MCC recurrence were included in many studies attempting to determine efficacy of specific treatments for MCC, few studies reported outcomes specifically for MCC treated for recurrence.48,69,73,194,229,235,236,246,256,257,309 One retrospective analysis of 55 patients with recurrent MCC identified several factors associated with improved DSS after recurrence: location of primary MCC, type of recurrence, disease-free interval, and whether the patient was disease free after treatment for recurrence.309 Another retrospective analysis of 70 patients with locoregional MCC recurrence also found that the type of first recurrence and disease-free interval were prognosticic for development of subsequent distant recurrence, and that the disease-free interval was prognostic for OS.246

Management of MCC with local, locally advanced, regional, or disseminated recurrence is similar to clinical M1 disease. Systemic therapy,RT, or surgery, or a combination of modalities, are among treatment options for these patients. Clinical trial enrollment is preferred, if available. All patients should receive best supportive care, and depending on the extent of the disease and other patient-specific circumstances,pallative care alone may be the most appropriate option for some patients(See NCCN Guidelines for Palliative Care, available at www.NCCN.org).For recurrence of in-transit disease, the Panel recommends treating the patient as a Clinical N+ in-transit disease where a multidisciplinary consultation at an experienced center is encouraged and clinical trials,surgery,radiation, or certain systemic therapies may be considered as additional treatment.

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NCCN Comprehensive NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

References

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National Comprehensive NCCN Guidelines Version 1.2026 Cancer Merkel Cell Carcinoma

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28. Miller RW,Rabkin CS. Merkel cell carcinoma and melanoma:etiological similarities and differences. Cancer Epidemiol Biomarkers Prev 1999;8:153-158. Available at:https://www.ncbi.nlm.nih.gov/pubmed/10067813.

29. Ezaldein HH, Ventura A, DeRuyter NP, et al. Understanding the influence of patient demographics on disease severity, treatment strategy, and survival outcomes in merkel cell carcinoma: a surveillance,epidemiology, and end-results study. Oncoscience 2017;4:106-114.Available at:https://www.ncbi.nlm.nih.gov/pubmed/28966943.

30. Walsh NM. Primary neuroendocrine (Merkel cell) carcinoma of the skin: morphologic diversity and implications thereof. Hum Pathol 2001;32:680-689. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11486166.

31. Higaki-Mori H, Kuwamoto S, Iwasaki T, et al. Association of Merkel cell polyomavirus infection with clinicopathological differences in Merkel cell carcinoma. Hum Pathol 2012;43:2282-2291. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22795182.

32. Lai JH, Fleming KE, Ly TY, et al. Pure versus combined Merkel cell carcinomas: immunohistochemical evaluation of cellular proteins(p53,Bcl-2, and c-kit) reveals significant overexpression of p53 in combined tumors. Hum Pathol 2015;46:1290-1296. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26099430.

33. Engels EA, Frisch M, Goedert JJ, et al. Merkel cell carcinoma and HIV infection. Lancet 2002;359:497-498. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11853800.

34. Lanoy E, Costagliola D, Engels EA. Skin cancers associated with HIV infection and solid-organ transplantation among elderly adults. Int J

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NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma Merkel Cell Carcinoma

Cancer 2010;126:1724-1731. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19810102.

35. Kaae J, Hansen AV, Biggar RJ, et al. Merkel cell carcinoma:incidence, mortality, and risk of other cancers. J Natl Cancer Inst 2010;102:793-801. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20424236.

36. Koljonen V, Kukko H, Tukikaen E, et al. Incidence of Merkel cell carcinoma in renal transplant recipients. Nephrol Dial Transplant 2009;24:3231-3235. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19586970.

37. Koljonen V, Kukko H, Pukkala E, et al. Chronic lymphocytic leukaemia patients have a high risk of Merkel-cell polyomavirus DNA-positive Merkel-cell carcinoma. Br J Cancer 2009;101:1444-1447.Available at:https://www.ncbi.nlm.nih.gov/pubmed/1975594.

38. Koljonen V, Sahi H, Bohling T, Makisalo H. Post-transplant Merkel cell carcinoma. Acta Derm Venereol 2016;96:442-447. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26554531.

39. Clarke CA, Robbins HA, Talovich Z, et al. Risk of merkel cell carcinoma after solid organ transplantation. J Natl Cancer Inst 2015;107.Available at:https://www.ncbi.nlm.nih.gov/pubmed/25575645.

40. Paulson KG, Iyer JG, Blom A, et al. Systemic immune suppression predicts diminished Merkel cell carcinoma-specific survival independent of stage. J Invest Dermatol 2013;133:642-646. Available at:http://www.ncbi.nlm.nih.gov/pubmed/23190897.

41. Asgari MM, Sokil MM, Warton EM, et al. Effect of host, tumor,diagnostic, and treatment variables on outcomes in a large cohort with Merkel cell carcinoma. JAMA Dermatol 2014;150:716-723. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24807619.

42. Liang E, Brower JV, Rice SR, et al. Merkel cell carcinoma analysis of outcomes: A 30-year experience. PLoS One 2015;10:e0129476.Available at:https://www.ncbi.nlm.nih.gov/pubmed/26053480.

43. Bryant MK, Ward C, Gaber CE, et al. Decreased survival and increased recurrence in Merkel cell carcinoma significantly linked with

immunosuppression. J Surg Oncol 2020;122:653-659. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32562583.

44. Brewer JD, Shanafelt TD, Otley CC, et al. Chronic lymphocytic leukemia is associated with decreased survival of patients with malignant melanoma and Merkel cell carcinoma in a SEER population-based study.J Clin Oncol 2012;30:843-849. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22331952.

45. Yusuf MB, Gaskins J, Rattani A, et al. Immune status in Merkel cell carcinoma: Relationships with clinical factors and independent prognostic value. Ann Surg Oncol 2021;28:6154-6165. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33852099.

46. Jouary T, Kubica E, Dalle S, et al. Sentinel node status and immunosuppression: recurrence factors in localized Merkel cell carcinoma. Acta Derm Venereol 2015;95:835-840. Available at:http://www.ncbi.nlm.nih.gov/pubmed/25784178.

47.Aron ST,Canavan T,Yu SS.Organ transplant recipients with Merkel cell carcinoma have reduced progression-free, overall, and disease-specific survival independent of stage at presentation. J Am Acad Dermatol 2014;71:684-690. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25795399.

48. Hui AC, Stillie AL, Seel M, Ainslie J. Merkel cell carcinoma: 27-year experience at the Peter MacCallum Cancer Centre. Int J Radiat Oncol Biol Phys 2011;80:1430-1435. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20708847.

49.Smith FO, Yue B, Marzban SS, et al. Both tumor depth and diameter are predictive of sentinel lymph node status and survival in Merkel cell carcinoma. Cancer 2015;121:3252-3260. Available at:http://www.ncbi.nlm.nih.gov/pubmed/26038193.

50. Servy A, Maubec E, Sugier PE, et al. Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy. Ann Oncol 2016;27:914-919. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/26811346.

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National Comprehensive NCCen Cancer Network®

NCCN Guidelines Version 1.2026 Merkel Cell Carcinne

51. Feng H, Shuda M, Chang M, Chang Y, Moore Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008;319:1096-1100. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18202256.

52. Rollison DE, Giuliano AR, Becker JC. New virus associated with merkel cell carcinoma development. J Natl Compr Canc Netw 2010;8:874-880. Available at:http://www.ncbi.nlm.nih.gov/pubmed/20870633.

53. Batinica M, Akgul B, Silling S, et al. Correlation of Merkel cell polyomavirus positivity with PDGFRalpha mutations and surviving expression in Merkel cell carcinoma. J Dermatol Sci 2015;79:43-49.Available at: http://www.ncbi.nlm.nih.gov/pubmed/25936870.

54. Santos-Juanes J, Fernandez-Vega I, Fuentes N, et al. Merkel cell carcinoma and Merkel cell polyomavirus: a systematic review and meta-analysis. Br J Dermatol 2015;173:42-49. Available at:http://www.ncbi.nlm.nih.gov/pubmed/25919492.

55. Paulson KG, Lewis CW, Redman MW, et al. Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study. Cancer 2017;123:1464-1474. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27925665.

56. Miller DM, Shalhout SZ, Wright KM, et al. The prognostic value of the Merkel cell polyomavirus serum antibody test: A dual institutional observational study. Cancer 2024;130:2670-2682. Available at:https://www.ncbi.nlm.nih.gov/pubmed/38696121.

57. Bhatia K, Goedert JJ, Modali R, et al. Merkel cell carcinoma subgroups by Merkel cell polyomavirus DNA relative abundance and oncogene expression. International Journal of Cancer 2010;126:2240-2246. Available at:https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.24676.

58. Sihto H, Kukko H, Koljonen V, et al. Clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl Cancer Inst 2009;101:938-945. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19535775.

59. Moshiri AS, Doumani R, Yelistratova L, et al. Polyomavirus-negative merkel cell carcinoma: A more aggressive subtype based on analysis of

282 cases using multimodal tumor virus detection. J Invest Dermatol 2017;137:819-827. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28715175.

60. Harms KL, Zhao L, Johnson B, et al. Virus-positive Merkel cell carcinoma is an independent prognostic group with distinct predictive biomarkers. Clin Cancer Res 2021;27:2494-2504. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33547200.

61. Hall BJ, Pincus LB, Yu SS, et al. Immunohistochemical prognostication of Merkel cell carcinoma: p63 expression but not polyomavirus status correlates with outcome. J Cutan Pathol 2012;39:911-917. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22882157

62. Schrama D, Peitsch WK, Zapatka M, et al. Merkel cell virus status is not associated with clinical course of Merkel cell carcinoma.J Invest Dermatol 2011;131:1631-1638. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21562568.

63. Harms PW, Vats P, Verhaegen ME, et al. The distinctive mutational spectra of polyomavirus-negative Merkel cell carcinoma. Cancer Res 2015;75:3720-3727. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26238782.

