Background Merkel cell carcinoma (MCC) is an aggressive, high-grade, cutaneous neuroendocrine tumour (NET). Agents blocking programmed death 1/programmed death ligand 1 have efficacy in metastaticMCC(mMCC), but half of patients do not derive durable benefit. Somatostatin analogues (SSAs) are commonly used to treat low- and moderate-gradeNETs that express somatostatin receptors (SSTRs). Objectives To assessSSTRexpression and the efficacy ofSSAs inmMCC, a high-gradeNET. MethodsIn this retrospective study of 40 patients withmMCC,SSTRexpression was assessed radiologically by somatostatin receptor scintigraphy (SRS;n= 39) and/or immunohistochemically when feasible (n= 9). Nineteen patients (18 hadSRSuptake inMCCtumours) were treated withSSA. Disease control was defined as progression-free survival (PFS) of >= 120 days after initiation ofSSA. Results Thirty-three of 39 patients (85%) had some degree (low 52%, moderate 23%, high 10%) ofSRSuptake. Of 19 patients treated withSSA, seven had a response-evaluable target lesion; three of these seven patients (43%) experienced disease control, with a medianPFSof 237 days (range 152-358). Twelve of 19 patients did not have a response-evaluable lesion due to antecedent radiation; five of these 12 (42%) experienced disease control (medianPFSof 429 days, range 143-1757). The degree ofSSTRexpression (determined bySRSand/or immunohistochemistry) did not correlate significantly with the efficacy endpoints. Conclusions In contrast to other high-gradeNETs,mMCCtumours appear frequently to expressSSTRs.SSAs can lead to clinically meaningful disease control with minimal side-effects. Targeting ofSSTRs usingSSAor other novel approaches should be explored further formMCC.

Merkel cell carcinoma (MCC) is a rare and often aggressive skin cancer. The head and neck (HN) is a common location for MCC, and approximately 50% of patients present with stage I disease. Typically, surgery is the primary treatment. Postoperative radiation therapy (PORT) is often recommended to improve local control, as wide margins are generally not achievable in the HN region and MCC is a radioresponsive disease. It is unclear whether PORT may be safely omitted in selected low-risk stage IA cases. From our clinical observations, we hypothesized that PORT would reduce the risk of local recurrence (LR) in HNMCC, even in patients with low-risk characteristics. We conducted a retrospective analysis of 46 low-risk HNMCC cases treated with primary resection, identified from our repository of 1171 patients enrolled between 2006 and 2015. Inclusion criteria were (1) primary tumor ≤2 cm in maximum dimension, (2) negative margins on final pathology, (3) negative sentinel lymph node biopsy, and (4) no immunosuppression. We used the Kaplan-Meier method to estimate LR and overall survival (OS). Local recurrence was defined as tumor recurrence within 2 cm of the primary surgical bed. The cumulative incidence of disease-specific death (DSD) was estimated using death from non-MCC causes as a competing risk. The Fisher exact test was used for group comparisons. Low-risk HNMCC patients were treated with and without PORT (n=23, for both groups). No patients received adjuvant chemotherapy. There were no significant differences between the 2 groups in terms of sex, race, age at diagnosis, tumor size, depth of invasion, lymphovascular space invasion, and width of surgical margins. The median follow-up time was 3.55 years for the surgery alone group and 5.34 years for the surgery + PORT group. There was a significant difference in LR between the groups treated with and without PORT (P=.02). Among the 23 patients treated with surgery alone, 6 (26%) recurred locally. The median time to local recurrence was 11 months. Five of the LRs occurred in patients with primary tumors ≤5 mm in diameter, and the sixth was in an 8-mm tumor. Out of the 23 patients treated with both surgery and PORT, no patients recurred locally. The median RT dose was 50 Gy (range, 16-66 Gy). In general, the surgical bed with a minimum margin of 3 to 5 cm was irradiated with electrons/photons. Significant late toxicity (>grade 2 by Common Terminology Criteria for Adverse Events version 4) was not reported in patients who received PORT. There were 2 regional relapses in the surgery only group, and 1 in the surgery + PORT group. There was no difference in OS or DSD. Zero events in 1 group precluded multivariate analysis. PORT was associated with a significantly lower risk of local recurrence in patients with stage IA MCC of the head and neck.

