Primary cutaneous phalangeal neuroendocrine/squamous cell carcinoma with mixed axillary metastasis

Abstract

Cutaneous neuroendocrine tumours are rare and aggressive tumours associated with advanced age and immunosuppression. They are typically characterised by a high rate of local recurrence and nodal disease. The presence of a mixed squamous cell component is rare. These tumours are uncommonly found on the hand. We present a case and histological images of a 78-year-old woman with a primary CK20 negative TTF-1 positive cutaneous neuroendocrine tumour with squamous dedifferentiation arising from the fifth digit with axillary metastasis showing a mixed phenotype. Initial biopsy of the lesion was positive for chromogranin, synaptophysin and TTF-1, but negative for CK20, Melan-A and S100. After CT of the thorax abdomen and pelvis and octreotide single positron emission CT demonstrated a 15 mm axillary metastasis and no evidence of distal disease, our patient underwent an amputation of the affected digit and an axillary lymph node dissection. She is currently awaiting adjuvant chemoradiotherapy. Only two cases are reported in the literature to have mixed squamous/neuroendocrine features. We present the first case which is CK20 negative and TTF-1 positive.

Background

Skin carcinoma is the most common form of malignancy in the over 65 population. Most skin malignancies are squamous cell carcinoma (SCC), basal cell carcinoma or melanoma.¹ SCCs are more common on the digits. Less commonly seen are cutaneous metastatic tumours and primary cutaneous neuroendocrine tumours. Metastases are most commonly found in the ipsilateral nodal basin.

Case presentation

Our 78-year-old woman patient was referred for a biopsy of a painless, slowly enlarging, exophytic lesion on her left fifth finger. Her medical and surgical history were notable for mild cognitive impairment and peripheral vascular disease with associated recurrent lower limb ulceration. Physical examination of the lesion revealed an ulcerated, painless 3 cm lesion traversing the proximal interphalangeal joint, limiting flexion, concerning for a malignancy. A palpable lymph node in the left axilla was noted. Incisional biopsy of the lesion was performed.

Investigations

Initial biopsy of the lesion demonstrated dermal infiltration by large hyperchromatic cells and prominent nucleoli. Immunohistochemical staining was positive for chromogranin, synaptophysin and AE 1/3 and was focally positive for TTF-1. CK20, melan-A and S100 were negative. These results were concerning for a high grade neuroendocrine carcinoma. Radiological investigation was performed.

CT of the thorax abdomen and pelvis showed a 11 mm hyperenhancing left axillary node which was suspicious for metastatic disease. She underwent a whole body octreotide single positron emission CT and bone scan which showed somatostatin-receptor positivity in the soft tissue of the affected finger, and in a 15 mm axillary lymph node (figure 1) with no other evidence of distant disease. Her case was then reviewed at the multidisciplinary meeting.

Figure 1.

Preoperative staging octreotide single positron emission CT showing 15 mm nodal mass in left axilla.

Differential diagnosis

Initial differential diagnoses were of typical soft tissue malignancies such as an SCC, amelonotic melanoma or a sarcomatous tumour. Other causes of phalangeal swelling include infection, trauma and inflammation/arthritis. Of the differentials, only infection and malignancy are associated with axillary adenopathy. The patient’s normal white cell count, lack of systemic symptoms and denial of a history of trauma to the area made malignancy more likely than infection.

After initial biopsy was concerning for a neuroendocrine tumour, the differential was revised. The main differential diagnosis for this type of tumour is a Merkel cell carcinoma (MCC). MCCs are rare primary cutaneous tumours of the skin thought to originate from the mechanoreceptors in skin. They are typically aggressive tumours which are associated with a high rate of local recurrence and lymph node involvement at diagnosis.² MCCs are typically positive for CK20 (93%–95%) and negative for TTF-1 (98.9%).^{3 4} Our patient’s sample was positive for chromogranin, synpatophysin and TTF-1, however, negative for CK20 which is not typical for MCCs. After discussion at the neuroendocrine tumour multidisciplinary team (MDT), it was the consensus that diagnosis was a combined squamous/neuroendocrine tumour.

Treatment

Our patient underwent an amputation of the affected digit and an axillary dissection to excise the involved lymph nodes (figure 2). Postoperative pathological examination confirmed a mixed squamous cell and neuroendocrine carcinoma in the finger which was 32 mm in maximal dimension (figures 3 and 4A–D). While there was lymphovascular invasion, there was no clear evidence of bone or tendon involvement.

Figure 2.

Postamputation gross specimen showing the exophytic lesion.

Figure 3.