64. Wong SQ, Waldeck K, Vergara IA, et al. UV-associated mutations underlie the etiology of MCV-negative Merkel cell carcinomas. Cancer Res 2015;75:5228-5234. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26627015.

65. Goh G, Walradt T, Markarov V,et al. Mutational landscape of MCPYV-positive and MCPYV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget 2016;7:3403-3415. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26655088.

66. Amin MB, Edge S, Greene F, et al., eds. AJCC Cancer Staging Manual(ed 8th). New York: Springer International Publishing; 2017.

67.Smoller BR, Bichakjian CK, Brown JA, et al. Protocol for the examination of specimens from patients with merkel cell carcinoma of the skin, version 4.0.0.1. College of American Pathologists Cancer Protocol Templates 2017. Available at:

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National Comprehensive NCCn Medicine Network

NCCN Guidelines NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma Merkel Cell Carcinoma

https://documents.cap.org/protocols/cp-skin-merkelcell-17protocol-4001.pdf.

68. Bhatia S, Storer BE, Iyer JG, et al. Adjuvant radiation therapy and chemotherapy in Merkel cell carcinoma: survival analyses of 6908 cases from the National Cancer Data Base. J Natl Cancer Inst 2016;108.Available at: http://www.ncbi.nlm.nih.gov/pubmed/27245173.

69.Gillenwater AM, Hessel AC, Morrison WH, et al. Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival. Arch Otolaryngol Head Neck Surg 2001;127:149-154. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1117031.

70. Sandel HDt, Day T, Richardson MS, et al. Merkel cell carcinoma:does tumor size or depth of invasion correlate with recurrence,metastasis, or patient survival? Laryngoscope 2006;116:791-795.Available at: https://www.ncbi.nlm.nih.gov/pubmed/16652089.

71. Poulsen M, Round C, Keller J, et al. Factors influencing relapse-free survival in Merkel cell carcinoma of the lower limb-a review of 60 cases.Int J Radiat Oncol Biol Phys 2010;76:393-397. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19515508.

72.Fields RC, Busam KJ, Chou JF, et al. Recurrence after complete resection and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma. Cancer 2012;118:3311-3320. Available at:http://www.ncbi.nlm.nih.gov/pubmed/22072529.

73. Balakrishnan V, Berry S, Stew B, Sizeland A. Benefits of combined modality treatment of Merkel cell carcinoma of the head and neck: single institution experience. J Laryngol Otol 2013;127:908-916. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23952972.

74. Youden DR, Soyer HP, Youl PH, et al. Incidence and survival for Merkel cell carcinoma in Queensland, Australia, 1993-2010. JAMA Dermatol 2014;150:864-872. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24943712.

75. Kukko HM, Koljonen VS, Tukiainen EJ, et al. Vascular invasion is an early event in pathogenesis of Merkel cell carcinoma. Mod Pathol

2010;23:1151-1156. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20473275.

76. Andea AA, Coit DG, Amin B, Busam KJ. Merkel cell carcinoma:histologic features and prognosis. Cancer 2008;113:2549-2558.Available at: http://www.ncbi.nlm.nih.gov/pubmed/18798233.

77. Fields RC, Busam KJ, Chou JF, et al. Recurrence and survival in patients undergoing sentinel lymph node biopsy for kernel cell carcinoma: forial of 153 patients from a single institution. Ann Surg Oncol 2011;18:2529-2537. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21431988.

78. Harounian JA, Molin N, Galloway TJ, et al. Effect of sentinel lymph node biopsy and Ivi on Merkel cell carcinoma to RNAlingoscope 2021;131:E828-E835. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32663337.

79.Smith VA,Camp ER,Lentsch EJ.Merkel cell carcinoma:identification of prognostic factors unique to tumors located in the head and neck based on analysis of SEER data. Laryngoscope 2012;122:1283-1290. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19515508

80. Mott RT, Smoller BR, Morgan MB. Merkel cell carcinoma: a clinicopathologic study with prognostic implications. J Cutan Pathol 2004;31:217-223. Available at:https://www.ncbi.nlm.nih.gov/pubmed/14984573.

81. Marcoval J, Ferreres JR, Penin RM, et al. Merkel cell carcinoma:differences between sun-exposed and non-sun-exposed variants--a clinical analysis of 36 cases. Dermatology 2014;229:205-209. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25278300.

82.18yer JG, Storer BE, Paulson KG, et al. Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma. J Am Acad Dermatol 2014;70:637-643. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24521828.

83. Schwartz JL, Griffith KA, Lowe L, et al. Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol

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NCCN Comprehensive NCCN Guidelines Version 1.2026 Mater Cell Carinoma

2011;29:1036-1041. Available at:http://www.ncbi.nlm.nih.gov/pubmed/21300936.

84. Lim CS, Whalley D, Haydu LE, et al. Increasing tumor thickness is associated with recurrence and poorer survival in patients with Merkel cell carcinoma. Ann Surg Oncol 2012;19:3325-3334. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22820936.

85. Fleming KE, Ly TY, Pasternak S, et al. Support for p63 expression as an adverse prognostic marker in Merkel cell carcinoma: report on a Canadian cohort. Hum Pathol 2014;45:952-960. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24746200.

86. Butala AA, Jain V, Reddy VK, et al. Impact of tumor-infiltrating lymphocytes on overall survival in Merkel cell carcinoma. Oncologist 2021;6:263-69. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32886418.

87. Johnson ME, Zhu F, Li T, et al. Absolute lymphocyte count: a potential prognostic factor for Merkel cell carcinoma. J Am Acad Dermatol 2014;70:1028-1035. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2466998.

88. Paulson KG, Iyer JG, Tegeder AR, et al. Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol 2011;29:1539-1546. Available at:http://www.ncbi.nlm.nih.gov/pubmed/21422430.

89. Paulson KG, Iyer JG, Simonson WT,et al. CD8+ lymphocyte intratumoral infiltration as a stage-independent predictor of Merkel cell carcinoma survival: a population-based study. Am J Clin Pathol 2014;142:452-458. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25239411.

90.Kervarrec T,Gaboriaud P, Berthon P,et al. Merkel cell carcinomas infiltrated with CD33(+) myeloid cells and CD8(+) T cells are associated with improved outcome. J Am Acad Dermatol 2018;78:973-982 e978.Available at:https://www.ncbi.nlm.nih.gov/pubmed/29273486.

91. Feldmeyer L, Hudgens CW, Ray-Lyons G, et al. Density, distribution,and composition of immune infiltrates correlate with survival in Merkel

cell carcinoma. Clin Cancer Res 2016;22:5553-5563. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27166398.

92. Skelton HG, Smith KJ, Hitchcock CL, et al. Merkel cell carcinoma: analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival. J Am Acad Dermatol 1997;37:734-739.Available at: http://www.ncbi.nlm.nih.gov/pubmed/9366819.

93. Lombart B, Monteagudo C, Lopez-Guerrero JA, et al.Clinicopathological and immunohistochemical analysis of 20 cases of Merkel cell carcinoma in search of prognostic markers. Histopathology 2005;46:622-634. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15910593.

94. Schwartz JL, Bichakjian CK, Lowe L, et al. Clinicopathologic features of primary Merkel cell carcinoma: a detailed descriptive analysis of a large contemporary cohort. Dermatol Surg 2013;39:1009-1016. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23551620.

95. Henderson SA, Tetzlaff MT, Pattanapritachul P, et al. Detection of mitotic figures and G2+ tumor nuclei with histone markers correlates with worse overall survival in patients with Merkel cell carcinoma. J Cutan Pathol 2014;41:846-852. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25263506.

96. Miner AG, Patel RM, Wilson DA, et al. Cytokeratin 20-negative Merkel cell carcinoma is infrequently associated with the Merkel cell polyomavirus. Mod Pathol 2015;28:498-504. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25394777.

97. Howard RA, Dores GM, Curtis RE, et al. Merkel cell carcinoma and multiple primary cancers. Cancer Epidemiol Biomarkers Prev 2006;15:1545-1549. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16896047.

98. Koljonen V, Kukko H, Tukiainen E, et al. Second cancers following the diagnosis of Merkel cell carcinoma: a nationwide cohort study.Cancer Epidemiol 2010;34:62-65. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29061203.

99. Bzhalava D, Bray F, Storm H, Dillner J. Risk of second cancers after the diagnosis of Merkel cell carcinoma in Scandinavia. Br J Cancer

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NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

2011;104:178-180. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21081931.

100. Youlden DR, Youl PH, Peter Soyer H, et al. Multiple primary cancers associated with Merkel cell carcinoma in Queensland, Australia,1982-2011. J Invest Dermatol 2014;134:2883-2889. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24991966.

101. Pilotti S, Rilke F, Bartoli C, Grisotti A. Clinicopathologic correlations of cutaneous neuroendocrine Merkel cell carcinoma. J Clin Oncol 1988;6:1863-1873. Available at:https://www.ncbi.nlm.nih.gov/pubmed/3199169.

102.Eftekhari F, Wallace S, Silva EG, Lenzi R. Merkel cell carcinoma of the skin: imaging and clinical features in 93 cases. Br J Radiol 1996;69:226-233. Available at:https://www.ncbi.nlm.nih.gov/pubmed/8800866.

103. Saxena A, Rubens M, Ramamoorthy V, Khan H. Risk of second cancers in merkel cell carcinoma: a meta-analysis of population based cohort studies. J Skin Cancer 2014;2014:184245. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25574398.

104. Brenner B, Sulkes A, Rakowsky E, et al. Second neoplasms in patients with Merkel cell carcinoma. Cancer 2001;91:1358-1362.Available at:https://www.ncbi.nlm.nih.gov/pubmed/11283937.

