Melanoma of Unknown Primary Origin: A Case Report and Literature Review.

Diffuse liver infiltration by melanoma of unknown primary origin is rare. We encountered a unique case of diffuse liver infiltration by melanoma of unknown primary origin in our hospital. A 62-year-old woman was referred to our hospital for anorexia of 6 months duration and abdominal distension for 1 month. Ultrasonography (US), computerized tomography (CT) and magnetic resonance imaging (MRI) revealed an obvious enlarged liver without detectable nodules. She was diagnosed as liver metastasis by melanoma of unknown primary origin via percutaneous liver biopsy. The report demonstrates the difficulty of making a noninvasive diagnosis of diffuse hepatic infiltration on metastatic melanoma.

The distribution and incidence of melanoma vary among different races and ethnic groups. This study aimed to investigate the characteristics of cutaneous melanoma, mucosal melanoma, uveal melanoma, and melanoma of unknown primary (MUP) origin in a Japanese population. We studied these four types of melanoma in patients registered in Hospital Based Cancer Registries in Japan from 2011 to 2013. A total of 5566 patients with melanoma were identified. The distribution of sex, age, primary site, and clinical stage was analyzed. The number of patients, proportion in comparison with all melanoma cases, and crude incidence rate per 100 000 person-year of each melanoma type were 4481, 80.5%, and 1.24 in invasive cutaneous; 821, 14.8%, and 0.32 in mucosal; 163, 2.9%, and 0.064 in uveal; and 101, 1.8%, and 0.039 in MUP origin, respectively. Including the patients with in-situ cutaneous melanoma and stage unknown cutaneous melanoma, the crude incidence rate of cutaneous melanoma increased at 1.75. Almost half of the cutaneous melanomas were located in the lower limb. Cutaneous melanoma was the most common, but less frequent than that in western countries. Mucosal melanoma was quite rare, but its proportion and crude incidence rate were higher than those in western countries. Uveal melanoma was particularly rare, and its crude incidence rate was lower than that in western countries. MUP origin was also particularly rare, but it had almost the same incidence rate as that in other countries. Melanoma in Japan was heterogeneous among the four melanoma types and shares some attributes with that in western countries.

Metastatic melanoma of unknown primary origin accounts for approximately 2-6% of all melanoma cases. The prognostic significance of this diagnosis is still controversial. Of 3258 patients with malignant melanoma recorded during the period 1976-1996, 2.3% had metastases of unknown primary origin. Anatomic distribution, clinical stage, and survival probabilities were evaluated. Thirty patients were classified as having cutaneous or subcutaneous in-transit metastases, and they showed a 5-year survival rate of 83%. Thirty-seven patients were classified as having lymph node metastasis, and their 5-year survival rate was 50%. Disseminated disease was diagnosed in only 8 patients, who had a median survival of 6 months. Comparison of survival probabilities for patients with in-transit metastases and unknown primary tumors with the probabilities for those with cutaneous primary tumors revealed a significant advantage for the former group. No significant differences were found for patients with lymph node metastasis when those with unknown primary tumors were compared with those who had cutaneous melanomas with regional lymph node metastasis. The clinical disease course of patients with metastatic melanoma of unknown primary origin is similar to that of patients with primary cutaneous melanoma when the same clinical stages of the disease are compared. Based on the assumption that the majority of regional metastases develop from completely regressed primary cutaneous melanoma, recommendations for initial staging examinations in patients with unknown primary tumors are given in this article.

