Introduction: Lung cancer with breast metastasis is rare. However, differentiating between primary breast cancer and metastatic lung adenocarcinoma is of clinical importance. The metastasis cascade of how cancer cells migrate from the primary lung tumor to the breast is not clear yet.
Methods: Pathology and cytology databases were searched for patients diagnosed to have lung adenocarcinoma with breast metastasis. Their medical records, chest computed tomography images, and pathology slides were reviewed independently.
Results: We identified six lung adenocarcinoma patients with breast metastases in a 10-year period from a tertiary medical center. Interestingly, all breast metastases affected the same side as the primary lung cancers. In addition, all our cases shared other clinical manifestations, namely, ipsilateral pleural effusion/thickness and axillary lymph node enlargement.
Conclusion: Because this distinctive feature could not be explained by simple coincidence, we consider that lung adenocarcinoma may preferentially metastasize to the ipsilateral breast through a stepwise mechanism, involving pleural seeding, axillary lymph node metastasis, and retrograde lymphatic spreading into the breast.
Lung cancer is a highly malignant disease and usually, has widespread metastasis at initial presentation or during treatment course. The most commonly affected metastatic organs include lymph node, bone, lung, brain, liver, and adrenal gland. In fact, almost every organ could have been metastasized at late-stage disease. Although lung adenocarcinoma rarely metastasizes to the breast, it is of great clinical significance to differentiate primary from metastatic lesions because primary breast adenocarcinoma is a common malignancy with very different management and outcome. Traditionally, an ancillary panel of immunohistochemical staining can provide enough information for the differential diagnosis. Nowadays, because of advances in molecular pathology, specific genetic alterations, such as activating epidermal growth factor receptor (EGFR) mutations, may give an additional diagnostic clue to elucidate the origin of the cancer cells.
It is believed that cancer cells metastasize to regional lymph nodes through lymphatic channels, and metastasize to distant organs through hematogenous spreading. Although cancer cells continuously shed from the primary tumor and circulate around the body, only infrequently would they adhere to vessel wall, undergo extravasation, and develop overt metastasis.1 This tightly regulated interaction between cancer cells and microenvironment, the so-called seed and soil hypothesis, shows why cancer cells preferentially metastasize to some organs but not the others.
For symmetrically paired organs with similar volumes, such as breasts, it is expected that metastases for any given malignancy through hematogenous spread would affect either breast equally. On the contrary, if the metastasis occurs predominantly in one of the paired organs, it may imply that hematogenous spread is not the predominant route for metastasis. Recently, we observed a case of primary lung adenocarcinoma with metastasis at the ipsilateral breast. Because a previous study had shown that breast cancer predominantly affected the ipsilateral pleural cavity,18 we then initiated a study to investigate the laterality of primary lung adenocarcinoma and its breast metastasis in our patients.
PATIENTS AND METHODS
To identify lung adenocarcinoma patients with breast metastasis, we used the pathology database at the Department of Pathology and Laboratory Medicine of the Taipei Veterans General Hospital. The case-finding algorithm were: 1) using “breast” as the key word for “type of specimen” and 2) using “metastatic carcinoma” as the key words for “diagnosis.” We also used the cytology database at the Department of Chest Medicine. Because most patients in this database were diagnosed with primary lung cancer, we retrieved data of all cases whose specimen type was breast and the diagnosis was carcinoma. We then reviewed the medical records of these patients to determine the origin of the breast carcinomas. Only patients diagnosed with primary lung adenocarcinoma were included for further analysis. Serial chest computed tomography (CT) images of each case, at initial diagnosis and during treatment, were reviewed independently by two authors (CHC and WMH). This study was approved by the Institutional Review Board of Taipei Veterans General Hospital (approval number, 2012-04-027BC).
The index case was a 70-year-old woman, who presented with a centrally located lung adenocarcinoma at left upper lobe accompanied by ipsilateral malignant pleural effusion. After four cycles of chemotherapy with cisplatin and vinorelbine, she noted a painless lump in her left breast. Physical examination revealed a fixed hard mass at the upper outer quadrant of her left breast and a palpable lymph node in the left axilla. Because of her history of lung cancer, core-needle biopsy was performed before the planned surgical resection. Pathology disclosed atypical glands in the breast parenchyma (Fig. 1A). These atypical cells were immunoreactive for TTF-1 (Fig. 1B) and negative for ER, PR, and GCDFP-15 (Fig. 1C). Further, EGFR gene sequencing showed missense point mutation L858R at exon 21, the same mutation as the original lung tumor. The final diagnosis of the left breast mass was metastatic adenocarcinoma originating from lung. Because of disease progression, the patient’s treatment was shifted to erlotinib. After a 3-month course of treatment, follow-up chest CT scan showed significant reduction of the primary lung tumor, the metastatic breast lesion, and axillary lymph node (Fig. 2).
During 2001–2011, five additional lung adenocarcinoma patients with breast metastasis were identified from the cytology and pathology database. The clinical characteristics are summarized in Table 1. All patients were women and shared some clinical similarities: 1) breast metastasis was at the same side as the primary lung carcinoma, 2) presence of enlarged ipsilateral axillary lymph nodes, and 3) presence of ipsilateral pleural effusion and/or thickening (Fig. 3).
