Metastatic malignant melanoma in bone marrow with occult primary site – a case report with review of literature

Malignant melanoma accounts for 1–3% of all malignancies with an increasing incidence being seen worldwide [1]. Metastatic melanoma usually involves draining lymph nodes and occasionally adjacent skin first, but eventually metastasizes to distant visceral sites. The lung is most commonly involved followed by brain, liver, bone marrow, and intestine [2]. Metastases of melanoma to bone marrow are rare with widespread dissemination occurring in only 5–7% of cases [3]. In about 5–15% of cases, metastatic melanoma is detected in the absence of an identifiable primary tumor. In these cases it is generally believed that the primary tumor has regressed [4–6]. A search of the literature revealed many isolated case reports of metastatic melanoma to the bone marrow with a known primary [7]. However metastases to bone marrow with an occult primary have been reported rarely [8, 9]. Herein we report a case of malignant melanoma metastasized to bone marrow with an occult primary site, along with a relevant review of literature. The case described is unique, as it describes an unusual clinical presentation of metastases, diagnosed only after bone marrow examination.

Epithelial tumors of the thyroid, breast, lung, kidney and prostate commonly metastasize to the marrow [10]. However bone marrow infiltration of human melanoma is found in only 7% of in vivo staging procedures and in up to 45% of autopsy cases [11]. There are a number of reports of malignant melanoma showing infiltration of marrow [see Additional File 1] [3, 7–10, 12–29]. The male female ratio in reviewed cases was 1.33:1. Age ranged from 3 to 75 years (median 60; mean 51.5 years). Anemia was the most common hematologic manifestation (7 of 21 patients) followed by thrombocytopenia, pancytopenia and leukoerythroblastosis. One patient had carcinocythemia at the time of presentation. Most of the reviewed cases died due to the disseminated disease despite chemotherapy. Savage et al [3] studied 97 patients of malignant melanoma, of these, 5.4% had marrow involvement. Bone marrow involvement from retroperitoneal, anal, tonsillar, nasal, osseous and ocular melanoma has been described [18, 24, 25, 28, 29]. Interestingly, Spiller et al reported a case of giant congenital nevus with metastatic malignant melanoma in a child [27]. There was no identifiable change in the nevus to suggest the primary site for malignant transformation. The Metastatic involvement of bone marrow by melanoma with an occult primary has been reported rarely [8, 9]. In one such case, history of intense childhood exposure to ultraviolet light and an occupational exposure to organic dyes was present [9]. However we did not find past history of such exposures in the index patient. At initial presentation our patient had a two year history of weakness and right axillary swelling. The hemogram showed bicytopenia and leukoerythroblastosis. Extensive bone marrow involvement normally presents with pancytopenia but surprisingly our patient had normal white blood cell count with a left shift. Extreme leukocytosis in a case of metastatic melanoma has been reported by de Wolff et al [26]. It was attributed to either bone marrow invasion by metastases or due to production of cytokines or other mediators by tumor cells. In contrast, autoimmune neutropenia and thrombocytopenia have been reported in association with malignant melanoma as a rare paraneoplastic phenomenon [19, 30]. Interestingly Bhagwati et al [9] described microangiopathic hemolytic anemia and disseminated intravascular coagulation related to widely disseminated melanoma. The patient's lymph nodes were unremarkable on histopathology presumably due to hematogenous dissemination of the tumor. This in itself lends to a very poor prognosis [31]. Frank blood was obtained on surgical drainage of axillary swelling. Presumably, axillary hematoma might have been the site of lymph nodal metastases which was not revealed as pathologic examination was not performed on drained fluid. The simultaneous presentation of axillary node metastases and bone marrow involvement is exceptionally rare [11, 19]. The primary site might have regressed over the period of time in the index patient. Partial regression is a common feature in melanoma. Total regression is much less common, but numerous cases in which the primary tumor regressed completely after giving rise to nodal and distant metastases have been documented. In about 5–15% of the patients who present initially with metastases of melanoma, no primary tumor can be found [4–6]. Although the primary tumor may in some instances be in an internal organ, it was in most instances located in the skin and regressed spontaneously [32]. Parenthetically, the prognosis of patients with metastatic malignant melanoma and an unknown (presumably regressed) primary is the same as for the patients with an overt primary malignancy [6]. Malignant melanoma involves bone marrow with disseminated disease and is often amelanotic [20]. However while reviewing literature, we found only three cases of amelanotic melanoma [20, 21, 26]. If melanin is found in the tumor cells or macrophages as brown pigment, the diagnosis is relatively straightforward similar to the index case. On the other hand, differential diagnoses of amelanotic melanoma would be other solid tumors such as lymphomas, carcinomas and metastatic small round cell tumors. The primary site of the malignant deposits may be extremely difficult to determine on a morphological basis alone, but their origin can sometimes be inferred from their morphological appearance, especially in mucous producing carcinoma, squamous carcinoma, some adenocarcinomas, and in many cases of metastatic neuroblastoma. Melanoma should be suspected if the tumor comprises of histologically polygonal or spindle cells with prominent nucleoli. Immunohistochemical study is useful in supporting a diagnosis of malignant melanoma. Typically melanoma is reactive for vimentin, S-100 protein, HMB-45, melan -A, tyrosinase, and microphthalmia transcription factor [33]. HMB-45 is a much more specific marker than S-100 protein [34]. Our case is in fact entirely typical of malignant melanoma based on morphology and immunohistochemistry.

Despite the rarity of bone marrow involvement, clinicians must be aware of the varied clinical manifestations of disseminated malignant melanoma even if the primary site is not evident.