105.LyTY,Walsh NM,Pasternak S.The spectrum of Merkel cell polyomavirus expression in Merkel cell carcinoma, in a variety of cutaneous neoplasms, and in neuroendocrine carcinomas from different anatomical sites. Hum Pathol 2012;43:557-566. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21940035.

106. Ishida M, Okabe H. Merkel cell carcinoma concurrent with Bowen's disease: two cases, one with an unusual immunophenotype. J Cutan Pathol 2013;40:839-843. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23672777.

107. Iwasaki T, Matsushita M, Kuwamoto S, et al. Usefulness of significant morphologic characteristics in distinguishing between Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative Merkel

cell carcinomas. Hum Pathol 2013;44:1912-1917. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23664542.

108. Pulitzer MP, Brannon AR, Berger MF, et al. Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma. Mod Pathol 2015;28:1023-1032.Available at:https://www.ncbi.nlm.nih.gov/pubmed/26022453.

109.Saeb-Lima M, Montante-Montes de Oca D, Albores-Saavedra J.Merkel cell carcinoma with eccrine differentiation: a clinicopathologic study of 7 cases. Ann Diagn Pathol 2008;12:410-414. Available at:https://www.ncbi.nlm.nih.gov/pubmed/18995205.

110. Martin B, Poblet E, Rios JJ, et al. Merkel cell carcinoma with divergent differentiation: histopathological and immunohistochemical study of 15 cases with PCR analysis for Merkel cell polymavirus.Histopathology 2013;62:711-722. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23530855

111. Heenan PJ, Cole JM, Spagnool DV. Primary cutaneous neuroendocrine carcinoma(Merkel cell tumor). An adnexal epithelial neoplasm. Am J Dermatopathol 1990;12:7-16. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2138434.

112.Acebo E, Vidaurazaga N, Varas C,et al. Merkel cell carcinoma: a clinicopathological study of 11 cases. J Eur Acad Dermatol Venereol 2005;19:546-551. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16164706.

113. D'Agostino M, Cinelli C, Willard R, et al. Epidermotropic Merkel cell carcinoma: a case series with histopathologic examination. J Am Acad Dermatol 2010;62:463-468. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20159312.

114. Gong E, Zawacki L, Fan X, et al. Immunotherapy response in immunosuppressed patients with Merkel cell carcinoma: analysis of 183 patients. BMJ Oncol 2025;4:e000654. Available at:https://www.ncbi.nlm.nih.gov/pubmed/40099002.

115. Tseng YD, Nguyen MH, Baker K, et al. Effect of patient immune status on the efficacy of radiation therapy and recurrence-free survival among 805 patients with merkel cell carcinoma. Int J Radiat Oncol Biol

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Phys 2018;102:330-339. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30191867.

116. Mohsin N, Hunt D, Yan J,et al. Genetic risk factors for early-onset Merkel cell carcinoma. JAMA Dermatol 2024;160:172-178. Available at:https://www.ncbi.nlm.nih.gov/pubmed/38170500.

117. Paulson KG, Carter JJ, Johnson LG, et al. Antibodies to merkel cell polyomavirus T antigen oncoproteins reflect tumor burden in merkel cell carcinoma patients. Cancer Res 2010;70:8388-8397. Available at:http://www.ncbi.nlm.nih.gov/pubmed/20959478.

118.Samimi M, Molet L, Fleury M, et al. Prognostic value of antibodies to Merkel cell polyomavirus T antigens and VP1 protein in patients with Merkel cell carcinoma. Br J Dermatol 2016; 174:813-822. Available at:http://www.ncbi.nlm.nih.gov/pubmed/26600395.

119. Touze A, Le Bidre E, Laude H, et al. High levels of antibodies against merkel cell polyomavirus identify a subset of patients with merkel cell carcinoma with better clinical outcome. J Clin Oncol 2011;29:1612-1619. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21422439.

120. Bittla P, Kaur S, Sojitra V, et al. Exploring circulating tumor DNA(ctDNA) and its role in early detection of cancer: A systematic review.Cureus 2023;15:e45784. Available at:https://www.ncbi.nlm.nih.gov/pubmed/37745752.

121.Akaike T, Jabbour AJ, Goff PH,et al. Merkel cell carcinoma refractory to anti-PD(L)1: utility of adding ipilimumab for salvage therapy.J Immunother Cancer 2024;12. Available at:https://www.ncbi.nlm.nih.gov/pubmed/39053946.

122. Akaike T, Thakuria M, Silk AW, et al. Circulating tumor DNA assay detects Merkel cell carcinoma recurrence, disease progression, and minimal residual disease: Surveillance and prognostic implications. J Clin Oncol 2024;42:3151-3161. Available at:https://www.ncbi.nlm.nih.gov/pubmed/39052958.

123. Anderson SE, Beer KT, Banic A, et al. MRI of merkel cell carcinoma: histologic correlation and review of the literature. AJR Am J Roentgenol 2005;185:1441-1448. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16303995.

124.Kouzmina M, Koljonen V, Leikola J, et al. Frequency and locations of systemic metastases in Merkel cell carcinoma by imaging. Acta Radiol Open 2017;6:2058460117700449. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28540062.

125. Gollub MJ, Gruen DR, Dershaw DD. Merkel cell carcinoma: CT findings in 12 patients. AJR Am J Roentgenol 1996;167:617-620.Available at:https://www.ncbi.nlm.nih.gov/pubmed/8751663.

126.Gupta SG,Wang LC,Penas PF,et al. Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: The Dana-Farber experience and meta-analysis of the literature. Arch Dermatol 2006;142:685-690. Available at:http://www.ncbi.nlm.nih.gov/pubmed/16785370.

127. Peloschek P, Novotny C, Mueller-Mang C, et al. Diagnostic imaging in Merkel cell carcinoma: lessons to learn from 16 cases with correlation of sonography, CT, MRI and PET.Eur J Radiol 2010;73:317-323.Available at:https://www.ncbi.nlm.nih.gov/pubmed/19108971.

128.Girard R,Djelouah M,Barat M,et al.Abdominal metastases from Merkel cell carcinoma: Prevalence and presentation on CT examination in 111 patients. Diagn Interv Imaging 2022;103:41-48. Available at:https://www.ncbi.nlm.nih.gov/pubmed/3446553

129. Colgan MB,Tarantola TI,Weaver AL,et al.The predictive value of imaging studies in evaluating regional lymph node involvement in Merkel cell carcinoma. J Am Acad Dermatol 2012;67:1250-1256. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22552001.

130.Kwekkeboom DJ,Hoff AM,Lamberts SW,et al.Somatostatin analogue scintigraphy. A simple and sensitive method for the in vivo visualization of Merkel cell tumors and their metastases. Arch Dermatol 1992;128:818-821.Available at:https://www.ncbi.nlm.nih.gov/pubmed/1599271.

131. Guitera-Rovel P, Lumbroso J, Gautier-Gougis MS, et al. Indium-111 octroidet scintigraphy of Merkel cell carcinomas and their metastases.Ann Oncol 2001;12:807-811. Available at:https://www.ncbi.nlm.nih.gov/pubmed/11484956.

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132. Durani BK, Klein A, Henze M, et al. Somatostatin analogue scintigraphy in Merkel cell tumours. Br J Dermatol 2003;148:1135-1140.Available at:https://www.ncbi.nlm.nih.gov/pubmed/12828740.

133. Belhocine T, Pierard GE, Fruhling J, et al. Clinical added-value of 18FDG PET in neuroendocrine-merkel cell carcinoma. Oncol Rep 2006;16:347-352. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16820914.

134. Concannon R, Larcos GS, Veness M. The impact of (18)F-FDG PET-CT scanning for staging and management of Merkel cell carcinoma:results from Westmead Hospital, Sydney, Australia. J Am Acad Dermatol 2010;62:76-84. Available at:http://www.ncbi.nlm.nih.gov/pubmed/20082888.

135. Maury G, Dereure O, Du-Thanh A, et al. Interest of(18)F-FDG PET-CT scanning for staging and management of merkel cell carcinoma: a retrospective study of 15 patients. J Eur Acad Dermatol Venereol 2011;25:1420-1427. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21366705.

136.Siva S,Byrne K, Seel M,et al.18F-FDG PET provides high-impact and powerful prognostic stratification in the staging of Merkel cell carcinoma: a 129. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23753187

137. Hawryluk EB, O'Regan KN, Sheehy N, et al. Positron emission tomography/computed tomography imaging in Merkel cell carcinoma: a study of 270 scans in 97 patients at the Dana-Farber/Brigham and Women's Cancer Center. J Am Acad Dermatol 2013;68:592-599.Available at: http://www.ncbi.nlm.nih.gov/pubmed/23127473.

138.Ibrahim SF,Ahronowitz I,McCalmont TH,et al.18F-fluorodeoxyglucose positron emission tomography-computed tomography imaging in the management of Merkel cell carcinoma: a single-institution retrospective study. Dermatol Surg 2013;39:1323-1333.Available at: https://www.ncbi.nlm.nih.gov/pubmed/23777452.

139.Treglia G,Kakhki VR,Giovanella L,Sadeghi R. Diagnostic performance of fluorine-18-fluorodeoxyglucose positron emission tomography in patients with Merkel cell carcinoma: a systematic review

and meta-analysis. Am J Clin Dermatol 2013;14:437-447. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23959776.

140. Buder K, Lapa C, Kreissl MC, et al. Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging.BMC Cancer 2014;14:268. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24742330.

141.George A,Girault S, Testard A, et al. The impact of (18)F-FDG-PET/CT on Merkel cell carcinoma management: a retrospective study of 66 scans from a single institution. Nucl Med Commun 2014;35:282-290.Available at: https://www.ncbi.nlm.nih.gov/pubmed/24240193.

142.Byrne K,Siva S,Cait L,et al.15-year experience of 18F-FDG PET-imaging in response assessment and restaging after definitive treatment of Merkel cell carcinoma. J Nucl Med 2015;56:1328-1333. Available at:http://www.ncbi.nlm.nih.gov/pubmed/26159592.

