Metastatic Malignant Melanoma With Neuroendocrine Differentiation

A Case Report and Review of the Literature

Carl Christofer Juhlin; Jan Zedenius; Felix Haglund


J Med Case Reports. 2020;14(44) 

In This Article

Case Presentation

Our patient was a 74-year-old man of Middle Eastern ethnicity with a previous medical history including hypertension, benign prostatic hyperplasia, polycythemia vera, and duodenal ulcers. He received metoprolol (100 mg daily) as well as aspirin (75 mg daily), had a history of tobacco smoking, but ceased tobacco use 15 years prior to the current admission. He did not consume alcohol. He was born in Iraq and arrived in Sweden 2002. He was previously employed as a medical secretary but he had retired at the time of admission. His previous social history is largely unknown, but he was married, and he had three children (two sons and one daughter) according to previous medical files.

In the early spring of 2019, he developed dyspnea and flank pain, and following investigations at a secondary care institution, a subsequent radiological computed tomography (CT) examination revealed at least six lesions in his liver, of which the largest deposit measured 13 mm. In addition, a 50 mm large soft tissue expansion in conjunction to his chest wall with engagement and destruction of the eighth rib was observed. In his lungs, 13 nodular lesions were detected of which the largest measured 8 mm. A bone metastasis to the right acetabular region was also visualized, in addition to a 10 mm large lesion in his left adrenal gland. The latter nodule was present already on a radiological examination performed 12 years earlier and found stationary with no increase in overall size; it was therefore believed to be benign. To summarize, the lesions observed were highly suspicious for metastatic deposits from a CUP. An ultrasonography-guided core-needle biopsy of the chest wall lesion was performed, and a diagnosis of metastatic NEC was rendered. The material was immediately sent for second opinion consultation at our tertiary unit.

The histopathological examination revealed a tumor with a predominant solid growth pattern, diffusely infiltrating the surrounding fibrotic stroma (Figure 1a). The tumor cells displayed round to slightly polygonal nuclei, focally pleomorphic, with an evenly distributed chromatin (Figure 1b). Several nuclear inclusions were observed, as were comedo-like tumor necrosis and apoptotic bodies. No prominent nucleoli or cytoplasmic pigmentation was noted. The immunohistochemical analysis was carried out in a routine pathology laboratory setting with clinically accredited antibodies and standardized methodology. The profiling was consistent with a tumor uniformly positive for SYP and CD56 (Table 1; Figure 1c, d). Unexpected and diffuse cytoplasmic immunoreactivity was noted for insulinoma-associated protein 1 (INSM1), and subsets of cells were also positive for ISL LIM homeobox 1 (ISLET1; Figure 1e, f). The tumor was negative for melanoma antigen (Melan A) and human melanoma black 45 (HMB45; Figure 1g, h) but was strongly positive for vimentin (Figure 1i). Scattered tumor cells were positive for cytokeratin OSCAR. The tumor cells were negative for: pan-cytokeratin (CK MNF 116); cytokeratins 5, 7, 19, and 20; epithelial membrane antigen (EMA); GATA binding protein 3 (GATA3); hepatocyte-specific antigen; P63; prostate-specific antigen (PSA); thyroid transcription factor 1 (TTF1); paired box 8 (PAX8); caudal type homeobox 2 (CDX2); carcinoembryonic antigen (CEA); CgA; secretagogin; steroidogenic factor 1 (SF1); inhibin alpha; glucagon-like peptide 1 (GLP1); and pancreatic and duodenal homeobox 1 (PDX1) (data not shown). The Ki-67 index was 50%. The P53 immunoreactivity was focal and weak, not suspicious for an underlying TP53 gene alteration. The pathology report concluded the presence of a metastatic, high-grade malignant tumor with a neuroendocrine profile and unknown primary location; the absent CgA immunoreactivity could argue in favor of a NEC because this tumor entity occasionally downregulates CgA expression upon tumoral de-differentiation. The keratin-negative profile did, however, also raise the suspicion of a non-NET with a neuroendocrine differentiation, but the paraffin block was exhausted after cutting material for immunohistochemistry; therefore, no additional analyses could be performed.

Figure 1.