The standard of care for Merkel cell carcinoma (MCC) typically involves both surgery and post-operative radiation therapy (PORT), as recommended by NCCN guidelines. A few series have demonstrated excellent results with surgery alone for well selected stage I tumors. However, it is unclear whether PORT may be safely omitted in all cases of favorable Stage IA MCC. Between 1983 and 2015, 783 patients with localized MCC were prospectively enrolled in an IRB-approved database. Since 2007, 25 patients with favorable stage IA MCC at low risk for local recurrence were observed after excision and did not receive PORT. The 5 features used to identify low risk cases were: primary tumor ≤2cm, clear pathologic margins, a negative sentinel node biopsy, no lymphovascular space invasion, and no systemic immune suppression. A retrospective study was performed to analyze local recurrence, overall survival (OS) and MCC specific survival (MCCSS) for these cases of MCC treated without PORT, and compared with 37 historical controls who met the favorable criteria and had received PORT. PORT fields typically encompassed the surgical resection bed with a 3-5 cm margin. Median PORT dose was 50 Gy in 25 fractions. Patients in both groups did not receive chemotherapy. Fisher's exact test was performed to detect differences in local recurrence rates. Cox proportional hazards model and competing risks regression model were used to calculate differences in OS and MCCSS. Both groups were comparable in demographics, tumor size and pathological margin width. 15 of the cases that did not receive PORT and 8 of the PORT controls had a primary tumor in the head and neck region. The remaining patients had tumors located on the trunk or extremities. At a median follow-up of 3.6 years, overall local control rate for all patients was 92%, OS was 80% and MCCSS was 85.5%. Compared to those who received PORT, there was a significantly higher local recurrence rate among those who did not receive PORT (LR: 20% vs. 0%, p=0.008, Fisher's exact). All 5 local recurrences arose in those who did not receive PORT, within the surgical bed that would have been included in a standard PORT field. Further, all local recurrences were in the head and neck region and in tumors ≤5 mm. Risk of local recurrence was significantly greater for primaries in the head and neck compared with primaries in all other sites (p = 0.005, Fisher's Exact). The OS (p=0.8) and MCCSS (p=0.5) were similar in both groups. Carefully selected patients with stage IA MCC in non-head and neck locations treated without PORT have an extremely low risk of relapse and excellent survival. MCCs arising within the head and neck region have a significantly higher risk of local failure and PORT is recommended.

Le carcinome de Merkel est un cancer cutané rare mais aggressif, avec une mortalité de 46 %. Alors que l'exérèse chirurgicale fait partie de la prise en charge initiale standard, l'intérêt de la radiothérapie post-opératoire n'est pas clairement établi pour le contrôle local de la maladie. Une étude rétrospective de 1254 patients a révélé que 39 % des patients traités par chirurgie seule ont récidivé localement, par rapport à seulement 12 % des patients traités par chirurgie et radiothérapie. En revanche, dans une autre cohorte de 243 patients traités par chirurgie seule, seulement 3,8 % ont récidivé localement. Afin d'établir une meilleure qualité de soins pour les patients à faible risque, nous avons tenté de résoudre cette divergence de la literature. Au sein d'une cohorte de 1057 patients porteurs d'un CM entre 2004 et 2014, nous avons mené une étude rétrospective pour identifier les patients « à faible risque » réunissant les 5 critères d'inclusion suivants : – tumeur primitive ≤ 2 cm de diamètre ; – marges d'exérèse microscopiquement négatives ; – absence d'invasion angiolymphatique dans la tumeur primitive ; – absence de immunodépression chronique ; – absence de métastase ganglionnaire dans le ganglion sentinelle. Ils ont été suivis longitudinalement pour capturer l'existence ou non d'une radiothérapie post-opératoire et d'une récidive locale et la survie. Quarante-neuf patients répondaient aux 5 critères de risque faible et avaient des données de suivi adéquates. Vingt et un ont été traités par chirurgie seule, 28 ont reçu une radiothérapie adjuvante post-opératoire au site de la tumeur primitive. Les 2 groupes étaient comparables en termes d'âge médian au diagnostic et de sexe. Quatre patients ont récidivé localement (19 %) parmi ceux traités par chirurgie en monothérapie, tandis qu'il n'y eut aucune récidive chez les patients traités par chirurgie et radiothérapie adjuvante. La survie spécifique de la maladie était similaire dans les 2 groupes. Le caractère rétrospectif de l'étude et le large interval de recrutement des patients doivent nous rendre prudents quant à l'interprétation d'une relation de cause à effet. Néanmoins, nos résultats semblent indiquer qu'il existe un risque non négligeable de récidive locale du CM en cas d'exérèse chirurgicale seule même chez les patients à faible risque initial. Bien que ce risque puisse être acceptable pour certains patients, l'ajout une radiothérapie adjuvante peut réduire le risque de récidive locale. En revanche, elle ne semble pas influencer le développement de métastases à distances et le risque de décès lié a la maladie. Il est donc légitime de discuter au cas par cas de la relation bénéfice-risque de la radiothérapie locale chez les patients porteurs d'un CM. Même les patients ayant un CM à faible risque présentent une chance non-négligeable de récidive locale en cas de monothérapie chirurgicale.