143. Liu J, Larcos G, Howle J, Veness M. Lack of clinical impact of(18)F-fluorodeoxyglucose positron emission tomography with simultaneous computed tomography for stage I and II Merkel cell carcinoma with concurrent sentinel lymph node biopsy staging: A single institutional experience from Westmead Hospital, Sydney. Australas J Dermatol 2017;58:99-105. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26459330.

https://www.ncbi.nlm.nih.gov/pubmed/26459330.

144.Sollini M.,Taralli S,Miella M.,et al.Somatostatin receptor positron emission tomography/computed tomography imaging in Merkel cell carcinoma. J Eur Acad Dermatol Venereol 2016;30:1507-1511. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26446694.

145.Ben-Haim S, Garkaby J, Primashvili N, et al. Metabolic assessment of Merkel cell carcinoma: the role of 18F-FDG PET/CT. Nucl Med Commun 2016;37:865-873. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27092665.

146. Poulsen M, Macfarlane D, Veness M, et al. Prospective analysis of the utility of 18-FDG PET in Merkel cell carcinoma of the skin: A Trans Tasman Radiation Oncology Group Study, TROG 09:03. J Med Imaging Radiat Oncol 2018;62:412-419. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29405630.

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147. Feletti A, Marton E, Rossi S, et al. Pituitary metastasis of Merkel cell carcinoma. J Neurooncol 2010;97:295-299. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19806319.

148. Abul-Kasim K, Soderstrom K, Hallsten L. Extensive central nervous system involvement in Merkel cell carcinoma: a case report and review of the literature. J Med Case Rep 2011;5:35. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21269448.

149. Caramanti RL, Chaddad Neto FE, Megins LC, et al. Brain metastasis of Merkel cell carcinoma- A rare case report. Surg Neurol Int 2019;10:172. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31583169.

150.Singh N, Alexander NA, Lachance K, et al. Clinical benefit of baseline imaging in Merkel cell carcinoma; Analysis of 584 patients. J Am Acad Dermatol 2021;84:330-339. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32707254.

151. Saqlain F, Shalhout SZ, Emerick KS, et al. Diagnostic yield of staging brain magnetic resonance imaging is low in Merkel cell carcinoma: A single-institution cohort study. J Am Acad Dermatol 2021;87:434-435. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34499987.

152. Goepfert H, Remmler D, Silva E, Wheeler B. Merkel cell carcinoma(endocrine carcinoma of the skin) of the head and neck. Arch Otolaryngol 1984;110:707-712. Available at:https://www.ncbi.nlm.nih.gov/pubmed/6487123.

153.Ball NJ,Tanhuanco-Kho G. Merkel cell carcinoma frequently shows histologic features of basal cell carcinoma: a study of 30 cases. J Cutan Pathol 2007;34:612-619. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17640231.

154. Gollard R, Weber R, Kosty MP, et al. Merkel cell carcinoma of 22 cases with surgical, pathologic, and therapeutic considerations.Cancer 2000;88:1842-1851. Available at:https://www.ncbi.nlm.nih.gov/pubmed/10760761.

155. Warner TF, Uno H, Hafez GR, et al. Merkel cells and Merkel cell tumors. Ultrastructure, immunocytochemistry and review of the literature.

Cancer 1983;52:238-245. Available at:https://www.ncbi.nlm.nih.gov/pubmed/6344978.

156. Johansson L, Tennvall J, Akerman M. Immunohistochemical examination of 25 cases of Merkel cell carcinoma: a comparison with small cell carcinoma of the lung and oesophagus, and a review of the literature. APMIS 1990;98:741-752. Available at:https://www.ncbi.nlm.nih.gov/pubmed/1698390.

157. Haag ML, Glass LF, Fenske NA. Merkel cell carcinoma. Diagnosis and treatment. Dermatol Surg 1995;21:669-683. Available at:http://www.ncbi.nlm.nih.gov/pubmed/7633811.

158.Schmidt U, Muller U, Metz KA, Leder LD. Cytokeratin and neurofilament protein staining in Merkel cell carcinoma of the small cell type and small cell carcinoma of the lung. Am J Dermatopathol https://www.ncbi.nlm.nih.gov/pubmed/9700371.

159. Bobos M, Hytiroglou P, Kostopoulos I, et al. Immunohistochemical distinction between merkel cell carcinoma and small cell carcinoma of the lung. Am J Dermatopathol 2006;28:99-104. Available at:https://www.ncbi.nlm.nih.gov/pubmed/16625069.

160.Kolhe R,Reid MD,Lee JR,et al.Immunohistochemical expression of PAX5 and TdT by Merkel cell carcinoma and pulmonary small cell carcinoma: a potential diagnostic pitfall but useful discriminatory marker.Int J Clin Exp Pathol 2013;6:142-147. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23329999.

161.Byrd-Gloster AL,Khoor A,Glass LF,et al.Differential expression of thyroid transcription factor 1 in small cell lung carcinoma and Merkel cell tumor. Hum Pathol 2000;31:58-62. Available at:https://www.ncbi.nlm.nih.gov/pubmed/10665914.

162. Hanly AJ, Elgart GW, Jorda M, et al. Analysis of thyroid transcription factor-1 and cytokeratin 20 separates merkel cell carcinoma from small cell carcinoma of lung. J Cutan Pathol 2000;27:118-120.Available at: http://www.ncbi.nlm.nih.gov/pubmed/10728812.

163. Ordonez NG. Value of thyroid transcription factor-1 immunostaining in distinguishing small cell lung carcinomas from other small cell

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carcinomas. Am J Surg Pathol 2000;24:1217-1223. Available at:https://www.ncbi.nlm.nih.gov/pubmed/10976695.

164. Busam KJ, Jungbluth AA, Rekthman N, et al. Merkel cell polymavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. Am J Surg Pathiol 2009;33:1378-1385. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19609205.

165. Sidiropoulos M, Hanna W, Raphael SJ, Ghorab Z. Expression of TdT in Merkel cell carcinoma and small cell lung carcinoma. Am J Clin Pathol 2011;135:831-838. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21571955.

166. Panase G, McNiff JM,Ko CJ. Basal cell carcinoma: CD56 and cytokeratin 5/6 staining patterns in the differential diagnosis with Merkel cell carcinoma. J Cutan Pathol 2017;44:553-556. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28403527.

167. Koljonen V, Haglund C, Tukiainen E, Bohling T. Neuroendocrine differentiation in primary Merkel cell carcinoma-possible prognostic significance. Anticancer Res 2005;25:853-858. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15868919.

168.Knopf A, Bas M, Hofafauer, B et al. Clinopicathological characteristics of head and neck Merkel cell carcinomas. Head Neck 2017;39:92-97.Available at:https://www.ncbi.nlm.nih.gov/pubmed/27447124.

169. Asioli S, Righi A, de Biase D, et al. Expression of p63 is the sole independent marker of aggressiveness in localised(stage I-II) Merkel cell carcinomas. Mod Pathol 2011;24:1451-1461. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21765392.

170. Sihto H, Kukko H, Koljonen V, et al. Merkel cell polyomavirus infection, large T antigen, retinoblastoma protein and outcome in Merkel cell carcinoma. Clin Cancer Res 2011;17:4806-4813. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21642382.

171.Zaragoza J, Kervarrec T, Touze A, et al. A high neutrophil-to-lymphocyte ratio as a potential marker of mortality in patients with Merkel cell carcinoma: A retrospective study. J Am Acad Dermatol 2016;75:712-721 e711. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27544490.

172. Lilo MT, Chen Y, LeBlanc Re INSM1 is more sensitive and interpretable than conventional immunohistochemical stains used to diagnose Merkel cell carcinoma. Am J Surg Pathol 2018;42:1541-1548.Available at:https://www.ncbi.nlm.nih.gov/pubmed/30080705.

173.Smith KJ,Kselton HG,3rd, Holland TT,et al.Neuroendocrine(Merkel cell) carcinoma with an intraepidermal component. Am J Dermatopathol 1993;15:528-533. Available at:https://www.ncbi.nlm.nih.gov/pubmed/8311181.

174.Foote M, Veness M, Zarate D, Poulsen M. Merkel cell carcinoma:the prognostic implications of an occult primary in stage IIIB(nodal)disease.J Am Acad Dermatol 2012;67:395-399. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22030017.

175.Tarantola TI, Vallow LA, Halyard MY, et al. Unknown primary Merkel cell carcinoma: 23 new cases and a review. J Am Acad Dermatol 2013;68:433-440. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23182060.

176.Chen KT, Papavasiliou P, Edwards K, et al. A better prognosis for Merkel cell carcinoma of unknown primary origin. Am J Surg 2013;206:752-757. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23835211.

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177.Vandeven N,Lewis CW,Makarov V,et al.Merkel cell carcinoma patients presenting without a primary lesion have elevated markers of immunity, higher tumor mutation burden, and improved survival. Clin Cancer Res 2018;24:963-971. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29246939.

178.Wright GP, Holtzman MP. Surgical resection improves median overall survival with marginal improvement in long-term survival when compared with definitive radiotherapy in Merkel cell carcinoma: A propensity score matched analysis of the National Cancer Database. Am J Surg 2018;215:384-387. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29157891.

179. Kukko H, Bohling T, Koljonen V, et al. Merkel cell carcinoma- a population-based epidemiological study in Finland with a clinical series of 181 cases. Eur J Cancer 2012;48:737-742. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21729823.

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180.Kim JA,Choi AH. Effect of radiation therapy on survival in patients with resected Merkel cell carcinoma: a propensity score surveillance,epidemiology, and end results database analysis: JAMA Dermatol 2013;149:831-838. Available at:http://www.ncbi.nlm.nih.gov/pubmed/23864085.