H&E slide of the primary tumour showing a keratin pearl of squamous cell carcinoma surrounded by the neuroendocrine component.

Figure 4.

Four immunohistochemistry stains from primary tumour demonstrating the mixed phenotype. (A) p63 for the squamous component, (B–D) chromogranin, synaptophysin and CD56 for neuroendocrine component.

Two of ten lymph nodes examined in the axillary clearance were positive for metastatic disease. One node was 32 mm in dimension with entire replacement of the node with metastatic disease. This node had both neuroendocrine and SCC metastatic components (figure 5). The second node was positive for metastatic neuroendocrine carcinoma only.

Figure 5.

H&E slide of the larger lymph node showing the presence of both the neuroendocrine component and (left) and squamous component (right).

The primary tumour was composed of large nests and sheets of hyperchromatic cells with stippled chromatin and a high nuclear:cytoplasm ratio and small foci of keratinisation.

Immunohistochemical staining showed strong and diffuse expression of CD56, chromogranin, synpatophysin and p63, with patchy TTF-1 and CK5/6 positivity. CK20 and CK7 were negative. Final pathological staging was pT2 pN1b pM0, due to rarity of similar tumours, it was staged as an MCC.⁵

Outcome and follow-up

Our patient was discharged back to her long term care facility day one postoperatively, and reviewed in the outpatient’s clinic 2 weeks later. The histological slides were sent for external review which agreed with the internal MDT. Our patient was referred to medical and radiation oncology for consideration of chemoradiotherapy.

Discussion

Few case reports of mixed squamous cell/neuroendocrine carcinoma are found in the literature. Controversy exists as to whether these lesions are due to neuroendocrine dedifferentiation or collision of two separate tumours.^6–8 Only two published cases of mixed axillary metastatic disease in patients with combined SCC/neuroendocrine tumours are found in the published literature.^{8 9} Both of these tumours were positive for CK20, TTF-1 negative and in patients with renal transplants. The first was on the pinna of the ear in a 51-year-old man with a renal transplant and multiple non-melanoma skin cancers. The second was found on the forearm of a 49-year-old man with a history of renal transplant. Our case is unique in that the lesion was negative for CK20 and positive for TTF-1. Additionally, our patient was not immunocompromised at presentation. Owing to the rarity of our patient’s tumour extensive MDT discussion was warranted. The consensus was to treat this as MCC.

MCC was first described as a trabecular carcinoma after a case series of five poorly differentiated carcinomas of the dermis and subcutaneous tissues, and was ascribed the name Merkel cell due to the presence of hard dense granules which are typical of the mechanoreceptor.^{10 11} Merkel cells are mechanoreceptor–neurotactile cells located in the stratum basale of the epidermis. They are commonly found in hairless skin and are involved in light touch recognition and discrimination of texture. Approximately 40% are found on the extremeties.¹² In case studies of finger Merkel cell tumours, the vast majority are found on the dorsum of the finger and proximally. Examples include: the dorsum of the proximal phalynx in an 87-year-old Caucasian man, a 78-year-old Caucasian man, a 22-year-old Caucasian woman and an 87-year-old Asian woman.^12–15 It is an uncommon neuroendocrine tumour which has been increasing in incidence. It is associated with a high rate of local recurrence and lymph node involvement at diagnosis.² A summary of comparative immunohistochemical feature is listed in table 1.^{3 4 16}

Table 1.

A comparison of the typical immunohistochemical features of Merkel cell carcinoma and of our patient^{2 3 13}

Marker	Typical MCC	Our patient
CD56	Positive (100%)	Positive
Chromogranin	Positive (73%–87%)	Positive
CK7	Negative (73%)	Negative
CK20	Positive (93%–95%)	Negative
Synaptophysin	Positive (84%–97%)	Positive
TTF-1	Negative (98.9%)	Positive

Alternatively, cutaneous SCC arises following the malignant transformation of keratinocytes in the epidermis. Although it may be found on the dorsum of the hand when located in an extremity, it is most commonly found distal to the distal interphalangeal joint near the nail bed.¹⁷

Learning points

• Primary cutaneous neuroendocrine tumours are rare but have high metastatic potential.

• The presence of any concerning cutaneous lesion warrants an examination of the relevant nodal basins. This is evident in our case of a rare finger malignancy which had metastasised to the axilla.

• The immunohistochemical pattern of this lesion is a rare finding. Unlike the other two cases in the literature, our case is unique in that the lesion was negative for CK20 and positive for TTF-1.

• We propose that adjuvant management of such lesions should follow guidelines for Merkel cell carcinoma, the most similar histologically.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).