Microscopic findings of the initial core-needle biopsy from the 50 mm soft tissue expansion adjacent to the chest wall. This lesion was initially believed to constitute a metastatic neuroendocrine carcinoma. All microscopic images are magnified × 200 unless otherwise stated. a. Routine hematoxylin and eosin staining depicting a tumor with a predominant solid growth pattern infiltrating the surrounding stroma. b. Routine hematoxylin and eosin section at × 600 magnification, illustrating nuclear pleomorphism. c. Widespread cytoplasmic synaptophysin immunoreactivity. d. Uniform CD56 immunoreactivity. e. Diffuse cytoplasmic insulinoma-associated protein 1 staining. f. Focal ISL LIM homeobox 1 nuclear staining (subsets of tumor cells). g. Negative staining for melanoma antigen. h. Negative staining for human melanoma black 45. i. Diffuse positivity for vimentin

Our patient was discussed at a multidisciplinary conference and was recommended to commence chemotherapy (carboplatin and etoposide). On admission to our hospital, he was confined to a wheelchair and in considerable pain from his groin and lumbar regions. His groin was investigated, and a 20 mm enlarged lymph node was palpable and was assumed to be part of his disseminated disease. He had substantial bilateral pitting edema over his lower extremities but was without dyspnea. He had no fever or symptoms indicating an infection. No neurological examination was performed. His blood pressure was measured several times during the hospitalization, but was 123/89 mm Hg shortly after admission, with a pulse rate of 113 and a saturation of 93% without oxygen supply. His hemoglobin count was 170 gram/L (reference, 134–170), his erythrocyte count was 5.5 (× 1012/L) (reference, 4.2–5.7), his leukocyte count was 8.0 (× 109/L) (reference, 3.5–8.8), and his thrombocyte count was 117 (× 109/L) (reference, 145–348). Liver parameters were mostly normal (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, and bilirubin), except for hypoalbuminemia (24 g/L, reference, 34–45). His renal function was not impaired, as made evident by a normal plasma creatinine and a calculated glomerular filtration rate (GFR) of 75 mL/minute (reference, > 60 mL/minute). Following the first round of chemotherapy, he developed partly therapy-resistant back pain, and was planned for external radiation directed at his pelvis and lower back for palliative purposes. Besides the chemotherapy treatment, he was administered fentanyl (75 micrograms/hour, transdermal administration) for his back pain, ondansetron (4–8 mg intravenously) against chemotherapy-induced nausea, and sodium phosphate laxatives against morphine-instigated constipation. He was also administered furosemide intravenously (20–40 mg) when needed. Cortisone (betamethasone) was also administered orally using a standardized gradual reduction scheme.

Shortly afterwards, he developed a left-sided, pathological hip fracture (Figure 2a). Following surgery, the excised femoral head and neck was sent for histopathological examination. Histological evaluation of material decalcified by formic acid and microwave treatment revealed infiltration by a nest-forming tumor with large atypical nuclei displaying multiple nucleoli and a partly loose chromatin (Figure 2b, c). Nuclear inclusions were noted. The mitotic rate was 20 mitoses/10 high-power fields. Tumor necrosis was noted (Figure 2b). Immunohistochemistry revealed partial expression of SYP, Melan A, and HMB45 (Table 1; Figure 2d–f), as well as positive immunoreactivity towards SOX10 (Figure 2g). Moreover, vimentin immunoreactivity was noted, as well as absent staining of CK MNF 116, CK7, CK20, desmin, myogenin, CD10, and CgA (data not shown). The diagnosis was consistent with a metastatic epithelioid malignant melanoma with neuroendocrine differentiation.

Figure 2.

Radiological and microscopic findings of the subsequent surgical excision from a pathological hip fracture caused by a metastatic malignant melanoma with neuroendocrine differentiation. All microscopic images are magnified × 200 unless otherwise stated. a. Representative plain radiology scan displaying the pathological hip fracture from which the metastatic melanoma was diagnosed. b. Routine hematoxylin and eosin staining. Note the comedo-like necrosis in the central area. c. Routine hematoxylin and eosin at × 400 magnification, illustrating the nest-forming tumor with nuclear inclusions. d. Focal synaptophysin immunoreactivity (subsets of tumor cells). e. Focal melanoma antigen immunoreactivity (subsets of tumor cells). f. Focal human melanoma black 45 immunoreactivity (subsets of tumor cells). g. Diffuse nuclear SOX10 expression

He subsequently developed bilateral pleural effusions, and despite intermittent treatment with pleurocentesis, he developed respiratory failure, which was aggravated by the occurrence of lobar pneumonia. Given his status, no clinical investigations regarding the occurrence of an undiagnosed primary cutaneous or mucosal malignant melanoma were initiated. Ultimately, he developed septicemia and died only 3 months after initial presentation. No autopsy was performed.