Bilateral breast metastases from anaplastic lymphoma kinase-positive lung cancer in a male: a case report

Abstract

Background

Distant metastases from lung cancer are commonly found in the brain, bone, and liver. Metastases to the breast from non-mammary malignancies are extremely rare, and their clinical presentations remain unclear.

Case presentation

We herein report a case of bilateral breast metastases from anaplastic lymphoma kinase-positive advanced lung cancer in a 51-year-old Japanese male patient. During the course of systemic treatment for advanced lung cancer, computed tomography revealed bilateral breast enlargement without contrast enhancement, a finding consistent with gynecomastia. While other metastatic lesions responded to chemotherapy, both breast masses grew vertically like nodules. The breast masses were immunohistochemically diagnosed as metastases from lung cancer and were removed surgically. Simultaneous bilateral breast metastases from malignancies of other organs, like ones in this case, have rarely been described.

Conclusions

It is important to keep in mind that breast metastases from nonmammary malignancies are a possible explanation for unusual breast findings in a patient with a history of malignancies.

Background

Breast cancer is one of the most common malignant tumors worldwide [1]. However, metastases to the breast from nonmammary malignancies are scarcely found, accounting for 0.3–2.7% of breast malignancies [2]. Common origins of breast metastases include primary melanomas, lymphomas, and leukemias [3].

Lung cancer is diagnosed as frequently as breast cancer, and its common metastatic sites are the brain, bone, and liver; however, metastases to the breast are rarely found [4,5,6]. Given the fact that the prevalence of anaplastic lymphoma kinase (ALK) rearrangement is as low as 2–6% of all lung cancer cases, metastases to the breast from ALK-positive lung cancer seem to be highly unusual [7, 8].

Radiologically, the majority of metastases to the breast have been reported to be detected as an incidental finding on imaging in routine practice being scanned for evaluation of treatment response in patients with a history of malignancy [9]. Moreover, previous studies have reported that metastases from nonmammary primaries are more commonly found in the ipsilateral breast than in bilateral breasts and in women than in men [10].

Here we report a case of bilateral breast metastases from ALK-positive lung cancer in a male, which were found during the course of systemic treatment.

Case presentation

A 51-year-old Japanese man with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0 was referred to our department with complaints of gradually progressed bilateral nipple retraction for a year and breast masses with pain for 3 weeks. He was being treated for ALK-positive lung cancer, cT3N3M1b, stage IV since the diagnosis was made at the age of 41 years with no burden of comorbidities. There was no particular past medical or dental history and no oral medication. He had no significant family history of potential future health risks for the patient, including cancer, in the family (second-degree relatives). He was not a smoker and only drinks socially. He works in the hospitality industry. He was initiated on combination chemotherapy with cisplatin (75 mg/m²) and pemetrexed (500 mg/m²) and maintained stable disease for 4 months. During the treatment, he was recruited for the phase 2 clinical trial to assess the efficacy of alectinib (300 mg twice daily) in patients with ALK-positive lung cancer. By administering alectinib, the lung cancer remarkably diminished and he had achieved clinical complete response for almost 3 years. After disease progression with alectinib, the sample from swelling axially lymph node was acquired by lymphadenectomy and confirmed the presence of L1196M mutation in ALK gene using reverse transcription polymerase chain reaction (RT–PCR). The other ALK tyrosine kinase inhibitor (TKI) treatments [ceritinib (750 mg once daily), brigatinib (180 mg once daily), lorlatinib (100 mg once daily)] were sequentially administered over a 9-year period. At 50 years of age, he had been treated with lorlatinib for 3.5 years and computed tomography (CT) performed to evaluate the response to systemic treatment identified bilateral breast enlargement without contrast enhancement, a finding consistent with gynecomastia (Fig. 1A). The patient did not notice any abnormalities with his breasts at that time. These observations initially led physicians to presume that breast enlargement was gynecomastia and did not warrant further examination. At the age of 51, lorlatinib had become no longer effective due to deterioration of pulmonary carcinomatous lymphangiomatosis. He was aware of bilateral nipple retraction but had no concern with it. Following lorlatinib, treatment regimen consisting of atezolizumab (1200 mg), bevacizumab (15 mg/kg), carboplatin (AUC, 5 mg/mL/min), and paclitaxel (175 mg/m²; ABCP) was administered to the patient. A total of 4 months after ABCP therapy was initiated, both breast masses gradually grew in a vertical direction similar to nodules, with contrast enhancement in CT, while other metastatic lesions including pulmonary carcinomatous lymphangiomatosis responded to ABCP therapy (Fig. 1B). Thus, the patient was suspected of having male breast cancer and consulted our department for further evaluation.

