Article Text
PDF
Abstract
A man presents a 4 mm skin tumour at his general practitioner. The tumour is removed on the suspicion of a dermatofibroma. Important differential diagnoses are sebaceous neoplasms, melanomas, Merkel cell carcinomas and large cell neuroendocrine carcinoma, and metastases of neuroendocrine neoplasms from the gut or lung. Immunohistochemical staining excluded sebaceous neoplasm, melanoma and Merkel cell carcinoma, however, was positive for multiple neuroendocrine markers. Relevant scans showed no signs of a primary tumour anywhere else. The final diagnosis was a primary low-grade neuroendocrine carcinoma of the skin. At 30 months follow-up, there was no sign of recurrence.
- Dermatology
- Neuroendocrinology
- Pathology
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
Background
Neuroendocrine neoplasms (NENs) are most frequently discovered in the gastrointestinal and bronchopulmonary tract, while other primary anatomical locations are uncommon. Low-grade, well-differentiated NENs are associated with a good prognosis. They are diagnosed by their histological appearance, potential hormone production and characteristic immunohistochemical staining patterns, in which they are often positive for chromogranin, synaptophysin and neuron-specific enolase.1 A primary location in the skin is often associated with high-grade NEN or Merkel cell carcinoma (MCC) but can also be a metastasis from a non-cutaneous high-grade visceral NEN.2
To our knowledge, only 17 cases of primary low-grade NENs of the skin have previously been described. These are referred to as low-grade neuroendocrine carcinomas of the skin (LGNECS), usually presenting as asymptomatic cutaneous nodules on the head or trunk of elderly patients.2 LGNECS tumours are histologically similar to its counterparts arising in other anatomical regions.
Case presentation
A man in his late 30s presented to his general practitioner with a small skin tumour of 4 mm underneath his left nipple that caused pain when he was wearing clothes. The tumour had been present for 5–6 years. The patient had an excellent performance status and no comorbidities. The general practitioner suspected a dermatofibroma and removed the skin tumour.
Investigations
On the H&E-stained slides, a 4 mm tumour was found in the dermis. The tumour had a solid pattern in the centre and a more organoid pattern without any necrosis or mucin in the border of the tumour, deeper in the dermis (figure 1A).
Histopathological features on H&E-stained slides. (A) The tumour was 4 mm with a solid pattern in the centre and more organoid pattern without necrosis in the border of the tumour (×2). (B, C) The tumour cells were uniform with oval to round nuclei with dispersed chromatin, inconspicuous nucleoli and eosinophilic and fine granular cytoplasm (×10) (×40).
The tumour cells were fairly uniform with oval to round nuclei with dispersed chromatin, inconspicuous nucleoli and eosinophilic and fine granular cytoplasm (figure 1B). The mitotic counts were 8 per 2 mm2.
The immunohistochemical staining was positive in the peripheral part of the tumour for synaptophysin, CD56, S-100 and SOX-10, special AT-rich sequence-binding protein 2 (SATB2), ISLET-1 and dot-like positive stain for pan cytokeratin (AE1/AE3). The centre of the tumour stained negative for synaptophysin but was partly positive for CD56, S-100 and SOX-10. Staining was negative for cytokeratin 7 (CK7), cytokeratin 20 (CK20), thyroid transcription factor-1 (TTF-1), melanoma antigen (Melan A), chromogranin A, CDX-2, serotonin, melanoma-specific antigen (MSA), microphthalmia transcription factor (MITF), CD45, CD3 and CD20. Furthermore, there was negative staining for Merkel Cell Polyomavirus (MCPyV). The KI-67 index varied but was up to 10% (figure 2).
Immunohistochemical staining revealed expression of (A) ISLET-1 and dot-like positive stain for pan cytokeratin (AE1/3) (×20) and (B) synaptophysin (×2) in the peripheral part of the tumour, (C) CD56 in the centre of the tumour and (D) SOX-10 (×2) and (E) S-100 (×2) in the peripheral part as well as the centre of the tumour. The Ki-67 index (×20) varied between the border (F) and the centre (G) of the tumour but was up to 10%.
After removal of the tumour, a whole-body fluorodeoxyglucose positron emission tomography (FDG-PET) scan was negative, while a Gallium-PET scan highlighted two cutaneous lesions above the umbilicus, equivalent to the position of two birthmarks. A secondary surgical removal was performed with 1 cm excision distance from the previous location of the primary tumour as well as removal of the two birthmarks. The birthmarks were not malignant.