Although more than 90% of melanomas have a cutaneous origin, melanomas sometimes present metastatically with no apparent primary lesion. Metastatic melanoma of unknown primary origin (MUP) is estimated to comprise 2–6% of all melanoma cases. A 62-year old female visited the Dermatology Department with spreading black pigmentation on her left 1st thumbnail and brown macules on the periungal skin that began 2 years earlier. She was diagnosed with malignant melanoma, acral lentiginous type, by biopsy and underwent left thumb amputation. Interestingly, she underwent a left-side modified radical mastectomy in 2003 because of a 4-cm palpable mass in the left axilla. She was diagnosed with metastatic malignant melanoma in a left axillary lymph node and underwent a full work-up to identify the primary site of the melanoma. No primary site was found and she was diagnosed with MUP at that time. We concluded that the melanoma of the left thumb was the primary site and the metastatic melanoma in the axilla was a metastasis from the left thumb melanoma because the metastatic lymph node and involved thumb were both on the left side of the body, and the sequential relationship and histologic findings of the axillary lymph node and left thumb were consistent. There are several hypotheses supporting the pathogenesis of the appearance of the primary lesion after detecting a metastatic site. According to one hypothesis, the primary site may either have a slow growth rate or it may involute; therefore, the primary site rarely becomes manifest during the clinical course of the disease. Although it was impossible to confirm that the melanoma of the left thumb was the primary site, we consider this case interesting for understanding the pathogenesis of MUP and for reminding physicians to conduct careful periodical work-ups of melanoma patients, especially those with MUP.

BackgroundMelanoma is usually discovered from an irregular skin patch or a modification of a preexisting patch. Cutaneous and lymph node metastases are common. Muscle metastases are rare. We report a case of melanoma with infiltration of the gluteus maximus, which had normal dermatological examination.Case presentationA 43-year-old Malagasy man with no history of skin surgery was admitted with progressively worsening dyspnea. On admission, he presented with superior vena cava syndrome, painless cervical lymphadenopathy, and a painful swelling in the right buttock. Skin and mucous membrane examination did not reveal any abnormal or suspicious lesions. The biology was limited to a C-reactive protein of 40 mg/L, a white blood cell count of 23 G/L, and a lactate dehydrogenase level of 1705 U/L. The computed tomography scan showed several lymphadenopathies, compression of the superior vena cava, and a tissue mass at the expense of the gluteus maximus. Cervical lymph node biopsy and cytopuncture of the gluteus maximus were consistent with a secondary melanoma location. A stage IV melanoma of unknown primary origin, and with stage TxN3M1c associated with lymph node metastases and extension to the right gluteus maximus, was suggested.ConclusionsMelanoma of unknown primary origin accounts for 3% of diagnosed melanomas. Diagnosis is difficult in the absence of a skin lesion. Patients are diagnosed with multiple metastases. Muscle involvement is unusual and may suggest a benign pathology. In this context, biopsy remains essential for diagnosis.

Melanoma of unknown primary origin: A population-based study in the Netherlands

We herein describe the case of a 77-year-old Japanese man who presented with progressive thrombocytopenia. No lymphadenopathies, bone lesions, hepatosplenomegaly or masses within any internal organs were detectable. Bone marrow smears revealed diffuse infiltration of large atypical cells morphologically resembling mature lymphoid neoplasms. A flow cytometric analysis showed that the tumor cells strongly expressed CD56 without myeloid or lymphoid antigens, suggesting that they were non-hematologic in origin. Ultimately, amelanotic malignant melanoma of unknown primary origin was diagnosed based on positive immunostaining for S100 proteins, HMB-45 and Melan-A. This case illustrates the usefulness of flow cytometric analyses for making such diagnoses. We also review the available literature on similar cases.

(1) Background: The purpose of this retrospective study was to evaluate the recurrence and survival rates of metastatic melanoma of unknown primary origin (MUP), in order to further refine current recommendations for the surgical treatment; (2) Methods: Medical data of all MUP patients registered between 2000 and 2011, were analyzed. Seventy-eight patients were categorized in either lymph node (axilla, groin, head-and neck) or subcutaneous MUP. Axillary node MUPs were generally treated with dissections of levels I-III, inguinal node MUPs with combined superficial and deep groin dissections, and head-and-neck node MUPs with neck dissections to various extents, based on lymph drainage patterns. Subcutaneous lesions were excised with 1–2 cm margins. The primary outcome was treatment outcomes in terms of (loco)regional recurrence and survival rates; (3) Results: Lymph node MUP recurred regionally in 11% of patients, with an overall recurrence rate of 45%. In contrast, subcutaneous MUP recurred locally in 65% of patients with an overall recurrence rate of 78%. This latter group had a significantly shorter disease-free interval than patients with lymph node MUP (p = 0.000). In the entire study population, 5-year and 10-year overall survival rates were 56% and 47% respectively, with no differences observed between the various subgroups; (4) Conclusion: The relatively low regional recurrence rate after regional lymph node dissection (11%) supports its current status as standard surgical treatment for lymph node MUP. Subcutaneous MUP, on the contrary, appears to recur both locally (65%) and overall (78%) at a significantly higher rate, suggesting a different biological behavior. However, wide local excision remains the best available option for this specific group.