Fig. 1

Computed tomography (CT) of the patient’s chest. Bilateral breast enlargement without contrast enhancement (A). Growing bilateral breast masses at the time of the consultation (B)

His physical examination revealed a blood pressure of 119/79 mmHg, a heart rate of 92 beats per minute, and oxygen saturation measured by pulse oximetry was 98% on room air. His temperature was 36.5 ℃. Laboratory tests at admission revealed a white blood cell count of 4180/μL, hemoglobin level of 11.0 g/dL, and platelet count of 176,000/μL. Other biochemical tests including liver and renal function showed no significant abnormalities apart from abnormally low albumin levels (3.9 g/dL). The carcinoembryonic antigen level was 3.4 ng/mL and the cytokeratin fragment 19 level was 2.1 ng/mL. There were no signs of inflammation and no findings for infection. Testing for hepatitis B and C infection and human immunodeficiency virus infection showed negative. Urinalysis demonstrated a specific gravity of 1.016, pH 5.5, protein 1+ , and urobilinogen ± . Physical examination revealed hard breast tumors with each nipple retraction, measuring approximately 2 cm × 2 cm at the right side and 2 cm × 1 cm at the left side, respectively, in his bilateral breast (Fig. 2A). Mammography revealed a microlobulated round mass with an unclear boundary in the subareolar area of each breast (Fig. 2B). Ultrasonography showed solid hypoechoic masses that measured about 20 mm and were located below each nipple (Fig. 2C, D).

Fig. 2

Breast images of the patient. Gross appearance of the breast (A). Bilateral microlobulated round masses on mammography (B). Hypoechoic irregular-shaped masses in the subareolar area of the right breast (C) and left breast (D) on ultrasound sonography

Pathological analysis of core needle biopsy specimens obtained from the breast masses indicated that the breast lesions were adenocarcinomas with morphological characteristics similar to those observed in the primary lung cancer specimens collected previously from the same patient (Fig. 3A, B). Immunohistochemical examinations revealed positive staining for thyroid transcription factor 1 (TTF-1), ALK, and cytokeratin (CK) 7 and negative staining for mammaglobin, estrogen receptor, gross cystic disease fluid protein 15, and CK20 (Fig. 3C–F). These findings suggested that the breast masses represented metastases from the lung cancer.

Fig. 3

Histological findings. Lung adenocarcinoma primary diagnosed from an axillary lymph node biopsy [hematoxylin and eosin (HE), ×20] (A); cancer cells of the left breast (HE, ×20) (B); positive immunohistochemical staining for ALK (×20) (C); positive immunohistochemical staining for TTF-1 (×20) (D), negative immunohistochemical staining for mammaglobin (×20) (E), and negative immunohistochemical staining for estrogen receptor (×20) (F)

He underwent bilateral breast tumorectomy and both tumors were pathologically diagnosed as the metastases from lung cancer as well as core needle biopsy examination. Subsequently, RT–PCR results indicated the presence of G1202R mutation in addition to L1196M in the breast tumor. As no progression lesion was found by removing the bilateral breast tumors, he continued to receive ABCP therapy. After he completed four cycles of ABCP therapy, maintenance therapy with atezolizumab and bevacizumab was continued. As of 8 months after tumorectomy, the patient remained in the stable disease status.