181. Sattler E, Geimer T, Sick I, et al. Sentinel lymph node in Merkel cell carcinoma: To biopsy or not to biopsy? J Dermatol 2013;40:374-379.Available at: http://www.ncbi.nlm.nih.gov/pubmed/23414107.

182.Haymerle G, Fochtmann A, Kunstfeld R, et al. Merkel cell carcinoma: Overall survival after open biopsy versus wide local excision.Head Neck 2016;38 Suppl 1:E1014-1018. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26041367.

183.Chen MM, Roman SA, Sosa JA, Judson BL. The role of adjuvant therapy in the management of head and neck merkel cell carcinoma: an analysis of 4815 patients. JAMA Otolaryngol Head Neck Surg 2015;141:137-141. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25474617.

184.Vargo JA, Ghareeb ER, Balasubramani GK, Beriwal S. RE:Adjuant radiation therapy and chemotherapy in Merkel cell carcinoma:Survival analyses of 6908 cases from the National Cancer Data Base.J Natl Cancer Inst 2017;109. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28423400.

185.Singh B, Qureshi MM, Truong MT, Sahni D. Demographics and outcomes of stage I-II Merkel cell carcinoma treated with Mohs micrographic surgery compared with wide local excision in the National Cancer Data Base. J Am Acad Dermatol 2018;79:126-134 e123.Available at:https://www.ncbi.nlm.nih.gov/pubmed/29408552.

186.O'Connor WJ, Roenigk RK, Brodland DG. Merkel cell carcinoma.Comparison of Mohs micrographic surgery and wide excision in eighty-six patients. Dermatol Surg 1997;23:929-933. Available at:http://www.ncbi.nlm.nih.gov/pubmed/9357504.

187. Boyer JD, Zitelli JA, Brodland DG, D'Angelo G. Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad

Dermatol 2002;47:885-892. Available at:http://www.ncbi.nlm.nih.gov/pubmed/12451374.

188. Senchenkov A, Barnes SA, Moran SL. Predictors of survival and recurrence in the surgical treatment of merkel cell carcinoma of the extremities.J Surg Oncol 2007;95:229-234. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17323336.

189.Kline L, Coldiron B. Mohs micrographic surgery for the treatment of Merkel cell carcinoma. Dermatol Surg 2016;42:945-951. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27467228.

190.Mattavelli I, Patuzzo R, Torri V, et al. Prognostic factors in Merkel cell carcinoma patients undergoing sentinel cell biopsy. Eur J Surg Oncol 2017;43:1536-1541. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28583789.

191. Bajetta E, Celio L, Platania M, et al. Single-institution series of early-stage Merkel cell carcinoma: long-term outcomes in 95 patients managed with surgery alone. Ann Surg Oncol 2009;16:2985-2993.Available at: https://www.ncbi.nlm.nih.gov/pubmed/19609619.

192. Maloney NJ, Nguyen KA, So NA, et al. Risk factors for and prognostic impact of positive surgical margins after excision of Merkel cell carcinoma.J Am Acad Dermatol 2021;87:444-446. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34537251.

193. Jabbour J, Cumming R, Scolyer RA, et al. Merkel cell carcinoma:assessing the effect of wide local excision, lymph node dissection, and radiotherapy on recurrence and survival in early-stage disease-results from a review of 82 consecutive cases diagnosed between 1992 and 2004. Ann Surg Oncol 2007;14:1943-1952. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17356954.

194. Lok B, Khan S, Mutter R, et al. Selective radiotherapy for the treatment of head and neck Merkel cell carcinoma. Cancer 2012;118:3937-3944. Available at:http://www.ncbi.nlm.nih.gov/pubmed/22180314.

195. Howle JR, Hughes TM, Gebski V, Veness MJ. Merkel cell carcinoma: an Australian perspective and the importance of addressing the regional lymph nodes in clinically node-negative patients. J Am Acad

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Dermatol 2012;67:33-40. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/21996296.

196.Timmer FC, Klop WM, Relyveld GN, et al. Merkel cell carcinoma of the head and neck: emphasizing the risk of undertreatment. Eur Arch Otorhinolaryngol 2016;273:1243-1251. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25759258.

197. Han AY, Patel PB, Anderson M, et al. Adjuvant radiation therapy improves patient survival in early-stage merkel cell carcinoma: A. 15-year single-institution study. Laryngoscope 2018;128:1862-1866. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29314048.

198. Jaouen F, Kervarrec T, Caille A, et al. Narrow resection margins are not associated with mortality or recurrence in patients with Merkel cell carcinoma: A retrospective study. J Am Acad Dermatol 2021;84:921-929.Available at:https://www.ncbi.nlm.nih.gov/pubmed/33253832.

199. Tarabadks ES,Fu T, Lachance K,et al. Narrow excision margins are appropriate for Merkel cell carcinoma when combined with adjuvant radiation: Analysis of 188 cases of localized disease and proposed management algorithm. J Am Acad Dermatol 2021;84:340-347. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32711093.

200.Dancey AL,Rayatt SS,Soon C,et al. Merkel cell carcinoma: a report of 34 cases and literature review. J Plast Reconstr Aesthet Surg 2006;59:1294-1299. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17113506.

201. Andruska N, Fischer-Valuck BW, Mahapatra L, et al. Association between surgical margins larger than 1 cm and overall survival in patients with Merkel cell carcinoma. JAMA Dermatol 2021;157:540-548.Available at:https://www.ncbi.nlm.nih.gov/pubmed/33760021.

202. Yan L, Sun L, Guan Z, et al. Analysis of cutaneous Merkel cell carcinoma outcomes after different surgical interventions. J Am Acad Dermatol 2020;82:1422-1434. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30296537.

203. Curtis KK, Fakult NJ, Strunck JL, et al. Establishing consensus for Mohs micrographic surgical techniques in the treatment of melanoma in situ for future clinical trials: A modified delphi study. J Natl Compr Canc

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204.Gunaratne DA, Howle JR, Veness MJ. Sentinel lymph node biopsy in in Merkel cell carcinoma: a 15-year institutional experience and statistical analysis of 721 reported cases. Br J Dermatol 2016;174:273-281.

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205.Sims JR, Grotz TE, Pockaj BA, et al. Sentinel lymph node biopsy in Merkel cell carcinoma: The Mayo Clinic experience of 150 patients. Surg Oncol 2018;27:11-17. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29549898.

206. Conic RR, Ko J, Saridakis S, et al. Sentinel lymph node biopsy in Merkel cell carcinoma: Predictors of sentinel lymph node positivity and association with overall survival. J Am Acad Dermatol 2019;81:364-372.Available at: https://www.ncbi.nlm.nih.gov/pubmed/30902726.

207. Shibayama Y,Imafuku S, Takahashi A, Nakayama J. Role of sentinel lymph node biopsy in patients with Merkel cell carcinoma:statistical analysis of 403 reported cases. Int J Clin Oncol 2015;20:188-193. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24687530.

208.Kachare SD,Wong JH,Vohra NA,et al.Sentinel lymph node biopsy is associated with improved survival in Merkel cell carcinoma.Ann Surg Oncol 2014;21:1624-1630. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24378985.

209.Frohm ML,Griffith KA, Harms KL,et al. Recurrence and survival in patients with Merkel cell carcinoma undergoing surgery without adjuvant radiation therapy to the primary site. JAMA Dermatol 2016;152:1001-1007.Available at:https://www.ncbi.nlm.nih.gov/pubmed/27248515.

210.Fritsch VA,Camp ER,Lentsch EJ. Sentinel lymph node status in Merkel cell carcinoma of the head and neck: not a predictor of survival.Head Neck 2014;36:571-579. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24446426.

211.Stadelmann WK,Cobbins L, Lentsch EJ. Incidence of nonlocalization of sentinel lymph nodes using preoperative lymphoscintigraphy in 74 consecutive head and neck melanoma and Merkel cell carcinoma patients. Ann Plast Surg 2004;52:546-549;

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National Comprehensive NCCN Guidelines Version 1.2026 Cancer Merkel Cell Carcinoma

discussion 550. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/15166975.

212. Hoetzenecker W, Guenova E, Bottinger TU, et al. Mapping of specific sentinel node locations for skin cancer of the head. Eur J Dermatol 2011;21:354-358. Available at:

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213. Willis Al, Ridge JA. Discordant lymphatic drainage patterns revealed by serial lymphoscintigraphy in cutaneous head and neck malignancies. Head Neck 2007;29:979-985. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17525953

214. Allen PJ, Busam K, Hill AD, et al. Immunohistochemical analysis of sentinel lymph nodes from patients with Merkel cell carcinoma. Cancer 2001;92:1650-1655. Available at:http://www.ncbi.nlm.nih.gov/pubmed/11745244.

215. Su LD, Lowe L, Bradford CR,et al. Immunostaining for cytokeratin 20 improves detection of micrometastatic Merkel cell carcinoma in sentinel lymph nodes.J Am Acad Dermatol 2002;46:661-666. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12004304.

216. Schmalbach CE, Lowe L, Teknos TN, et al. Reliability of sentinel lymph node biopsy for regional staging of head and neck Merkel cell carcinoma. Arch Otolaryngol Head Neck Surg 2005;131:610-614.

Available at:http://www.ncbi.nlm.nih.gov/pubmed/16027284.

217. Loyo M, Schussel J, Colantuoni E, et al. Detection of Merkel cell virus and correlation with histologic presence of Merkel cell carcinoma in sentinel lymph nodes. Br J Cancer 2012;106:1314-1319. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22415238.

218. Collins BT, Elmberger PG, Tani EM, et al. Fine-needle aspiration of Merkel cell carcinoma of the skin with cytomorphology and immunocytochemical correlation. Diagn Cytopathol 1998;18:251-257.Available at: https://www.ncbi.nlm.nih.gov/pubmed/9557258.

