Small Cell Variant of Metastatic Melanoma: A Mimicker of Lymphoblastic Leukemia/Lymphoma

Making the diagnosis of malignant melanoma can be difficult due to histological diversity. Adding to the diagnostic challenge, melanoma frequently presents as a noncutaneous or metastatic disease without an apparent primary site [1, 2]. Often, the patient might have the history of malignant melanoma, but that information is not provided to the pathologist who is making the diagnosis. Furthermore, melanomas can exhibit immunophenotypic aberrations, such as epithelial and neuroendocrine markers, which may create further diagnostic challenge [3]. We have studied a case of a rare variant of metastatic melanoma in a 64-year-old male who presented with a large lung mass and a right-sided pleural effusion. The clinical, histologic, and immunohistochemical features of this tumor are presented with a discussion of the differential diagnosis.

A 64-year-old man presented with shortness of breath, weakness, and tiredness. During patient’s workup, he was found to have a lung mass and right pleural effusion. A video-assisted thoracoscopic surgery (VATS) for pleural decortication was done. No history of melanoma or other malignancy was reported to us. The pleural biopsy was fixed in neutral buffered formalin and embedded in paraffin for histologic processing. Tissue sections were stained with hematoxylin and eosin for conventional histology. Immunohistochemical studies were also performed. Microscopic examination of the biopsy revealed sheets of small round blue cells infiltrating into the adipose tissue in a lace-like pattern, whereby they grew along the fibrous septa of the adipose tissue entrapping normal fat in a honeycomb fashion (Fig. 1a, b). On higher magnification, the tumor showed small, monotonous cells that resemble a small round blue cell tumor or a lymphoma. The cells were characterized by round to oval nuclei, inconspicuous nucleoli, and scant amount of eosinophilic cytoplasm (Fig. 1c). Mitotic figures and apoptotic bodies were seen throughout the excisional biopsy (Fig. 1d). Melanin pigment was not observed.

Immunohistochemical stains for melanocytic markers, including S-100 protein, Mart-1, and HMB-45, highlighted the neoplastic cells (Fig. 2a, b). An interesting finding was strong CD56 membranous positivity, while other neuroendocrine markers, including synaptophysin, chromogranin, and neuron-specific enolase (NSE) were negative (Fig. 2c). This tumor was also positive for CD117 immunostain. The neoplastic cells were negative for CD45, CD34, pancytokeratins, TTF-1, and cytokeratin 8, WT1, and desmin. Flow cytometry was also done showing that the neoplastic cells were positive for CD56 and negative for CD45. These findings were most consistent with the diagnosis of metastatic small cell melanoma.

After making the diagnosis, the information was obtained that the patient had melanoma in situ, lentigo maligna type, with focal regression of the forehead, 2 years prior in a shave biopsy (Fig. 3a, b). No invasion was identified, but a dermal focus of malignant melanoma (4 mm) was seen that was most consistent with a microsatellite lesion. Because of a positive margin, a wide excision was then performed with negative margins.

Melanomas are well-known for their variety of cytomorphological features, architectural patterns, and stromal changes. Signet-ring cell, small cell, metaplastic (chondroid, osteoid), myxoid, rhabdoid, and balloon cell are just some of the unusual cytomorphologic variants of melanoma [4]. They can mimic carcinoma, mesenchymal tumors, germ cell tumors, leukemia/lymphomas, plasmacytomas, and even benign stromal reactions and tumors [5]. Therefore, special studies designed to detect melanocytic differentiation are needed.

Small cell melanoma is a rare variant of malignant melanoma composed of small monomorphic cells with round to oval nuclei, inconspicuous nucleoli, and scant cytoplasm. This variant was first described by Reed et al. [6] in 1965. Their study described 12 cases of malignant melanoma with undifferentiated and lymphoblastic morphology that arose in giant congenital nevi [6]. In children, recent publications reported that small cell melanoma is most frequently encountered in the setting of a malignant melanoma that has arisen in a giant congenital nevus or as a de novo childhood neoplasm [7]. In adults, this variant has been described at both mucosal and cutaneous sites [8-10]. In addition to cutaneous and mucosal small cell melanoma, few case series have described metastatic small cell melanoma at visceral sites including the ovary and stomach [11-13].

Metastasis of cutaneous melanoma to the lung is a well-known location and constitutes approximately 5% of all secondary malignancies of the lung [14]. However, involvement of the pleura is rare, and has been associated with darkly pigmented pleural fluid due to melanin pigment [15]. Literature regarding pathological details of melanoma with pleural involvement is scarce. Epithelioid, myxoid, and amelanotic variants have been described [16-18].

