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When Blind Pathologists Lead Mute Clinicians: Autopsy of a Misdiagnosis Involving a Metastatic Lung Adenocarcinoma to the Breast Mimicking Primary Invasive Ductal Carcinoma

Gama, Alcino MD; Novo, Jorge Eduardo MD

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doi: 10.1097/PCR.0000000000000498
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A 59-year-old woman with a medical history of stage IV lung adenocarcinoma undergoing chemotherapy for the past 3 years presented for evaluation of right breast and axilla palpable masses. Mammography and breast ultrasound demonstrated diffuse skin thickening of the right breast with 2 spiculated lesions measuring approximately 1.1 cm (8:00, 7 cm from the nipple) and 1.0 cm (9:00, 10 cm from the nipple). Several abnormal right axillary lymph nodes were noted. Three core biopsies were performed of the 2 breast masses and a suspicious axillary lymph node. Unfortunately, the relevant medical history was not made available to the pathologist.

On hematoxylin-eosin stain, the breast mass biopsies showed identical findings: a high-grade, moderately to poorly differentiated invasive carcinoma with glandular formation and micropapillary features. The tumor was highly pleomorphic with numerous mitotic figures (Fig. 1). The infiltrative pattern was irregular, and while an in situ component was not identified, the lesion demonstrated classic morphologic features of an invasive ductal carcinoma. The lymph node biopsy demonstrated morphologically similar metastatic tumor almost entirely replacing lymphoid tissue. Following standard protocol, the case was reviewed at the daily quality assurance committee meeting for consensus, receiving unanimous agreement with the diagnosis “invasive ductal carcinoma with micropapillary features, grade 3 (3+3+2),” and “metastatic poorly differentiated carcinoma with micropapillary features, consistent with the known breast primary.” The breast tumor marker panel was that of a triple-negative breast cancer with a high Ki-67 proliferative index. Another day, another breast cancer successfully diagnosed.

Poorly differentiated invasive carcinoma with infiltrative, pleomorphic glands and moderate mitotic activity (hematoxylin-eosin stain, original magnification [A] ×40, [B] ×200).

This feeling of confidence was quickly dispelled following a phone call from the oncology team a couple of hours following release of the report, challenging the diagnosis given this patient was being treated for a lung primary. A barrage of phone calls followed: the radiology fellow knew of the history, but did not challenge the pathology report and informed the patient of the newly diagnosed second cancer. The case was re-reviewed, and additional stains were performed to confirm the nature of the lesion. The tumor was positive for TTF-1 and Napsin A, while negative for mammaglobin, BRST-2 (GCDFP-15), and GATA3, confirming the lesion as a metastatic lung adenocarcinoma (Figs. 2A–E). The case was reviewed again at the quality assurance meeting, once again fooling our pathology practice only to elicit a collective gasp upon presenting the immunohistochemical proof.

Immunohistochemical stains supporting a lung metastasis (A, TTF-1, original magnification ×200, positive; B, napsin A, original magnification ×200, positive; C, mammaglobin, original magnification ×200, negative; D, BRST-2, original magnification ×200, negative; E, GATA-3, original magnification ×200, negative).


While less than 24 hours passed between the notification from the oncology team to the amending of the report, and the patient did not suffer any consequences other than psychological harm, the experience highlights the dangers pathologists face when they find themselves comfortable with routine cases while blinded to key clinical facts.

Although metastatic tumors to the breast are rare, they usually constitute a major diagnostic dilemma. Lymphomas and melanomas are the most common noncarcinoma metastases to the breast.1 Both entities present with characteristic morphologic features most of the time, and ruling out invasive ductal carcinoma is typically not challenging. Metastatic adenocarcinomas, on the other hand, can appear morphologically identical to primary breast cancers and become a major pitfall, especially if no clinical history is provided.2 Although some radiologists advocate the use of elastography as a potential tool to predict metastasis over breast primary,3 other groups claim that there are no specific imaging patterns to suggest metastatic disease.4 Ali et al2 reviewed 14 cases of lung cancer metastatic to the breast, including 11 lung adenocarcinomas. They suggested the following “red flag” morphologic features to suspect metastatic adenocarcinomas over breast primary: well-circumscribed lesions lacking an in situ component, distant metastases with negative axillary lymph nodes, and non–high-grade triple-negative breast tumors.

In our case, the clinical history would have been the only reason to include lung adenocarcinoma in the differential diagnosis: the patient presented with a morphologically compatible, infiltrating carcinoma along with metastatic axillary lymph nodes. While the absence of an in situ component could have raised the suspicion of a metastatic lesion, it is not uncommon for high-grade, in particular triple-negative breast cancers, to lack an in situ component; in addition, lymphovascular space invasion can mimic a carcinoma in situ, further leading the pathologist astray. The overlap in morphology was sufficient to mislead an entire pathology practice, including numerous senior pathologists.

The pathologist of record becomes the go-to individual to address the discrepancy, and the pathologist must bear this responsibility; however, when does the sacred duty to “do no harm” come into play for the clinician? As illustrated in this report, a single sentence on the requisition (“history of lung cancer”) would have avoided this diagnostic error. It is the duty of the clinician to do no harm, by challenging the pathologist when the diagnosis is unexpected or would significantly alter the prognosis and treatment plan. The healthy skepticism of the oncology team saved the patient from unnecessary suffering and procedures.


Transfer of care from the clinician to the pathologist is an integral step for a safe, high-quality health care system in which relevant information must be clearly given to the next team, including pathology, to avoid misdiagnosis and erroneous management. Nonetheless, the pathologist, in the absence of this information, should strive to maintain a voice of doubt in the back of our minds as we see “routine” lesions, to ask ourselves if we are comfortable beyond reasonable doubt and the evidence is unequivocal. Although common diagnoses will always occur more frequently, the pathologist must always be on alert for mimickers and metastases, which can be solved though immunohistochemical stains, chart review, a friendly second pair of eyes, quality committee reviews, a phone call, and a healthy dose of humility and patience.


1. Georgiannos SN, Chin J, Goode AW, et al. Secondary neoplasms of the breast: a survey of the 20th century. Cancer 2001;92(9):2259–2266.
2. Ali RH, Taraboanta C, Mohammad T, et al. Metastatic non–small cell lung carcinoma a mimic of primary breast carcinoma—case series and literature review. Virchows Arch 2018;472(5):771–777.
3. Sousaris N, Mendelsohn G, Barr RG. Lung cancer metastatic to breast: case report and review of the literature. Ultrasound Q 2013;29(3):205–209.
4. Pesce K, Chico MJ, Delgado JS, et al. Metastases to the breast, an uncommon diagnosis: what do radiologists need to know?Radiologia (Engl Ed) 2019;61(4):324–332.

breast cancer; communication; metastatic lung adenocarcinoma; misdiagnosis

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