219. Righi A, Asioli S, Caliendo V, et al. An ultrasonography-cytology protocol for the diagnostic management of regional nodes in a subset of patients with Merkel cell carcinoma of the skin. Br J Dermatol

2013;168:563-570. Available at:

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220.Shield PW, Crous H. Fine-needle aspiration cytology of Merkel cell carcinoma-a review of 69 cases. Diagn Cytopathol 2014;42:924-928.Available at: https://www.ncbi.nlm.nih.gov/pubmed/24678011.

221.Cipolletta Campanile A,Malzone MG,Sanna V,et al.Cytological and immunocytochemical features of Merkel cell carcinoma on fine needle cytology samples: A study of 22 cases. Endocr Pathol 2015;26:243-249. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25982258.

222.Veness MJ, Perera MJ, McCourt J, et al. Merkel cell carcinoma: improved outcome with adjuvant radiotherapy. ANZ J Surg 2005;75:275-281. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15932436.

223.McAfee WJ,Morris CG, Mendenhall CM, et al. Merkel cell carcinoma: treatment and outcomes. Cancer 2005;104:1761-1764.Available at: http://www.ncbi.nlm.nih.gov/pubmed/16136596.

224. Tsang G,O'Brien P, Robertson R, et al. All delays before radiotherapy risk progression of Merkel cell carcinoma. Australas Radiol 2004;48:371-375. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15344989.

225. Clark JR, Veness MJ, Gilbert R, et al. Merkel cell carcinoma of the head and neck: is adjuvant radiotherapy necessary? Head Neck 2007;29:249-257. Available at:https://www.ncbi.nlm.nih.gov/pubmed/17163472.

226. Koh CS, Veness MJ. Role of definitive radiotherapy in treating patients with inoperable Merkel cell carcinoma: the Westmead Hospital experience and a review of the literature. Australas J Dermatol 2009;50:249-256. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19916967.

227.Fang LC, Lemos B, Douglas J, et al. Radiation monotherapy as regional treatment for lymph node-positive Merkel cell carcinoma.Cancer 2010;116:1783-1790. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20162707.

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National Comprehensive NCCen Cancer Network®

NCCN Guidelines VCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

228.Samimi M, Touze A, Laude H, et al. Vitamin D deficiency is associated with greater tumor size and poorer outcome in Merkel cell carcinoma patients. J Eur Acad Dermatol Venereol 2014;28:298-308.Available at:https://www.ncbi.nlm.nih.gov/pubmed/23368852.

229. Gunaratne DA, Howle JR, Veness MJ. Definitive radiotherapy for Merkel cell carcinoma confers clinically meaningful in-field locregional control: A review and analysis of the literature. J Am Acad Dermatol 2017;77:142-148 e141. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28495499.

230. Mendenhall WM, Morris CG, Kirwan JM, et al. Management of cutaneous Merkel cell carcinoma. Acta Oncol 2018;57:320-323.

Available at: https://www.ncbi.nlm.nih.gov/pubmed/28712323.

231. Fenig E, Brenner B, Katz A, et al. The role of radiation therapy and chemotherapy in the treatment of Merkel cell carcinoma. Cancer 1997;80:881-885. Available at:

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232. Veness M, Foote M, Gebski V, Poushen M. The role of radiotherapy alone in patients with merkel cell carcinoma: reporting the Australian experience of 43 patients. Int J Radiat Oncol Biol Phys 2010;78:703-709.Available at: https://www.ncbi.nlm.nih.gov/pubmed/19939581.

233. Sundaresan P, Hruby G, Hamilton A, et al. Definitive radiotherapy or chemoradiotherapy in the treatment of Merkel cell carcinoma. Clin Oncol(R Coll Radiol) 2012;24:e131-136. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22626522.

234. Harrington C, Kwan W. Outcomes of Merkel cell carcinoma treated with radiotherapy without radical surgical excision. Ann Surg Oncol 2014;21:3401-3405. Available at:https://www.ncbi.nlm.nih.gov/pubmed/25001091.

235. Veness M, Howle J. Radiotherapy alone in patients with Merkel cell carcinoma: the Westmead Hospital experience of 41 patients. Australas J Dermatol 2015;56:19-24. Available at:https://pubmed.ncbi.nlm.nih.gov/25369110/.

236. Bishop AJ,Garden AS,Gunn GB,et al. Merkel cell carcinoma of the head and neck: Favorable outcomes with radiotherapy. Head Neck

2016;38 Suppl 1:E452-458. Available at:

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237. Alexander NA, Schaub SK, Goff PH, et al. Increased risk of recurrence and disease-specific death following delayed postoperative radiation for Merkel cell carcinoma. J Am Acad Dermatol 2024;90:261-268. Available at:https://www.ncbi.nlm.nih.gov/pubmed/37778663.

238.Lodde GC, Leiter U, Gesierich A, et al. Clinical course of Merkel cell carcinoma: A DeCOG multicenter study of 1049 patients. Eur J Cancer 2025;221:115406. Available at:

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239. Strom T, Carr M, Zager JS, et al. Radiation therapy is associated with improved outcomes in Merkel cell carcinoma. Ann Surg Oncol 2016;23:3572-3578. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27251134.

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240. Lewis KG, Weinstock MA, Weaver AL, Otley CC. Adjuvant local irradiation for Merkel cell carcinoma. Arch Dermatol 2006;142:693-700.Available at: http://www.ncbi.nlm.nih.gov/pubmed/16785371.

241.Straker RJ,3rd,Carr MJ,Sinnamon AJ,et al. Predictors of false negative sentinel lymph node biopsy in clinically localized Merkel cell carcinoma. Ann Surg Oncol 2021;28:6995-7003. Available at:

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242.Zeifouni NC,Giordano CN,Kane JM,3rd.In-transit Merkel cell carcinoma treated with isolated limb perfusion or isolated limb infusion: a case series of 12 patients. Dermatol Surg 2011;37:357-364. Available at:https://www.ncbi.nlm.nih.gov/pubmed/21324044.

243.Hindmarch JJ,Coker DJ,Waugh R,et al.Treatment of in-transit Merkel cell carcinoma by isolated limb infusion with cytotoxic drugs. J Surg Case Rep 2022;2022:rjac172. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35422991.

244.Kiyohara T,Shijimaya T,Miyamoto M,et al.In-transit recurrence of Merkel cell carcinoma associated with Bowen's disease: The first reported case successfully treated by avelumab. J Dermatol 2019;46:440-443. Available at:

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National Comprehensive NCCn Cancer Network®

NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma Merkel Cell Carcinoma

245. Rusheen J, Clune J, Ariyan S, et al. Case report: Metastatic Merkel cell carcinoma presenting seven years after loco-regional disease resection of primary tumor with interval in-transit and nodal metastases.Front Oncol 2023;13:1217816. Available at:https://www.ncbi.nlm.nih.gov/pubmed/37476373.

246. Grotz TE, Tarantola TI, Otley CC, et al. Natural history of merkel cell carcinoma following locoregional recurrence. Ann Surg Oncol 2012;19:2556-2562. Available at:https://www.ncbi.nlm.nih.gov/pubmed/22453243.

247. Shaw JH, Rumball E. Merkel cell tumour: clinical behaviour and treatment. Br J Surg 1991;78:138-142. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2015460.

248. Mehrany K, Otley CC, Weenig RH, et al. A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma. Dermatol Surg 2002;28:113-117; discussion 117. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11860419.

249. Deneve JL, Messina JL, Marzban SS, et al. Merkel cell carcinoma of unknown primary origin. Ann Surg Oncol 2012;19:2360-2366.

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250. Boyle F, Pendlebury S, Bell D. Further Insights into the natural history and management of primary cutaneous neuroendocrine (Merkel cell) carcinoma. Int J Radiat Oncol Biol Phys 1995;31:135-233. Available at:https://www.ncbi.nlm.nih.gov/pubmed/7836085.

251. Perez MC, Oliver DE, Weitman ES, et al. Management of sentinel lymph node metastasis in Merkel cell carcinoma: Completion lymph adenectomy, radiation, or both? Ann Surg Oncol 2019;26:379-385.Available at:https://www.ncbi.nlm.nih.gov/pubmed/30311164.

252. Lee JS, Durham AB, Bichakjian CK, et al. Completion lymph node dissection or radiation therapy for sentinel node metastasis in merkel cell carcinoma. Ann Surg Oncol 2019;26:386-394. Available at:https://www.ncbi.nlm.nih.gov/pubmed/30556118.

253.Ko JS, Prieto VG,Elson PJ, et al. Histological pattern of Merkel cell carcinoma sentinel lymph node metastasis improves stratification of

Stage III patients. Mod Pathol 2016;29:122-130. Available at:http://www.ncbi.nlm.nih.gov/pubmed/26541273.

254. Nguyen AT, Luu M, Lu DJ, et al. Quantitative metastatic lymph node burden and survival in Merkel cell carcinoma. J Am Acad Dermatol 2021;84:312-320. Available at:

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255.Finnigan R, Hruby G, Wratten C, et al. The impact of preradiation residual disease volume on time to locoregional failure in cutaneous Merkel cell carcinoma--a TROG substudy. Int J Radiat Oncol Biol Phys 2013;86:91-95. Available at:

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256. Poulsen MG, Rischin D, Porter I, et al. Does chemotherapy improve survival in high-risk stage I and II Merkel cell carcinoma of the skin? Int J Radiat Oncol Biol Phys 2006;64:114-119. Available at:http://www.ncbi.nlm.nih.gov/pubmed/16125873.

257. Meeuwissen JA, Bourne RG, Kearsley JH. The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma.Int J Radiat Oncol Biol Phys 1995;31:325-331. Available at:https://www.ncbi.nlm.nih.gov/pubmed/2271206.

258. Mojica P, Smith D, Ellenhorn JD. Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin. J Clin Oncol 2007;25:1043-1047. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17369567.

259. Wong WG, Stahl K, Olecki EJ, et al. Survival benefit of guideline-concordant postoperative radiation for local Merkel cell carcinoma. J Surg Res 2021;266:168-179. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34015514.