To our knowledge, we are the first to describe a case of metastatic small cell melanoma in the pleura of an adult, presumably from progression to a rare leukemic melanoma. This case caused significant diagnostic difficulty as it mimicked lymphoblastic lymphoma. Lymphoblastic lymphoma is a rare disease accounting for approximately 8% of all lymphoid malignancies [19]. In tissue sections, scanning magnification would show sheets of small round blue cells that diffusely infiltrate the tissues and entrap fat without destroying it. High power would show a monotonous population of small round blue neoplastic cells with similar morphology to the cells seen in our case. The lymphoblasts are characterized by small to intermediate sized cells with round or oval nuclear shape, dispersed nuclear chromatin, inconspicuous or small nucleoli, and scanty, faintly basophilic cytoplasm [19]. Immunohistochemical stains were the tool that helped us differentiate those two entities. Lymphoblastic lymphoma would be positive for CD34 or/and CD45, while negative for melanocytic markers such as S-100, MART1, and HMB-45.

Small cell melanoma can also be confused with other small round blue cell malignant tumors such as metastatic small cell carcinoma, other lymphomas, malignant peripheral nerve sheath tumor, Ewing’s sarcoma, Merkel cell carcinoma, olfactory neuroblastoma, and germ cell tumors. Based on the location, the differential diagnosis for our case included mainly metastatic small cell pulmonary carcinoma, other lymphomas, and Ewing’s sarcoma. Achieving the correct diagnosis requires extensive analysis including the presence of unique morphologic features, various immunohistochemical stains, and medical history.

Metastatic small cell pulmonary carcinoma entered our differential diagnosis as it is composed of small round blue cells and our patient presented with a lung mass. However, most of those tumors would show mainly a diffuse growth pattern and would not infiltrate and entrap fat, as seen in our case. In addition, another hint that can help pathologists favor small cell carcinoma is a vague neuroendocrine architecture, such as rosettes, or organoid growth that can be seen in few cases. Immunohistochemistry guided us toward the correct diagnosis as the tumor was negative for cytokeratin, synaptophysin, chromogranin, and TTF-1 which are usually positive in small cell pulmonary carcinoma.

As working diagnosis in our case to rule out small cell carcinoma, immunostain for CD56 was performed and showed diffuse positive staining. CD56 is normally expressed on neurons, glial tissue, skeletal muscle, and natural killer cells [3]. It is known to be a neuroendocrine marker, but it lacks the specificity that other neuroendocrine markers (synaptophysin and chromogranin) have [3]. In our case, due to the fact that the neoplastic cells were negative for synaptophysin and chromogranin, we cannot label this melanoma to have true neuroendocrine markers. However, we would like to point out that melanoma can have an abnormal phenotype which includes the expression of antigens that are commonly seen in other lesions such as cytokeratins, desmin, epithelial membrane antigen (EMA), smooth muscle actin (SMA), and CD68 [3, 5, 20]. In addition, some melanomas do not express markers commonly associated with melanocytic phenotypes, and this is a particularly treacherous diagnostic pitfall [20].

The behavior of this rare variant of melanoma is still unknown. Some studies such as that by Barnhill et al. [21]suggested that small cell melanoma may be an independent risk factor for poor prognosis. Other studies, such as that by Kirkham [22], suggested that this variant might behave in the same manner as other types of melanomas. Unfortunately, we were not able to obtain our patient’s previous cutaneous biopsy to examine for a small cell morphology in the primary melanoma. Additional studies with long-term clinical follow-up are required in order to find out if pure small cell morphology is an independent risk factor for poor prognosis in melanoma.

In summary, our case shows again the cytomorphology and phenotypic variants of melanoma with a focus on differential diagnoses and variations of pleural metastasis. We would like to increase pathologists’ awareness of this rare entity of small cell melanoma as misdiagnosis can potentially jeopardizes the health and survival of patients, especially as it closely mimics lymphoma. We advocate that the possibility of small cell melanoma should be considered in the differential diagnosis of small round blue cell tumors. The use of a panel of melanocytic markers and careful evaluation of melanin production can help achieve the correct diagnosis.

This study was prepared in compliance with all ethical and confidentiality guidelines and principles.

The authors declare that there are no conflicts of interest regarding the publication of this paper.