Breast metastasis from extramammary malignancy is rare.2 Although it represents only approximately1% of all breast malignancies, differentiating primary from metastatic mammary carcinoma is of great clinical significance because of the differing management options. Morphologically, elastosis and carcinoma in situ, which are common in primary mammary carcinoma, are extremely rare in breast metastasis.3 The result of an immunohistochemical panel is a useful supplement in differential diagnosis. Primary mammary carcinoma is frequently immunoreactive for ER, PR, and GCDFP-15. However, S100, WT-1, PSA, and TTF-1 are the representative markers for melanoma, ovarian serous papillary carcinoma, prostate carcinoma, and lung adenocarcinoma, respectively. In some patients, such as our index case, specific gene mutation could provide additional evidence for the origin of the cancer cells. Classic activating EGFR mutations at the tyrosine kinase domain occur almost exclusively in lung adenocarcinomas, as in our index patient, and are not seen in primary mammary carcinomas.4
We searched our pathology and cytology database to determine the crude incidence of breast metastasis in lung adenocarcinoma patients in the past 10 years in our institute. From approximately 6000 cases, we identified a total of six cases; to our surprise, they shared some clinical similarities. First, breast metastases were all at the same side as their primary lung cancers. In addition, they all had ipsilateral axillary lymphadenopathy, and interestingly, ipsilateral pleural effusion and/or pleural thickening. We reviewed the literature for similar case reports, which gave detailed clinical data regarding the laterality of the primary lung cancer and breast metastasis. As of January 2013, 13 cases were identified and remarkably, 10 of them also showed ipsilateral breast metastases as ours (Table 1).5–13,16,17
The most common modes of lung cancer metastasis are direct invasion, pleural seeding, hematogenous dissemination, and lymphatic spreading. If lung adenocarcinoma metastasizes to the breast predominantly through hematogenous dissemination, the chance of either breast being affected should be equal. Under this premise, the probability of six lung adenocarcinoma patients to have ipsilateral breast metastases would be 1.6% (0.56 = 0.016). Direct tumor invasion is probably the simplest explanation for ipsilateral breast involvement; however, chest CT of our cases indicated this to be unlikely because the fat planes between the chest wall and breast tissue were all intact (Figs. 2 and 3). Hence, lymphatic spreading might be the most plausible route. Indeed, intralymphatic tumor emboli could be easily demonstrated by D2-40 immunostaining, a marker for lymphatic endothelium, in our cases (Fig. 1D). Similar findings have also been reported by Ho et al.10 In fact, using 99mTc-antimony colloid SPECT/CT scan, Barber et al.14 demonstrated a communication of breast lymphatic drainage with the intrapulmonary lymphatic system in a breast cancer patient. They considered this communication a potential mechanism for the presence of metastatic mediastinal lymphadenopathy in breast cancer patients. Therefore, it is possible that lung cancer may metastasize retrogradely to the ipsilateral breast through the same lymphatic channel.
However, we consider the mechanism being more complicated because all our cases had simultaneous ipsilateral pleural and axillary lymph node metastases (Table 1). It is plausible that established breast metastases may further drain to axillary lymph nodes just as primary mammary carcinomas do. Nevertheless, if this is true, it would be more common to see breast than axillary lymph node metastases, which is not consistent with our clinical experience. In addition, in some of our cases, serial chest CT scans showed that axillary lymph node enlargement appeared before the occurrence of breast nodules. Therefore, we hypothesize that lung cancer cells may predominantly metastasize to ipsilateral axillary lymph nodes first, then spread retrogradely to the intramammary lymphatic system, and finally establish breast metastasis. In fact, this retrograde lymphatic spreading has also been observed in other types of cancer.19,20
Previous studies have suggested a lymphatic drainage from mediastinal lymph nodes, through intercostal and/or supraclavicular lymphatic vessels, to ipsilateral axillary lymph nodes (Fig. 4A).15 Alternatively, we propose that lung cancer cells might first result in malignant pleural effusion, seed on the parietal pleura, invade the lymphatic vessels in chest wall, and then drain off to ipsilateral axillary lymph nodes (Fig. 4B). The latter pathway may explain the unique presentation of the clinical trio of ipsilateral pleural effusion/thickness, axillary lymph node enlargement, and breast metastasis, in all our cases.
Although the mechanism is still hypothetical, our clinical observations strongly suggest that one should carefully examine the ipsilateral axillary lymph node and breast when treating a lung adenocarcinoma patient with pleural metastasis and/or chest wall invasion. However, there are limitations in this study. Above all, the case numbers are very small, and therefore, the statistical errors could be high. In addition, there is no any objective molecular evidence supporting our presumptive metastatic cascade. Recently, it has been shown that new genomic strategies could help to elucidate the clonal evolution of cancer,21,22 which may aid to determine the metastatic cascade in the future studies.
In conclusion, although breast metastasis from lung cancer is rare, an accurate diagnosis is of great clinical importance. In addition to the morphological and immunohistochemical characteristics, EGFR gene sequencing may provide another clue to the diagnosis. Cancer cells can metastasize to either breast through the hematogenous route; however, in lung adenocarcinoma, cells seem to preferentially spread to the ipsilateral breast, probably through a retrograde axillary lymphatic drainage.
We thank Ms. Angela Song-En Huang for English editing. This work was supported by grants from Taipei Veterans General Hospital (V102A-010).
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Adenocarcinoma; Breast; Lung cancer; Metastasis
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