The Imitation Game: Melanoma Metastasis Poses as a Primary Breast Tumor

Abstract

Metastatic melanoma to the breast is a rare phenomenon often mistaken for primary breast cancer due to overlapping clinical and imaging characteristics. We report the case of a 51-year-old woman with a history of melanoma resected 7 years earlier, presenting with severe left hip pain and a 6-month history of a right breast lump. Imaging revealed extensive metastatic disease, including lesions in the femoral head, breast, lung, adrenal gland, and thoracic spine. Pathologic examination of the hip lesion obtained during total arthroplasty, as well as biopsies of the breast and lung, confirmed metastatic melanoma. Histology revealed pleomorphic tumor cells with necrosis, while immunohistochemical analysis demonstrated SOX10 and S100 positivity, confirming the diagnosis. Genetic testing identified microsatellite stability with a tumor mutational burden of 16 mutations per mega base. This case shows the importance of thorough cancer histories and the use of immunohistochemical staining to distinguish metastatic melanoma from primary breast malignancies. Despite timely diagnosis and intervention, the patient’s condition deteriorated rapidly, reflecting the aggressive nature of metastatic melanoma. This case highlights the need for vigilance in patients with a history of melanoma presenting with new breast masses to ensure accurate diagnosis and appropriate management.

Introduction

Melanoma, a highly malignant skin tumor characterized by the abnormal proliferation of melanocytes, typically affects individuals in their sixth to seventh decade. Melanoma incidence is increasing worldwide, and up to 20% of cases eventually develop metastatic disease. ¹ The most common sites of melanoma spread include the pulmonary system, brain, hepatic tissue, and skeletal system. ²

Invasive breast cancer is the most commonly diagnosed noncutaneous malignancy among women. Metastatic involvement of the breast is rare, accounting for approximately 2% of malignant breast lesions, and typically originates from primary tumors such as malignant melanoma, carcinomas, sarcomas, and lymphomas. ³ As cutaneous melanoma becomes more frequent and its incidence continues to rise, we anticipate that this observation will become more common. Due to their rarity, however, metastatic breast lesions are frequently misdiagnosed as primary breast cancers, leading to potentially inappropriate treatment approaches, disseminated disease, and a poor prognosis. ⁴

We report a rare case of metastatic malignant melanoma to the breast, detailing its clinical presentation, histopathological and immunohistochemical characteristics, and emphasizing the importance of current diagnostic and treatment strategies in managing this unusual condition.

Case Presentation

We present the case of a 51-year-old female with past medical history of type 2 diabetes mellitus (T2DM), morbid obesity, hypertension, and melanoma status postresection 7 years ago who presented with the chief complaint of severe left hip pain. Her social history was significant for smoking 40+ years, and she denied any drug or alcohol use. She reported that her hip felt like it was “popping in and out of socket.” She was able to ambulate without assistance in the days prior to her presentation. The day of her presentation, she was sitting on the commode and her left hip pain suddenly became 10/10 in intensity. She could not rise from the commode or ambulate even with assistance. She was brought to the hospital with a suspected hip fracture/dislocation. In addition to the left hip pain, 6 months prior, she noted a hard and fixed lump in her right breast. She denied any overlying skin changes or palpable lymph nodes.

A biopsy of the left forearm at the time of her initial melanoma diagnosis revealed stage IIc melanoma, classified as pT4bN0, with an 8.4 mm thick ulcerated lesion. Sentinel lymph node biopsy was negative (0/2). The lesion was subsequently excised, and no adjuvant therapy was administered. The patient was advised to undergo follow-up skin examinations every 6 months for the first 2 years, followed by annual visits thereafter. However, she was lost to follow-up and did not seek medical care for several years. She also did not adhere to routine mammographic screening and had a history of poor compliance with medications for her T2DM.

