Merkel Cell Carcinoma Patients Presenting Without a Primary Lesion Have Elevated Markers of Immunity, Higher Tumor Mutation Burden, and Improved Survival

Abstract

Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared with similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear. Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole-exome sequence data were analyzed from 16 tumors. As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared with MCC-KP patients (HR, 0.297; < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR, 0.296; = 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP ( < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; < 0.001). In addition, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, = 0.016). This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. In addition, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival. .

S2k guidelines for Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) – update 2018

“…Häufig wird bei Patienten mit unknown primary der Tumor in den inguinalen Lymphknoten gefunden. [20][21][22][23].…”

“…In patients with unknown primary, the tumor is often detected in the inguinal lymph nodes. There is data suggesting that patients with unknown primary and stage IIIB disease seem to have a considerably better prognosis than patients with a known primary tumor at the same disease stage .…”

“…While the prognosis of patients with MCC strongly depends on the disease stage, large epidemiological studies have also shown significant regional differences. Five‐year survival rates of patients with primary tumors < 2 cm are between 66 % and 75 %; for primary tumors > 2 cm, between 50 % and 60 %; for individuals with nodal involvement, between 42 % and 52 %; and for patients with distant metastatic disease, between 17 % and 18 % .…”

S2k‐Leitlinie Merkelzellkarzinom (MZK, MCC, neuroendokrines Karzinom der Haut) – Update 2018

“…Häufig wird bei Patienten mit unknown primary der Tumor in den inguinalen Lymphknoten gefunden. Es gibt Hinweise, dass Patienten mit unknown primary im Stadium IIIB eine deutlich bessere Prognose zu haben scheinen, als Patienten mit einem bekannten Primärtumor im Stadium IIIB .…”

“…Die Prognose des MCC hängt stark vom Stadium der Erkrankung ab; allerdings zeigen größere epidemiologische Studien auch starke regionale Unterschiede. Die Fünfjahresüberlebensraten für Primärtumoren mit einem Durchmesser < 2 cm liegt zwischen 66 % und 75 %, für Primärtumoren mit einem Durchmesser > 2 cm zwischen 50 % und 60 %, für Patienten mit Lymphknotenmetastasen zwischen 42 % und 52 %, und für Patienten mit Fernmetastasen zwischen 17 % und 18 % .…”