October 2023 – Breast Pathology

Metastatic lung adenocarcinoma.

The histologic sections in this case demonstrate an infiltrative neoplasm composed of glands and papillae within a desmoplastic stroma. The cells show mild to moderate cytologic atypia, with nuclear pleomorphism, occasional prominent nucleoli, hyperchromasia, and rare intranuclear inclusions.

By immunohistochemistry, the neoplastic cells are strongly and diffusely positive for TTF-1, and are negative for ER, PR, and thyroglobulin. The overall morphology and immunophenotype are most consistent with an adenocarcinoma of lung metastatic to the breast.

Metastases to the breasts from extramammary sites are rare, and incidences of such have been reported as 0.4%-3%. The most common malignancies to secondarily involve the breasts are leukemia/lymphoma and malignant melanoma.^1,2  Carcinomas may metastasize to the breast as well, including ovarian, lung, renal, and thyroid.^2,3 Metastases to the breasts are most often encountered in patients with advanced and disseminated disease. In such settings, the patient’s extramammary primary malignancy is generally known to the care team. When the extramammary primary is occult, the distinction of a metastasis from a primary carcinoma of the breast is especially important for prognosis and therapeutic decisions.³ 

The morphologic distinction between metastatic lung adenocarcinoma and primary breast carcinoma in the breast can be extremely difficult. In cases in which knowledge of a lung mass is unknown to the pathologist, metastatic lung carcinomas may be confused with triple negative primary breast carcinomas. Morphologic features that may suggest a primary breast carcinoma include the presence of an in-situ component and elastosis.¹ Assessment of these helpful features may be limited in core biopsy specimens. 

In this case, a papillary architectural component was noted with positivity for TTF-1 confirmed. These findings were consistent with metastatic lung carcinoma but also raised the differential diagnosis of a metastatic thyroid carcinoma. Thyroglobulin IHC testing was also performed, with a negative result, making a metastatic thyroid carcinoma unlikely. 

Finally, while TTF-1 carries a high sensitivity and specificity for primary lung adenocarcinoma, aberrant TTF-1 expression has been described in a number of other entities, including extra-pulmonary neuroendocrine tumors and carcinomas arising from the bladder, prostate, gastrointestinal tract, and gynecologic organs.^5,6 In the breast, carcinoma diagnoses, particularly those that are hormone receptor negative, may trigger expanded immunohistochemistry panels to confirm breast origin, including addition of markers such as mammaglobin, GATA3, or TRPS1.^1-4

Radiology of the breast itself may not always be of help, as metastases to the breast may present as a solitary nodule or multiple nodules, with well- or ill-defined borders. More extensive imaging to include other sites may be useful, and other metastatic deposits may be identified.^3,4 In this case, a single mass lesion was identified in the left breast, ipsilateral to the patient’s confirmed lung mass.

References

1. Wang X, Luo Y, Liu L, Wei J, Lei H, Shi S, Yang L. Metastatic adenocarcinoma to the breast from the lung simulates primary breast carcinoma-a clinicopathologic study. Transl Cancer Res. 2021 Mar;10(3):1399-1409. doi:10.21037/tcr-20-2250. PMID: 35116465; PMCID: PMC8798917
2. Sousaris N, Mendelsohn G, Barr RG. Lung cancer metastatic to breast: case report and review of the literature. Ultrasound Q. 2013 Sep;29(3):205-9. doi:10.1097/RUQ.0b013e3182a00fc4. PMID: 23975047.
3. Ali RH, Taraboanta C, Mohammad T, Hayes MM, Ionescu DN. Metastatic non-small cell lung carcinoma a mimic of primary breast carcinoma-case series and literature review. Virchows Arch. 2018 May;472(5):771-777. doi:10.1007/s00428-017-2262-4. Epub 2017 Nov 5. PMID: 29105026.
4. Noguera J, Martínez-Miravete P, Idoate F, Díaz L, Pina L, Zornoza G, Martínez-Regueira F. Metastases to the breast: a review of 33 cases. Australas Radiol. 2007 Apr;51(2):133-8. doi:10.1111/j.1440-1673.2007.01681.x. PMID: 17419856.
5. Casteillo F, Fournel P, Da Cruz V, Karpathiou G, Boutet C, Jacquin JP, Tissot C, Meyer-Bisch V, Péoc'h M, Forest F. TTF-1-positive metastatic endometrioid carcinoma: a case report and review of literature of a potential diagnostic pitfall. Appl Immunohistochem Mol Morphol. 2020 Jan;28(1):e6-e9. doi:10.1097/PAI.0000000000000539. PMID: 28777147.
6. Matoso A, Singh K, Jacob R, Greaves WO, Tavares R, Noble L, Resnick MB, Delellis RA, Wang LJ. Comparison of thyroid transcription factor-1 expression by 2 monoclonal antibodies in pulmonary and nonpulmonary primary tumors. Appl Immunohistochem Mol Morphol. 2010 Mar;18(2):142-9. doi:10.1097/PAI.0b013e3181bdf4e7. PMID: 19887917