Initial imaging of the hip showed a lytic lesion of the left greater trochanter, indicative of a pathologic fracture. MRI was obtained which confirmed a pathologic fracture of the greater trochanter (Figure 1). Orthopedic surgery was consulted for the hip fracture and completed a total left hip arthroplasty. Pathologic specimens were obtained during the procedure. A computed tomography angiography of the chest was obtained and revealed a large right lower lobe cavitary mass concerning for malignancy, other suspected metastatic lesions were noted in the left adrenal gland, mediastinal and right hilar adenopathy, and multilevel thoracic spine metastasis. Ultrasound of the breast showed a 3.8 cm × 4.3 cm × 2.9 cm lobulated, hypoechoic mass at the 12 o’clock position (Figure 2). The lesion was classified as BIRADS 5, suspicious for malignancy. Hematology oncology was consulted due to the pathologic fracture and multiple areas suspicious for metastatic disease. Initial thought process was that the patient had had a breast mass for almost 6 months and a large right lobe mass due to multiple sites of obvious metastatic cancer. However, lung cancer could not be excluded as a primary in the setting of smoking history and patient was an active smoker. Metastatic melanoma was also included in the differentials since the patient had a history of melanoma removal 7 years prior.

Figure 1.

Left hip MRI demonstrating a pathologic fracture of the greater trochanter.

Figure 2.

Right breast ultrasound demonstrating a 3.8 cm × 4.3 cm × 2.9 cm lobulated, hypoechoic mass at the 12 o’clock position.

Biopsy of the femoral head bone and articular surface showed degenerative joint disease marrow involved with metastatic melanoma. Pathology also confirmed right breast and right lower lobe lung metastatic melanoma. The breast tissue was malignant pleomorphic tumor with epithelioid cells with background tumor necrosis (Figure 3). The malignant cells were positive for SOX10 and S100 (Figure 4). Tumor genetic characteristics were found to be Microsatellite stable with a tumor mutational burden of 16 mutations per mega base. Specific driver mutations were also queried. Unfortunately, the patient’s condition deteriorated quickly due to her numerous areas of metastatic disease.

Figure 3.

Intermediate magnification (100 ×) demonstrates that the neoplasm is composed of infiltrating nests and sheets of malignant cells with high-grade cytologic atypia.

Figure 4.

Immunohistochemical stain for SOX10 demonstrating strong nuclear positivity in the malignant cells, confirming melanocytic origin.

During her second admission, the patient was hospitalized with COVID-19 infection and developed progressive lower extremity weakness that ultimately progressed to paralysis. MRI of the spine revealed cord compression at the T9 level with significant spinal cord flattening. She was started on intravenous dexamethasone, and neurosurgery was consulted. Given the extent of her disease, the neurosurgical team recommended palliative radiation therapy rather than surgical intervention. Radiation oncology proposed external beam radiation therapy to the T8 to T10 region, with a total dose of 30 Gy administered over 10 daily fractions. However, after multidisciplinary discussion and in alignment with the patient’s overall prognosis and wishes, the decision was made to forgo further treatment. The patient was transitioned to comfort-focused care and passed away shortly thereafter.

Discussion

Metastatic malignant melanomas have significant morbidity and mortality rates, representing about 38.5% of all metastatic tumors. ⁵ In the United States, the American Cancer Society reported that about 100 640 new melanomas would be diagnosed in 2024. Hematogenous or lymphatic metastases can virtually involve any organ. However, studies found that metastases to the breast from malignant melanoma or other extra-mammary tumors are rare, accounting for 1.3% to 2.7% of all malignant breast tumors. ⁶