Outcome and follow-up
The patient’s health was unaffected by the diagnosis. He has been followed every 6 months with CT/MRI scans for 30 months now, and there is no sign of recurrence or of any other primary neuroendocrine tumour (NET).
Discussion
The first LGNECS was reported in 1975 by Dijk and Ten Seldam and was defined as a primary cutaneous carcinoid at the time.3 Since then, 17 cases have been reported.4–16 In recent literature, these tumours have been designated as LGNECS but have been reported under a range of other names including primary cutaneous carcinoid. It is a rare lesion, and there are several differential diagnoses including sebaceous neoplasms, melanoma, MCC and large cell NEC (non-Merkel cell type), and metastases of NET or NEC origin that is, from the gut or lung.
In this report, the clinical and histopathological presentation suggest a primary low-grade NET of the skin, which is indistinguishable from well-differentiated NETs in other organs. The cells display low-grade atypia and low mitotic activity. The positive stain for neuroendocrine markers rules out sebaceous neoplasms. Likewise, the negative stain for Melan A, MITF and MSA combined with the positive stain for neuroendocrine markers rules out malignant melanoma.17 MCC and non-Merkel cell type both present with rapid growth, a high mitotic rate and high KI-67 index. MCC is positive for CK20, whereas non-MCC type is positive for CK7. This tumour was negative for both markers. Likewise, we found negative staining for MCPyV, which is positive in up to 80% of MCC.18 Furthermore, we found negative stain for TTF-1, CDX-2 and serotonin. We found no basis for CD56-positive lymphoma due to negative CD45, CD20 and dot-like positive stain for pan cytokeratin.
The stains for neuroendocrine cells, CD56 and Synaptophysin (figure 2B,C) were performed twice due to lack of staining central in the tumour; however, these did not differ from the first stain. This variable staining has not been reported in previous literature. We did, however, consider these staining positive and tried to exclude the most obvious differential diagnosis.
Normally, neuroendocrine metastatic tumours of the skin are poorly differentiated carcinomas with gut or lung origin.19 It can be challenging to distinguish primary neuroendocrine skin tumours from metastatic visceral NETs of the skin. Cutaneous metastases can be the first signs of a disseminated visceral tumour.20 However, we found no evidence of other lesions on the FDG-PET scan or Gallium-PET scan except from the two cutaneous lesions, equivalent to the position of two birthmarks. After 30 months of follow-up, there were no signs of visceral disease or another primary tumour.
The previous reports of LGNECS have demonstrated slow-growing, non-aggressive tumours with low metastatic potential. The average age at diagnosis was 68 years, and our patient is, hence, the youngest patient reported. Two of the 17 previous patients had lymph node metastases,9 15 while 2 had distant metastases.14 16 MacKenzie et al9 reported postsurgical recurrences of the disease 4 and 6 years after discovery, while Celasco et al13 reported a case of local recurrence in the same site 7 years after primary surgery. Overall, no deaths due to LGNECS have been reported.
We present the 18th case of LGNECS since 1975 in the youngest patient reported to this date. The tumour was histopathologically indistinguishable from visceral well-differentiated NET. We follow the patient with CT/MRI scans every 6 months, and 30 months after resection of the primary tumour no underlying visceral tumour has been found.
Learning points
Low-grade neuroendocrine carcinomas of the skin (LGNECS) are rare primary skin tumours.
LGNECS stains positive for CD56 and Synaptophysin.
A somatostatin receptor positron emission tomography/CT should always be performed for both staging and diagnosis.
The prognosis is excellent when the primary tumour is surgically removed.
Important differential diagnosis is sebaceous neoplasms, melanomas, Merkel cell carcinomas and large cell neuroendocrine carcinoma (non-Merkel cell type), and metastases of neuroendocrine neoplasms from, that is, the gut or lung.
Ethics statements
Patient consent for publication
References
Footnotes
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: SK, GD, MBN and LSK. The following authors gave final approval of the manuscript: SK, GD, MBN and LSK.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests GD received teaching activities for Ipsen, advanced Pharma and Sam Nordic.
Provenance and peer review Not commissioned; externally peer reviewed.