Discussion and conclusions

Here, we presented a case of a male patient with ALK-positive lung cancer in whom bilateral breast masses were initially misinterpreted as gynecomastia, but turned out to be bilateral metastases to the breast. The diagnosis of breast metastases from lung cancer was delayed until almost one year after the first detection of breast masses in CT. This report illustrates the importance of clinical suspicion of breast metastasis when the patient has a clinical history of nonmammary malignancies.

Common presenting symptoms in patients with breast metastases from nonmammary malignancies have been reported to include palpable breast masses, as in those with primary breast cancer [11]. In this case, the retracted nipples were observed before palpable firm masses, due to the presence of a metastatic tumor behind each nipple. When a male patient presents with a unilateral breast mass or bilateral breast masses behind one or both of the nipples, gynecomastia should also be considered as a differential diagnosis [12]. Certain imaging modalities, such as mammography and breast ultrasound, can reveal unusual growth of breast tissue and are useful for differential diagnosis between gynecomastia and breast malignancies [13]. However, the location of bilateral breast enlargement just below the nipples with no contrast enhancement in CT was considered consistent with features of gynecomastia. Imaging findings can also play an important role in suggesting breast tumors; however, they have low specificity in distinguishing primary breast cancer from metastases to the breast [14]. In the present case, metastatic lesions remained stable, except for the growing breast masses; therefore, primary breast cancer, rather than metastasis to the breast, was suspected.

Distinguishing a metastasis to the breast from a primary breast neoplasm is important, since it is of therapeutic and prognostic significance. For accurate differentiation, histological examinations play an important role [15]. In the present study, we performed core needle biopsy of breast masses, and the findings in the hematoxylin and eosin-stained specimens were consistent with those in the lung cancer specimens collected previously from the same patient. Furthermore, immunohistochemical comparison between the primary tumor and metastasis specimens is helpful to confirm a diagnosis [2]. In this case, the immunohistochemical detection of ALK fusion proteins improved diagnostic confidence owing to the detection specificity.

Of note, the patient showed bilateral breast metastases from lung cancer, which are very uncommon. The mechanism of metastatic spread to the breast from lung cancer has been reported to be hematogenous or lymphogenous; however, identifying the route of metastasis is difficult in real clinical practice due to the mechanistic variety and complexity [16]. In elderly individuals, blood flow reduction in breast tissue has been reported due to atrophy of the breast tissue into connective or adipose tissue, resulting in fewer cases of hematogenous metastasis to the breast [17]. Because neither lymphatic nor vascular invasion was seen in the resected specimens, it was difficult to determine the route of bilateral breast metastases from lung cancer in the present case. However, considering the inherently limited volume of breast tissue in male and the initial diagnosis of marked lymph node metastases, even though it is not evident, retrograde lymphatic spread may be a more likely reason for metastases to the breast in this case. Furthermore, harboring ALK-L1196M and -G1202R compound mutations in the breast metastases not only shows high ALK TKIs resistance, but also indicates metastases to the breast can be found in the terminal stage of lung cancer.The prognosis of patients with breast metastases from lung cancer has been reported to be poor [18]. The standard treatment for patients with metastatic lung cancer is systemic therapy, since lung cancer cells can spread around the body from the primary site [19]. Moreover, owing to markedly improved survival in metastatic lung cancer patients treated with modern systemic therapy, the expected survival benefit from surgical treatment of metastatic lesions is considered limited; thus, the decision whether or not to perform surgery should be made on a case-by-case basis [20]. In the current case, the patient received bilateral tumorectomy since breast lesions did not respond well to chemotherapy and only few more chemotherapy options were available. After surgical treatment, the patient continued the same medical treatment as before the surgery, and the postoperative course was uneventful (alive as of 5 months after surgery).

In conclusion, the case highlighted the importance of keeping breast metastasis in mind as a possible explanation for unusual breast findings in a patient with a history of malignancies. Accurate diagnosis of metastatic lesions with biopsies and immunohistochemical examinations is required for tailoring appropriate therapeutic strategies.