BackgroundMalignant melanoma metastasis to the breast is a rare disease.Case presentationWe present the case of a 58-year-old postmenopausal Caucasian woman with metastatic malignant melanoma of unknown origin of the right breast. She presented with a palpable lump in the inferior quadrant of her right breast. The investigations concluded it was breast metastasis from a malignant melanoma of unknown origin. The treatment consisted of mastectomy and axillary lymph node dissection. Two lymph nodes were positive for tumor cells and one showed extracapsular extension. Our patient did not receive immediate adjuvant therapy. Six weeks after the surgery, our patient presented a relapse in the right axilla (a 6 × 4 cm mass) with positive internal mammary lymph nodes and a single brain metastasis. This relapse motivated an adjuvant treatment with partial regression of the disease. Currently, our patient presents multiple metastases with poor prognosis.ConclusionsFrom this experience, we advocate an immediate aggressive handling of melanoma metastasis to the breast.

The aim of this study was to evaluate and compare the diagnostic accuracy of B-mode, Doppler ultrasonography and Acoustic Radiation Force Impulse (ARFI) elastography in the identification of axillary and inguinal lymph nodes metastasis in bitches with mammary neoplasms. The axillary (n = 96) and inguinal (n = 100) lymph nodes of 100 bitches were evaluated using B-Mode, Colour Doppler and ARFI-elastography. After this evaluation, mastectomy and lymph nodes excision were performed and these structures were histologically classified as free, reactive or metastatic. Ultrasonographic parameters were compared by Chi-Square or ANOVA tests and if they are significant, discriminative power analysis according to histopathological classification was performed (ROC analysis). The ARFI-elastography shear wave velocity (SWV) enabled metastasis identification in inguinal (sensitivity 95% specificity 87%) and axillary lymph nodes (sensitivity 100% specificity 94%). While B-Mode ultrasound Short/Long axis ratio evaluation of inguinal and axillary lymph nodes only resulted in a sensitivity around of 71% and specificity of 55%. In conclusion, B-Mode ultrasonography may contribute to diagnosis of metastasis in axillary and inguinal lymph nodes of bitches affected by mammary neoplasm with limited accuracy, while SWV evaluation proved to be an excellent diagnosis tool, which allows differentiation between free, reactive and tumour metastatic lymph nodes.

BACKGROUNDMelanoma is uncommonly found in lymph nodes, subcutaneous tissue, or visceral organs without a primary lesion, where it is identified as metastatic melanoma with unknown primary (MUP). Hepatic MUP is extremely rare and has a poor prognosis. There is limited information on its pathogenesis, clinical and imaging features, and pathological findings. There are no guidelines for the use of immune checkpoint inhibitors (ICIs) in hepatic MUP, and the treatment outcome has rarely been reported.CASE SUMMARYA 42-year-old woman presented to our hospital with hepatic tumors found incidentally during a routine check-up. Contrast-enhanced abdominal com-puterized tomography showed multiple mass lesions in the liver. Pathological results revealed melanoma, which was confirmed by immunohistochemical staining for HMB-45(+), Melan-A(+), S-100(+), and SOX10(+). There was no evidence of primary cutaneous, ocular, gastrointestinal, or anal lesion on a comprehensive examination. The patient was diagnosed with hepatic MUP. She received combined antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, ipilimumab) and programmed death protein-1 (PD-1, nivolumab). She died of hepatic failure 9 mo after hepatic MUP was diagnosed. This the first case of hepatic MUP treated with combined ipilimumab and nivolumab, who showed better outcome than previous cases.CONCLUSIONCombined ICIs of PD-1 and CTLA-4 may be considered as the first-line therapy for patients with hepatic MUP.

