Introduction

Neuroendocrine Tumors (NETs) are a heterogeneous group of neoplasms arising from the neuroendocrine system. They are composed by cells possessing both nerve and endocrine cell features. Neuroendocrine tumors may arise in the gastro-intestinal tract, ovaries, lungs and thymus. NETs may present with a wide variety of functional and non-functional endocrine syndromes, may be familial and have other associated tumors. Liver, bones and lymphnodes are common sites for metastatic disease. A rarer site of metastases of NET is the skin. We report the case of a patient with skin metastases from NET and review literature.

Case Report

We report a case of a 30-year-old white female with no co-morbidities, who arrived at our institution in January 2017, presenting abdominal pain, nausea, vomiting and diarrhea. Abdominal ultrasound showed two hepatic lesions of 10 and 4.6 cm in VI and VII hepatic segments, respectively. Abdomen CT-scan confirmed several hepatic metastases. At diagnosis, patient presented also cutaneous nodes, mainly localized on the right and left breast, on the left supraclavicular region and in paravertebral subcutaneous region. Hepatic biopsy was performed, with diagnosis of neuroendocrine tumor. On the basis of immunohistochemical stains, positive for cytokeratin AE 1/3, Synaptophysin, Chromogranin and CDX2, and negative for Cytokeratin 7 and 20, Thyroid Transcription Factor 1 (TTF-1), S100, Vimentin, Leukocyte Common Antigen (LCA), and on the basis of Ki-67 expression (45%), NET was classified as Grade 3 (G3). Primary cancer was not found. On March 2017 patient repeated a whole body CT-scan showing liver metastases, cutaneous thoracic nodes metastases, pleural node of 24 mm and supraclavicular nodes (Figure 1A and B).

A new biopsy of right cervical lymph node was performed. Diagnosis was poorly differentiated neuroendocrine carcinoma with intermediate and large cell types. Ki-67 expression was 40% and chromogranin A was > 700 ng/L (0-100). Endoscopy was negative. From March to July 2017, patient received 6 cycles of chemotherapy with cis-Platinum and Etoposide obtaining a partial response with disappearance of skin lesions. In November 2017 patient performed a whole body CT-scan showing the appearance of brain matastases, successively confirmed by NMR. Whole brain radiotherapy with conventional dose was administrated, subsequently the patient begun new chemotherapic treatment with Temozolamide and Capecitabine. In May 2018, after 3 cycles of treatment, new diffuse cutaneous nodes appeared all over the torax (Figure 1C). In June 2018 a new biopsy of skin metastases was performed and the pathology report was poorly differentiated Neuroendocrine Tumor (NEC G3), on the basis of haematoxylin/eosin and immunohistochemical stainings (Figure 2A).

Indeed, bioptic samples resulted positive for Chromogranin A and Synaptophysin, and Ki-67 was 40% (Figure 2 B-D). In order to eventually subject the patient to an immunotherapy or biological treatment, we also evaluated the mutational state of MET and genes involved in Mismatch Repair System (MLH1, MSH2, MSH6 and PMS2). No mutation was found. In July 2018 we started treatment with FOLFIRI. In October 2018 new cutaneous nodes were detected (Figure 1E). Whole body CT scan showed Stable Disease (SD) in lung lesions, while liver metastases increased in size and number (Figure 1D). Only MRI showed downsizing of brain metastases. From November 2018, FOLFOX chemotherapy was administrated without appearance of new skin lesions, on the contrary, those lesions already existing appeared reduced in size, as well as hepatic lesions (Figure 1 F and G). In January 2019 no new skin lesions were present. Additionally, a further decrease of the skin lesions was observed at subsequent checks made in April and October 2019. Currently, the patient is still subjected to FOLFOX chemotherapy, seen the good response attained, as also assessed by the cutaneous nodes reduction.

Discussion

Cutaneous metastases are uncommon in clinical practice. Melanoma, breast, stomach, lung, uterus, large intestine and kidney carcinomas are tumors that most frequently produce cutaneous metastases. The appearance of skin metastasis result in a poor prognosis, their presence is often associated with high morbidity and mortality. Some studies report cutaneous metastasis in about 9% of patients with metastatic cancer, others in 3-4% [1]. Neuroendocrine Tumors (NETs) begins in the hormone-producing cells of the neuroendocrine system that is found in organs such as lungs and gastrointestinal tract. Cutaneous metastases are more frequent in Merkel Cell Carcinoma but they are very rare for other types of NET [2]. From 1960 to today, in literature are described 41 cases of NET with skin metastasis (Table 1). 22 out of 41 patients were male and median age was 59 years (range from 19 to 82 year). 11 out of 41 patients had lung cancer; 10 out of 41 were patients with gastrointestinal carcinoma; 6 out of 41 were patients with carcinoma of unknown primary origin.

In clinical practice cutaneous metastases represent a sign of poor prognosis, but they can be useful to observe the therapeutic efficacy of a treatment. In our case report patient skin lesions resulted reduced as soon as the therapy showed beneficial effects; whereas, when skin lesions increased in number and size we could hypothesize a progression of the disease, and this was confirmed by the CT-scan. Moreover, in a small number of NETs skin lesions can occur not as metastases but as form of cutaneous manifestations of paraneoplastic lesions [3]. Paraneoplastic skin syndromes in patients with NETs are even more rare than cutaneous metastases. Examples of paraneoplastic skin manifestations in patients with NETs are necrolytic migratory erythema, dermatomyositis, granulomatous eruption, nodular panniculitis [4-7].

Conclusion

Despite more frequent and advanced imaging and endoscopic evaluations, NETs are still a difficult diagnosis to make given the wide range of its clinical presentation. Cutaneous metastases occur rarely and are usually associated with high morbidity and mortality. Importantly, the detection of skin lesions can be correlated with the progression of the disease and with the efficacy of the treatment. Therefore, cutaneous lesions and their localization represent optimal targets to monitor the benefit of a treatment.

Figure 1: CT scan analysis, liver and cutaneous metastases are shown (red arrows) at diagnoses (A-B), during second line chemotherapy (C), during third line chemotherapy (D-E), during the last chemotherapy treatment (F-G).

Figure 2: (A) Hematoxylin and Eosin staining showing neuroendocrine carcinoma with trabecular and organoid pattern composed of cell of uniform size with round and oval nuclei, incospicuous nucleoli, pyknotic nuclei and mitosis (magnification 20x). (B) Immunostaining showing diffuse and strong Chromogranin A expression (magnification 20x). (C) Immunostaining showing diffuse and strong Synaptophysin expression (magnification 20x). (D) Immunostaining showing a high Ki-67 expression that reflects high proliferative cell activity (magnification 20x).

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