260.Takagishi SR, Marx TE, Lewis C, et al. Postoperative radiation therapy is associated with a reduced risk of local recurrence among low risk Merkel cell carcinomas of the head and neck. Adv Radiat Oncol 2016;1:244-251. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28740894.

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261. Eich HT, Eich D, Staar S, et al. Role of postoperative radiotherapy in the management of Merkel cell carcinoma. Am J Clin Oncol

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National Comprehensive NCCn Cancer Network®

NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

2002;25:50-56. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/11823697.

262.Grotz TE,Joseph RW, Pockaj BA, et al. Negative sentinel lymph node biopsy in Merkel cell carcinoma is associated with a low risk of same-nodal-basin recurrences. Ann Surg Oncol 2015;22:4060-4066.Available at: http://www.ncbi.nlm.nih.gov/pubmed/25676844.

263.Hasan S, Liu L, Triplet J, et al. The role of postoperative radiation and chemoradiation in merkel cell carcinoma: a systematic review of the literature. Front Oncol 2013;3:276. Available at:https://www.ncbi.nlm.nih.gov/pubmed/24294591.

264. Palencia R, Sandhu A, Webb S, et al. Systematic literature review of current treatments for stage I-III Merkel cell carcinoma. Future Oncol 2021;17:4813-4822. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34494443.

265.Kang SH, Haydu LE, Goh RY, Fogarty GB, Radiotherapy is associated with significant improvement in local and regional control in Merkel cell carcinoma. Radiat Oncol 2012;7:171. Available at:https://www.ncbi.nlm.nih.gov/pubmed/23075308.

266.Jouary T,Leyral C,Dreno B,et al.Adjuvant prophylactic regional radiotherapy versus observation in stage l Merkel cell carcinoma: a multicentric prospective randomized study. Ann Oncol 2012;23:1074-1080. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21750118.

267. Sexton KW, Poteet SP, Hill JB, et al. Adjuvant Radiation Therapy Increases Disease-Free Survival in Stage IB Merkel Cell Carcinoma. Ann Plast Surg 2013;73:531-534. Available at:http://www.ncbi.nlm.nih.gov/pubmed/23657045.

268. Petrelli F, Ghidini A, Torchio M, et al. Adjuvant radiotherapy for Merkel cell carcinoma: A systematic review and meta-analysis. Radiother Oncol 2019;134:211-219. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31005218.

269. Hoeller U, Mueller T, Schubert T, et al. Regional nodal relapse in surgically staged Merkel cell carcinoma. Strahlenther Onkol 2015;191:51-58. Available at:

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270.Fujimura T,Furudate S,Kambayahsi Y,et al.Phospho-STAT5B Expression Is a Prognostic Marker for Merkel Cell Carcinoma. Anticancer Res 2017;37:2335-2341. Available at:

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271. Cramer JD, Suresh K, Sridharan S. Completion lymph node dissection for merkel cell carcinoma. Am J Surg 2020;220:982-986.Available at:https://www.ncbi.nlm.nih.gov/pubmed/32087988.

272.Strom T,Naghavi AO, Messina JL,et al.Improved local and regional control with radiotherapy for Merkel cell carcinoma of the head and neck. Head Neck 2017;39:48-55. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27300153.

273. Voog E, Biron P, Martin JP, Blay JY. Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma. Cancer 1999;85:2589-2595. Available at:

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274. Lewis CW,Qazi J, Hippe DS,et al. Patterns of distant metastases in 215 Merkel cell carcinoma patients: Implications for prognosis and surveillance. Cancer Med 2020;9:1374-1382. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31883234.

275. Maloney NJ, Nguyen KA, Bach DQ, Zaba LC. Sites of distant metastasis in Merkel cell carcinoma differ by primary tumor site and are of prognostic significance: A population-based study in the Surveillance,Epidemiology, and End Results database from 2010 to 2016. J Am Acad Dermatol 2021;84:568-570. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32781190.

276. Bhatia S, Nghiem P, Veeranki SP, et al. Real-world clinical outcomes with avelumab in patients with Merkel cell carcinoma treated in the USA: a multicenter chart review study. J Immunother Cancer 2022;10. Available at:https://www.ncbi.nlm.nih.gov/pubmed/35981787.

277. Cowey CL, Liu FX, Kim R, et al. Real-world clinical outcomes with first-line avelumab in locally advanced/metastatic Merkel cell carcinoma in the USA: SPEAR-Merkel. Future Oncol 2021;17:2339-2350. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33709776.

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278. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre,single-group, open-label, phase 2 trial. Lancet Oncol 2016;17:1374-1385. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27592805

279. Kaufman HL, Russell JS, Hamid O, et al. Updated efficacy of arvelumab in patients with previously treated metastatic Merkel cell carcinoma after>/=1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer 2018;6:7. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29347993.

280. D'Angelo SP, Russell J, Lebbe C, et al. Efficacy and safety of first-line avelumab treatment in patients with stage iv metastatic Merkel cell carcinoma: A preplanned interim analysis of a clinical trial. JAMA Oncol 2018;4:e180077. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29566106.

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281.D'Angelo SP, Bhatia S, Brohl AS, et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma(JAVELIN Merkel 200); updated overall survival data after>5 years of follow-up. ESMO Open 2021;6:100290. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34715570.

282. D'Angelo SP, Bhatia S, Brohl AS, et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial. J Immunother Cancer 2020;8. Available at:https://www.ncbi.nlm.nih.gov/pubmed/32414862.

283. D'Angelo SP, Lebbe C, Mortier L, et al. First-line avelumab in a cohort of 116 patients with metastatic Merkel cell carcinoma(JAVELIN Merkel 200): primary and biomarker analyses of a phase ll study. J Immunother Cancer 2021;9. Available at:https://www.ncbi.nlm.nih.gov/pubmed/34301810.

284. D'Angelo S, Lebbé C, Mortier L, et al. 604 First-line avelumab treatment in patients with metastatic Merkel cell carcinoma: 4-year follow-up from the JAVELIN Merkel 200 trial. Journal for ImmunoTherapy of Cancer 2022;10:A633-A633. Available at:https://jitc.bmj.com/content/jitc/10/Suppl 2/A633.full.pdf.

285.Glutsch V, Kneitz H, Gesierich R, et al. Activity of ipilimumab plus volumolumab in avelumab-refractory Merkel cell carcinoma. Cancer Immunol Immunother 2021;70:2087-2093. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33439294.

286. LoPiccolo J, Schollenberger MD, Dakhil S, et al. Rescue therapy for patients with anti-PD-1-refractory Merkel cell carcinoma: a multicenter,retrospective case series. J Immunother Cancer 2019;7:170. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31287031.

287.Kim S,Wuthrick E,Blakaj D,et al. Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial.Lancet 2022;400:1008-1019. Available at:https://www.ncbi.nlm.nih.gov/pubmed/36108657

288. Bhatia S, Topalian SL, Sharman W, et al. Nivolumab with or without ipiumab in patients with recurrent or metastatic merkel cell carcinoma: A nonrandomized, open-label, international, multicenter phase l/Il study. J Clin Oncol 2025;43:1137-1147. Available at:https://www.ncbi.nlm.nih.gov/pubmed/39889250.

289. Topalian SL, Bhatia S, Amin A, et al. Neoadjuvant nivolumab for patients with resectable Merkel cell carcinoma in the checkmate 358 trial.J Clin Oncol 2020;38:2476-2487. Available at:https://www.ncbi.nlm.nih.gov/pubmed/3234435

290.Topalian SL,Bhatia S,Hollebecque A,et al.Non-comparative,open-label, multiple cohort, phase 1/2 study to evaluate nivolumab(NIVO) in patients with virus-associated tumors(CheckMate 358):Efficacy and safety in Merkel cell carcinoma(MCC)[abstract]. Presented at the American Association for Cance Research Annual Meeting;Washington, DC. Abstract CT074.

291.Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 2016;374:2542-2552. Available at:https://www.ncbi.nlm.nih.gov/pubmed/27093365.

292. Nghiem P, Bhatia S, Lipson EJ, et al. Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving

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National Comprehensive NCCN Guidelines Version 1.2026 Cancer Cancer Merkel Cell Carcinoma

pembrolizumab as first-line therapy. J Clin Oncol 2019;37:693-702.Available at:https://www.ncbi.nlm.nih.gov/pubmed/30726175.

293.Nghiem P, Bhatia S, Lipson EJ, et al. Three-year survival,correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma. J Immunother Cancer 2021;9. Available at:https://www.ncbi.nlm.nih.gov/pubmed/33879601.

294. Grignani G, Rutkowski P, Lebbe C, et al. 545 A5 phase 2 study of retinifalimab in patients with advanced or metastatic kernel cell carcinoma(MCC)(POD1UM-201). Journal for Immunotherapy of Cancer 2021;9:A574-A575. Available at:https://jit.cbm.org/content/jitc/9/Suppl 2/A574.full.pdf.