Le carcinome neuroendocrine primitif cutané ou carcinome de Merkel (CM), est un cancer cutané rare mais agressif, avec une mortalité de 46 %. Il n'existe pas de marqueurs biologiques pour le suivi des patients. 80 % des CM présentent l'intégration clonale du polyomavirus des cellules de Merkel (MCPyV) et l'expression de l'oncoprotéine virale T (T-Ag). Une étude préliminaire a montré que les anticorps (Ac) contre T-Ag étaient corrélés à la masse tumorale. Nous avons cherché à savoir si leur présence avait une valeur pronostique et s'ils avaient un intérêt dans le dépistage des récidives de CM. Entre janvier 2008 et octobre 2013, nous avons prélevé 462 patients. Pour chaque patient, un suivi longitudinal recueillait l'existence ou non de récidive du CM et la survie. Les patients séropositifs pour T-Ag à la première analyse avaient des prélèvements successifs dans le temps à l'occasion de leur suivi. Mille trente échantillons de sérum ont été analysés. Le suivi moyen par patient était de 2,3 ans. Pour les 217 patients prélevés moins de 3 mois après le diagnostic, la survie médiane globale était de 608 jours et la survie médiane sans récidive de 495 jours. Cinquante-deux pour cent étaient séropositifs pour T-Ag. La présence d'Ac T-Ag était significativement plus rare chez les patients âgés ou immunodéprimés. La survie spécifique et la survie sans récidive étaient significativement plus élevées chez les patients séropositifs pour T-Ag en analyse multivariée, indépendamment de l'âge, du sexe, du stade de la maladie et du statut immunitaire. Chez les 131 patients séropositifs pour T-Ag ayant des prélèvements multiples, l'augmentation du taux d'Ac contre T-Ag était étroitement corrélée à l'existence d'une récidive clinique ou radiologique, avec une sensibilité de 82 % et une spécificité de 98 %. La présence d'Ac contre T-Ag apparaît comme un nouveau facteur pronostique indépendant dans le CM. Un traitement plus agressif et/ou un suivi plus rapproché pourraient être préconisés chez les patients séronégatifs pour T-Ag. Nos résultats confirment que le taux d'Ac contre T-Ag est étroitement corrélé à la masse tumorale. Chez ces patients, le suivi longitudinal de la sérologie dans le temps permet de détecter les métastases de CM, diminuant la fréquence des examens d'imagerie (plus coûteux et risqués). Ceci offre l'espoir d'améliorer, par une détection et un traitement précoces, le pronostic très sombre des patients métastatiques. La présence d'Ac contre T-Ag est un facteur de bon pronostic chez les patients ayant un CM. Chez les patients qui produisent ces Ac, leur dosage représente un outil précieux pour la détection précoce de métastases.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuro endocrine cancer with approximately 50% mortality. In our clinical practice, we perceive a relatively high incidence of non regional/distant nodal metastases (NRNM) i.e. metastases in lymph nodes away from the nodal drainage area of the primary tumor and not included in a traditional radiation therapy (RT) field and/or surgical nodal dissection field. This particular metastatic pattern of recurrence for MCC has not been described in the literature and is a necessary step to identify suitable surveillance strategies. In addition, due to the radiosensitivity of MCC, high risk cases could be potentially considered for a prophylactic regional treatment with RT. The purpose of this study is to describe the incidence of NRNM. From our Prospective IRB approved database, we identified 103 index cases of MCC with distant metastases (DM) that were seen at the UW clinical services. Cases were eligible if they either presented with DM and/or developed DM during the course of their disease. Unique patient, treatment and tumor factors were recorded. A total of 103 patients were seen between 2006 and 2013. Three did not have adequate follow-up information. There were 83 males and 20 females. The median age of presentation with DM is 64 yrs. Overall, 13 patients had immune suppression. Forty-nine percent of patients had NRNM in combination with other types of DM, including metastases to visceral organs, bone, skin etc. Of these, 50% were isolated NRNM i.e. without any other types of DM. 70% of the isolated NRNM were limited to infra diaphragmatic locations, mostly in the para and peri aortic nodal locations, irrespective of the site of origin of the primary disease. There was only 1 case of an isolated NRNM that was limited to a supra diaphragmatic location. The majority (20/27 cases) of isolated NRNM were node positive at presentation. Only 3 patients had immune suppression among the isolated NRNMs. The median survival of patients with isolated NRNMs is 365 days versus 302 days for other types of DM. In this large series of MCC patients, we present a common but previously unappreciated pattern of failure in the non-regional lymph nodes. Almost half the number of patients with DM have NRNM and the majority of isolated NRNMs are infra diaphragmatic in location. Identification of patient and tumor specific factors to detect those at highest risk for this pattern of failure, as well as specific prophylactic treatment options and surveillance strategies and are being actively explored by our group.