Metastases to the breast from malignant melanoma often occur in premenopausal females, a notably younger demographic compared to those affected by other tumors involving breast metastasis. The tumor typically averages 2 cm in size and generally lacks superficial or deep fixation, as observed in other cases. ⁷ It is bilateral in only 8% of instances, and changes in the nipple are rare. ⁸ Axillary lymph node involvement has been reported in 25% to 80% of cases. ⁹ The upper outer quadrant (UOQ) of the breast is affected in approximately 50% of cases, attributed to its rich blood supply and denser glandular tissue. Moreover, the UOQ is a common site for primary breast malignancies. In cases of breast metastases without evident features of a remote primary cancer, this overlapping characteristic may complicate the diagnostic process.^6,10 Therefore, it is imperative to have a complete history of the patient’s cancer history (including excised melanoma) to ensure recurrence of prior tumors is considered. Additionally, screening with mammography for premenopausal women is another key component to identifying suspicious lesions early. ¹¹

While metastases from extramammary tumors to the breast are infrequent, melanomas and lymphomas are the predominant sources of metastases to this site. Literature shows that the interval to metastasis varies considerably but typically averages around 4 years, with relatively few patients presenting without a prior history of melanoma. Our patient had a history of melanoma removal 7 years prior. ¹² Additionally, our patient did not follow-up for regular screening or mammograms, and her disease was advanced at the time of presentation.

Prior case reports have indicated that melanoma patients with breast metastases typically present with both regional spread and distant metastases, commonly affecting sites such as subcutaneous tissue, lungs, brain, and liver. In contrast, our patient exhibited metastatic melanoma involving the bone marrow in the setting of degenerative joint disease. Notably, a case described by Yi et al reported an isolated breast metastasis with no additional metastatic sites detected on PET-CT. ¹³

Recognizing the metastatic origin of a breast tumor through histological analysis can be challenging. Indeed, immunohistochemical staining serves as a crucial diagnostic tool, and considered the gold standard among various diagnostic evidence. The detection of BRAF V600E mutation offered vital molecular insights into the nature of the malignancy, impacting subsequent treatment decisions. Immunohistochemical evaluation of malignant melanoma commonly includes assessment of S100, the most sensitive marker for melanocytic lesions. Other markers—such as HMB45, Mart1/Melan-A, tyrosinase, and MITF—offer greater specificity but lower sensitivity compared to S100. In our patient, both SOX10 and S100 were positive. Additionally, Ki-67 is a useful adjunct for differentiating benign from malignant melanocytic tumors.^12,14

Breast metastasis is generally associated with a poor prognosis. In a study by Feng et al, 8 of 15 patients succumbed within 1 year of breast metastasis. ¹⁵ Likewise, Ravdel et al reported a median survival of 12.9 months in a cohort of 27 patients with melanoma metastatic to the breast. ¹⁶

Despite the absence of a national consensus on skin cancer screening in the United States, dermatologists and primary care providers are frequently tasked with determining appropriate surveillance intervals. For low-risk patients (AJCC stage IA-IIA), guidelines typically recommend skin examinations every 6 to 12 months for the first 1 to 2 years, then annually thereafter. ¹⁷ In contrast, high-risk patients (stage IIB-IV) benefit from more intensive follow-up, which may include clinical skin exams every 3 to 6 months during the first 2 to 3 years, every 6 to 12 months during years 4 and 5, and annually thereafter. ¹⁸ High-risk patients may also undergo surveillance imaging, with PET/CT or whole-body CT scans considered reasonable modalities, and brain MRI preferred for central nervous system surveillance, particularly in patients with stage III to IV disease. ¹⁹

Self-examination plays a crucial role in early detection, yet international data show low adherence rates. In a survey of 17 001 adults across 17 countries, over half (52.6%) had never performed a mole check, and only 4.8% reported doing so more than once a year. Factors associated with increased self-examination included female sex, higher education and income, lighter skin phototypes, prior skin cancer history, medical insurance, and sun-protective behaviors. ²⁰ Patients should be counseled to monitor for new nodules, nonhealing lesions, or unexplained skin changes, particularly near prior melanoma sites, as these may be early signs of recurrence or distant spread. ²¹

Conclusion

In summary, tumor metastasis to the breast is exceedingly rare. Nonetheless, in patients with a known history of melanoma or other malignancies, the potential for metastatic disease should be carefully considered when evaluating a newly detected breast mass.