Ipilimumab, an anti-CTLA-4 monoclonal antibody, is used in the treatment of metastatic melanoma. As with other immune checkpoint inhibitors, it can cause a spectrum of immune-related adverse events (irAEs), including a cutaneous pathology, in 25% of patients. To date, there have been five case reports of Sweet syndrome solely due to ipilimumab therapy. We present a suspected further case in a patient with metastatic melanoma of unknown primary origin, who concurrently developed vitiligo. A 65-year-old man presented to the dermatology department with a 2-week history of a mildly tender, erythematous papulonodular rash localized to the right forearm. He had also developed extensive vitiligo on all limbs over a similar period of time. Histology from a skin punch biopsy demonstrated a predominantly neutrophilic dermal inflammatory infiltrate without features of vasculitis, confirming Sweet syndrome. There were no recent medication changes or disease recurrence on repeat imaging. Nine months prior, the patient had been diagnosed with cerebral and pulmonary metastatic melanoma of unknown primary origin (BRAF V600 mutation positive). He underwent an evacuation of a left temporal cortical mass and subsequent stereotactic radiosurgery. The oncology team then commenced ipilimumab (3 mg kg–1) and nivolumab (1 mg kg–1) every 21 days. Four cycles were completed until discontinuation after 3 months due to multiple severe irAEs, namely, panhypopituitarism and liver toxicity. He was commenced on 80 mg (1 mg kg–1) oral prednisolone, which was slowly reduced over subsequent months and completed a few weeks prior to the development of Sweet syndrome and vitiligo. We prescribed topical clobetasol propionate 0.05% once daily, with resolution of Sweet syndrome after 2 months. The oncology team elected to withhold further immunotherapy due to the multiple irAEs, instead monitoring for melanoma recurrence by serial radiological imaging. The five previously documented cases of ipilimumab-associated Sweet syndrome report an average time to clinical presentation of 8.9 weeks. Our case differs as the patient developed Sweet syndrome 5 months after the discontinuation of immunotherapy. However, the development of any cutaneous adverse effect may have been masked by high-dose steroids for the other systemic irAEs soon after the fourth cycle of treatment. Despite a lack of temporality between immunotherapy and Sweet syndrome in our case, the addition of vitiligo at the same presentation suggests an irAE. This case highlights the importance of monitoring patients on immunotherapy for dermatological side-effects and working closely with oncology colleagues to manage these complex cases.

Melanoma is a form of skin cancer responsible for the majority of skin cancer-related deaths. Melanoma of unknown primary origin that presents as a periosteal scalp mass without overlying skin changes is rare and diagnostically challenging. Clinically, melanoma often presents as a skin lesion that is asymmetric, has irregular borders, exhibits multiple colors, is larger in size, and shows recent changes in appearance. The patient in this case is an 89-year-old male who initially presented with a subcutaneous cyst on the posterior scalp. Pathological examination of the excised mass ultimately confirmed malignant melanoma of unknown primary origin. A positron emission tomography scan performed after surgery revealed abnormal uptake in bilateral pulmonary nodules and multiple bilateral hilar lymph nodes. This case report highlights the clinical presentation, diagnostic challenges, and possible etiologies of melanoma with an unknown primary site that has metastasized to an unusual location.

A rare case of metastatic malignant melanoma of unknown primary origin to the right inguinal lymph nodes was reported. Although the melanoma was largely developed dimensioned 20×15×7cm, after extensive chemotherapy combined with radiotherapy and hyperthermia, we were able to excise the melanoma from the inguinal area. However, after 7 months it recurred. In addition 11 patients with malignant melanoma including the present case experienced by us in the Department of Dermatology, Saitama Medical Center, Saitama Medical School, between 1986 and 1991, were summarized and discussed.

The histopathology of metastatic lesions are usually the same as primary lesions in malignant tumors. We report a rare case of malignant melanoma that was mixed with a cervical lymph node metastatic lesion of undifferentiated cancer occurring in the maxillary gingiva. The patient was referred to our department because of pain in the area of the maxillary anterior teeth. After confirmation of undifferentiated cancer by biopsy, a right partial maxillectomy and extended supraomohyoid neck dissection were performed. Histopathological examination revealed that the primary lesion was undifferentiated cancer and the metastatic lesion was malignant melanoma. We suggested the possibility that a malignant melanoma of unknown primary origin and the undifferentiated cancer in the maxillary gingiva metastasized to the same cervical lymph node as a collision tumor.