A Spontaneous Regression of an Isolated Lymph Node Metastasis from a Primary Unknown Merkel Cell Carcinoma in a Patient with an Idiopathic Hyper-Eosinophilic Syndrome

Background

Merkel cell carcinoma (MCC) is a rare, aggressive primary cutaneous neuroendocrine tumor typically occurring on the head and neck of the elderly and generally presenting a poor prognosis [1–3]. Merkel cell polyomavirus (MCPyV) has been identified in up to 80% of cases suggesting its potential role in MCC tumorigenesis [4]. Despite its aggressiveness, a few reports of MCC complete spontaneous regression have been described in the literature, most of them following incisional biopsy, thus supporting the hypothetical role of surgery-induced inflammation in the regression process [5–24].

We report a rare case of an isolated, inguinal lymph node metastasis from a primary unknown MCC, spontaneously regressing after an ultrasound-guided core needle biopsy with a relapse in a nearby lymph node 5 months later, in a patient presenting with synchronous, idiopathic hyper-eosinophilic syndrome.

Case Report

We report on the case of a 69-year-old Caucasian male who was a smoker and who was regularly followed for an idiopathic hyper-eosinophilic syndrome. The patient had ischemic cardiovascular disease, mellitus diabetes, arterial hypertension, and dyslipidemia as relevant comorbidities. The patient’s history was uneventful, and he was asymptomatic. Clinical examination found a hard, irregular, left, inguinal lymph node of 1.5×1.5 cm of diameter.

The positron emission tomography (PET) scan confirmed the presence of an isolated, hyper-metabolic, inguinal adenopathy of 1.9 cm (Figure 1). The patient was referred for a percutaneous ultrasound-guided core biopsy, which revealed a metastasis of a poorly differentiated neuroendocrine carcinoma. The immunohistochemical staining of the biopsy showed that tumor cells were negative for cytokeratin 7 (CK-7), p40, thyroid transcription factor 1 (TTF-1), prostate-specific antigen (PSA), chromogranin-A, weakly positive for cytokeratin 20 (CK-20), moderately positive for synaptophysin, and strongly positive for CD56. The Ki-67 was elevated at 95%. Biochemical tests were in the normal range, but chromogranin-A was persistently elevated at 1400 ng/mL (normal value <101.9 ng/mL). Abdominal and pelvic ultrasound showed a polypoid tumor lesion of the left bladder wall of 2.1×1.5×2.0 cm. Cystoscopy found a low-grade, papillary, noninfiltrating urothelial carcinoma that was completely resected (pTa). Colonoscopy revealed 4 tubular adenomas with a low-grade dysplasia, which were radically resected.

In March 2017, an excisional, inguinal lymph node biopsy was programmed but clinical examination showed a complete regression of the lesion, confirmed by a PET scan revealing a residual, not hyper-metabolic adenopathy (Figure 2), histologically corresponding to a lymph node with a central sclero-hyalinosis and a normal cortex in the absence of any tumor infiltration (Figure 3). Five months later, another left, inguinal lymph node was clinically documented and confirmed by a PET scan, showing a hyper-metabolic adenopathy of 1.2 cm (Figure 4). The patient underwent another excisional biopsy. Histology revealed a massive infiltration of poorly differentiated, small, neuroendocrine tumor cells with a scant cytoplasm and prominent mitotic figures (Figure 5). Immunohistochemistry showed that tumor cells were positive for CD56 (Figure 6), synaptophysin, and cytokeratin AE1/AE3, and negative for CK-7, CK-20, chromogranin-A, and CM2B4 (anti-polyomavirus), according with the diagnosis of MCC metastasis.

As the patient refused the radical lymph node dissection, a regional radiotherapy was performed (50 Gy/25 fractions).

Ten months later, the patient was in good clinical conditions and free of tumor recurrence. The hyper-eosinophilic syndrome was stable; however, the serum levels of chromogranin-A were inexplicably elevated in the absence of any tumor evidence at the PET scan.

Discussion

First described by Toker in 1972 as “trabecular carcinoma” of the skin [1], MCC is an aggressive neuroendocrine skin tumor most commonly appearing on sun-exposed areas, particularly in the head and neck region [1–3].

MCC presents a poor prognosis, with a 5-year overall survival of 60% [3]. At diagnosis, the involvement of regional lymph nodes is reported in 10–45% of the cases and is strongly related to the prognosis [3]. Distant metastases have been described in 50% of patients, the common sites being lymph nodes, liver, bone, brain, lung, and skin [3]. The incidence of MCC has tripled over the last 15 years [3].

A new human polyomavirus (Merkel cell polyomavirus: MCPyV) was detected in 2008 in 80% of MCC tumors and subsequently confirmed by many studies [4]. Its role in MCC prognosis is still controversial and not well established [4].

The risk for MCC is highly increased in patients with chronic T-cell dysfunctions such as solid organ transplantation, HIV infection, and chronic lymphocytic leukemia [1–3].

Despite its aggressiveness, several reports have documented MCC complete spontaneous regression in the absence of any specific treatment [5–24].

First described by O’Rouke and Bell in 1986 [5], MCC complete spontaneous regression accounts for approximately 1.4% of all reported cases (15 out of 1100) as compared to all other cancers, which present an incidence rate of 1 out of 60 000 to 100 000 [5–24].

Interestingly, MCC complete spontaneous regression typically has rapid onset (1 to 5 months) and is persistent, with a few reported cases of recurrence; it occurs more frequent in women, and is usually associated with better disease-specific survival [5–24].

The complete spontaneous regression pathogenesis remains unclear. It has been suggested that T-cell-mediated immunity could play an important role in complete spontaneous regression pathogenesis. Several histopathologic studies showed accumulation of chronic inflammatory cells, mainly T-cells and foamy macrophages, after tumor biopsy. Furthermore, T-cell-related cytokines, such as interferons, can promote effective immune responses against neuroendocrine tumors [24–28]. Several reports suggest a potential role for diagnostic biopsy that could stimulate a T-cell mediated immune response, but data concerning the prognostic value of intra-tumoral and/or peri-tumoral CD8+ lymphocyte infiltration are still controversial [24–28].

Conclusions

In our case, the patient presented with a spontaneous regression of an isolated inguinal lymph node metastasis from an unknown primary MCC after a percutaneous, ultrasound-guided core needle biopsy, with a relapse in a nearby lymph node 5 months later.

The particularity of this case relies on the rarity of the MCC complete spontaneous regression in a patient without a primary tumor, which probably spontaneously regressed, and who had a synchronous idiopathic hyper-eosinophilic syndrome.