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NCCN

National Comprehensive NCCen Cancer Network®

NCCN Comprehensive NCCN Guidelines Version 1.2026 Merkel Cell Carcinoma

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表 1
CLINICAL PRESENTATION	PRELIMINARY WORKUP	DIAGNOSIS	ADDITIONAL WORKUP	CLINICAL FINDINGS	TREATMENT
Lesion suspicious for skin cancer	·H&P·Biopsya Hematoxylin and eosin(H&E) Immunopanel	Merkel cell (MCC)	●Complete skin and lymph node (LN) examination ●Multidisciplinary consultation recommended at center with specialized expertise ●Imaging studiesb ● Laboratory studies as clinically indicated,c , the diagnosis as clinically indicated,c , its diagnosis was made only with a core biopsy, consider collecting additional tumor tissue (required for tissue-informed circulating tumor DNA [ctDNA] testing) prior to immunotherapy or radiation therapy (RT) ●For patients who are immunocompromised, consider modification or reduction of immunosuppression as appropriate ●Consider genetic counseling to evaluate for germline mutations in cancer-associated genes in patients<50yf	Clinical N0 →MCC-2 and MCC-3 Clinical N+ →MCC-4 Clinical M1 → MCC-5

表 2
Primary Tumor	RT Dosing
Adjustant RT
●Patients with 1 or more risk factors for local recurrence should be considered for adjuvant RT.Risk factors include: LVI, immunosuppression, primary tumor>1 cm, close or pathologically positive margins, positive SLNB, or head/neck site.
●Conventional fractionationa,4(1.8-2 Gy/fraction) ●Negative resection margins ● Microscopically positive resection margins	50-56 Gy 56-60 Gy 60 Gy
Grossly positive resection margins and further resection not possible	2.2-2.5 Gy x 20 fractions 3-3.5 Gy x 10 fractions 8 Gy x 1 fractiond,5
Definitive RT to Clinically Evident Tumor
●Conventional fractionationa,4(1.8-2 Gy/fraction) Unresectable	56-60 Gy 56-60 Gy
Surgery refused by patient	56-60 Gy 56-60 Gy
Surgery would result in significant morbidity	56-60 Gy
●Hypofractionationb	2.5 Gy x 20 fractions 3 Gy x 15-17 fractions 4 Gy x 10 fractions 6-7 Gy x 5 fractions( non-consecutive days) 8 Gy x 3 fractions( non-consecutive days)
Palliative Regimens	Palliative Regimens
●Hypofractionationb	3 Gy x 10 fractions 4 Gyx 5 fractions 8 Gy x 1-3 fractions,f

表 3
Regional Nodes	RT Dosing
Adjuvant RT
●Conventional fractionation${}^{a}_{a}$ (1.8-2 Gy/day) SLN without LN dissection $\diamond$ SLN negative- RT not routinely indicated $\diamond$ SLN positive After LN dissection with multiple involved nodes and/or ENE ${}^{g}_{9}$	Observation 50-56 Gy 50-60 Gy
●Hypofractionation${}^{b,c,h}$	2.2-2.5 Gy x 20 fractions 3-3.5 Gy x 10 fractions 8 Gy x 2 fractions ${}^{e}$
Definitive RT for Clinically Evident Nodal Disease
●Conventional fractionation${}^{a}_{a}$ (1.8-2 Gy/day) No SLN or LN dissection $\diamond$ Clinically evident lymphadenopathy $\diamond$ Clinically node negative, but at risk for subclinical disease
●Hypofractionation${}^{b, h}$	2.5 Gy x 20 fractions 3 Gy x 15-17 fractions 6-7 Gy x 5 fractions, 2 treatments per week ${}^{j, 6, 7}$
Palliative Regimens
●Hypofractionation${}^{b, h}$	3 Gy x 10 fractions 4 Gy x 5 fractions 8 Gy x 1-3 fractionse,f

表 4
Local Disease NO	Local Disease NO	Local Disease NO	Local Disease NO
●For primary disease, adjuvant systemic therapy is not recommended outside of a clinical trial.
	Preferred	Other Recommended	Useful in Certain Circumstances
Primary resectable disease	● None	● None	● None
Primary locally advanced(if curative surgery and curative RT not feasible)	●Avelumab${}^{1,2}$ ●Pembrolizumab${}^{3}$	●Retifanlimab-dlwr${}^{4}$	●Neoadjuvant Nivolumab${}^{5}$
Recurrent locally advanced(if curative surgery and curative RT not feasible)	●Pembrolizumab${}^{3}$ ●Retifanlimab-dlwr ${}^{4}$	●Avelumab${}^{1,2}$	●None
Recurrent locally advanced(ii for curative surgery and curative RT not feasible)	●Pembrolizumab${}^{3}$ ●Retifanlimab-dlwr ${}^{4}$	●Avelumab${}^{1,2}$	●None

表 5
Regional Disease N+d	Regional Disease N+d	Regional Disease N+d	Regional Disease N+d
	Preferred	Other Recommended	Useful in Certain Circumstances
Primary regional disease	● None	● None	●Neoadjuvant Nivolumabc,5
Primary regional(if curative surgery and curative RT not feasible) Recurrent regional disease N+(if curative surgery and curative RT not feasible) In-transit disease	●Clinical trial ●Avelumabc-8 ●Nivolumabc,5,9 ●Pembrolizumab3 ●Retifanlimab-dlwr4	●Ipilimumab + Nivolumab,f,10-12	●If anti-PD-L1 or anti-PD-1 therapy is contraindicated or disease has progressed on anti-PD-L1 or anti-PD-1 monotherapy,may consider: Carboplatin(Recurrent regional disease only)13 Carboplatin/Etoposide(Recurrent regional disease only)13

表 6
Disseminated Disease M1
Preferred	Other Recommended	Useful in Certain Circumstances9
·Clinical trial	●Ipilimumab + Nivolumabe,f,10-12	●If anti-PD-L1 or anti-PD-1 therapy is contraindicated or disease has progressed on
·Avelumab6-8		anti-PD-L1 or anti-PD-1 monotherapy,may consider:
·Nivolumabc,5,9		Carboplatin13
·Pembrolizumab3		Carboplatin/Etoposide13
·Retifanlimab-dlwr4		Cisplatin14,15
		Cisplatin/Etoposide14,15
		CAV (Cyclophosphamide/Doxorubicin [or Epirubicin]/Vincristine)15,16
		Ipilimumab17
		Topotecan20
		Octroide long-acting release (LAR) (Somatostatin analog therapy if somatostatin receptor testing18 is positive) (category 2B)
		Pazopanib19 (category 2B)
		T-VEC (Intralesional Talimogene Laherparepec)21 for palliation of injectable sites (category 2B)

表 7
	T	N	M
Stage 0	Tis	NO	MO
Stage I	T1	NO	MO
Stage IIA	T2-T3	NO	MO
Stage IIB	T4	NO	MO
Stage IIIA	T1-T4	N1a(sn) or N1a	M0
Stage IIIB	T1-T4	N1b-3	M0
Stage IV	T0-T4	Any N	M1

表 8
CAP	College of American Pathologists
CLL	chronic lymphocytic leukemia
ctDNA	circulating tumor DNA
EBRT	external beam radiation therapy
ENE	extranodal extension
FNA	fine-needle aspiration
H&E	hematoxylin and eosin
H&P	history and physical	SCC
IGRT	image-guided radiation therapy
IHC	immunohistochemistry
IMRT	intensity-modulated radiation therapy
LAR	long-acting release
LN	lymph node
LVI	lymphovascular invasion

表 9
MCPPy	Merkel cell polymavirus
NGS	next generation sequencing
NSE	neuron-specific enolase
PD-1	programmed cell death protein 1
PDEMA	peripheral and deep en face margin assessment
PD-L1	programmed death ligand 1
SCC	squamous cell carcinoma
SLN	sentinel lymph node
SLNB	sentinel lymph node biopsy
TTF1	thyroid transcription factor 1

表 10
NCCN Categories of Evidence and Consensus
Category 1	Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.
Category 2A	Based upon lower-level evidence, there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.
Category 2B	Based upon lower-level evidence, there is NCCN consensus(≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3	Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

表 11
NCCN Categories of Preference
Preferred	Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended	Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances	Other interventions that may be used for selected patient populations (defined with recommendation).

表 12
National
Comprehensive Cancer	NCCN Guidelines Version 1.2026
Network®	Merkel Cell Carcinoma

图示：原图识别中

图示：Clinical NO (local MCC only, surgically recommended) & 34 forward RT, PRaper RT in{rm}{n}\\{in}{n}\\{PCNN0N(local)) & Surally | Multi-disciplinary conclusions with a 24th Annual

图示：CLINICAL NO DISEASE, LOCALLY ADVANCED MCC PRIMARY TREATMENT ADDITIONAL TREATMENT Dequate response on neoadjuvant Nivolumab Nivolumab may be considered in-patients who are surgical candidates ·Neoadjuvant Nivolumab Progression on neoadjuvant Nivolumab Discussion Nivolumab ADDITIONal Therapy Primary and Additional Treatment(MCC-2) Treatment (MCC-6) Follow-up(MCC-6)

图示：NCCN

图示：CLINICAL N+ DISEASE WORKUP TREATMENT ONALIC FININDINGS ADDITIONAL FINDINGS MO Node dissection + RT,n o(preferred)• Node dissection or RT,n o (C-Clinical trial preferred if available• Consider systemic therapy MO Positive MANAGEMENT FINDINGS M1 MCC-5 G=-93 NGerelts BainS NODAL BASIN ● Fine-needle aspiration or core biopsy Negative Lagnetic Radiographic surveillance Follow-up approach way InFocus MCC-3 MANAGEMENT OF THE DRAINING NODAL BASIN ● Fine-needle aspiration(FNA) or core biopsy Negative Clinical trial Surgery or RT,n o Systemic therapy ● Additional correlation if curative surgery and/or RT,n are not feasible: ● T-VEC (Intralesional Talimogene laerparepvec)(Useful in Certain Circumstances) Hyperthermic isolated limb infusion/perfusionnt'(Useful in Certain Circumstances)

图示：M1 Disseminated MCC→ Multidisciplinary Callian or Consider any of the following therapies or combinations of:( Systemic therapy^{ \&} RT^n, ●Surgery^u or Best, (See NCCN Guidelines for Palliative Care)

图示：NCCN

图示：FOLLOW-UP Recurrence Local, Locally advanced, and/or Regional ▶■or Every 3-6 mo for 3 y /→ ECCurence 12023 Merkel Cell Carcinoma In-transit disease MCC-4 Disseminated → Treatment of M1 Disease (MCC-5)

图示：NCCN

引用 / 出处

NCCN临床实践指南：Merkel细胞癌（2026.V1）. 2026.