Synchronous metaplastic breast carcinoma and lung adenocarcinoma: a rare case and review of the literature

Abstract

Synchronous primary cancers occur in 1.7% of breast cancer cases and metaplastic breast cancer (MBC) occurs in less than 1% of breast cancer cases. We present a previously healthy 66-year-old woman diagnosed with MBC after surgical resection of a presumed cyst. A second primary cancer, multifocal lung adenocarcinoma, was discovered during the staging process for her MBC. Remarkably she had not experienced pulmonary or constitutional symptoms at the time of diagnosis. She received chemotherapy with paclitaxel and carboplatin, followed by immunotherapy with nivolumab. At 24 months of follow-up after her initial diagnosis, she was breast cancer-free with stable pulmonary nodules. This case highlights that rather than assuming multifocal lesions represent metastasis, biopsies should be considered as clinical management could be significantly altered in the presence of a synchronous cancer. Furthermore, platinum-based chemotherapy agents have potential to be considered in the treatment of MBC.

Background

Breast cancer is a heavily researched and advanced area of oncology, with current US 5-year survival rates of 99% and 90% in localised and all stages of female breast cancer, respectively.¹ However, the literature concerning the management of breast cancer and another synchronous primary cancer is limited. The Surveillance, Epidemiology and End Results programme defines synchronous primary cancers as those diagnosed within 2 months of each other, and 1.7% of index breast cancer cases present with another synchronous cancer.² We report a case in which a largely asymptomatic woman was unexpectedly diagnosed with a rare form of primary breast cancer, metaplastic breast carcinoma (MBC), and then discovered to have a synchronous primary lung cancer. She was successfully managed with lumpectomy, chemotherapy, and immunotherapy and in remission 24 months after her initial diagnosis.

Case presentation

A 66-year-old healthy woman presented for surgical excision of a cystic lesion of her right breast after fluid re-accumulation after two aspirations. Her screening mammogram within the past year was classified as BI-RADS 2, benign. She had no personal history of breast cancer or family history of cancer. Her medical history and review of systems were unremarkable, although she had a 35-pack-year history of smoking. On physical examination, there was a smooth-walled, mobile lesion of the right breast located at the 5:00 axis, 3 cm from the nipple. No skin dimpling or nipple discharge was noted.

Resected pathology revealed a 1.8×1.5×1.5 cm metaplastic carcinoma with squamous differentiation and lymphovascular invasion, a Nottingham score of 9 and triple-negative status (estrogen receptor-negative, progesterone receptor-negative and Her2-neu-negative). This pathology was confirmed at a second institution. The surgical margins were uninvolved, and subsequent sentinel lymph node biopsy was negative, 0/3 nodes. The patient’s MBC was ascribed American Joint Committee on Cancer (AJCC) stage I, pT1cN0M0.

However, as part of the staging process, a positron emission tomography (PET)–CT showed multiple hypermetabolic pulmonary nodules throughout her right lung. At this time, the patient denied any cardiopulmonary symptoms including chest pain, haemoptysis, cough or shortness of breath. She also denied constitutional symptoms such as fever, fatigue, chills, loss of appetite, weight loss or malaise. Biopsy of one nodule revealed primary lung adenocarcinoma, staining CK7, TTF-1 and napsin-A positive. Mediastinal and hilar thoracic lymph nodes were negative by PET–CT. The patient declined surgical mediastinal nodal sampling. She was diagnosed with a synchronous primary lung adenocarcinoma, ascribed AJCC stage IIIA, T4N0M0.

Treatment

Bilateral breast MRI with and without contrast 1 month after lumpectomy showed residual seroma without residual neoplasm or other suspicious findings in the breast. The patient was treated with six cycles of paclitaxel and carboplatin to simultaneously target her breast and lung cancers. Radiation therapy was not administered because the incremental benefit on the breast cancer was considered small in the setting of synchronous multifocal lung cancer and chemotherapy. Interval chest CT showed no change in the multiple pulmonary nodules postchemotherapy. The tumour PD-L1 status was assessed to determine if second-line immunotherapy for the lung adenocarcinoma was a possibility versus surveillance. The patient was found to have a favourable PD-L1 score (85% positive) so nivolumab immunotherapy every 2 weeks was initiated. Interval chest CT after four cycles of nivolumab showed that the biopsied nodule had nearly resolved with additional stable lesions of scarring present. Nivolumab was continued every 2 weeks but was stopped after 16 cycles due to the patient developing hepatitis thought to be a side effect of the medication.

Outcome and follow-up

At 24 months of follow-up after her initial diagnosis, the patient continued to be breast cancer-free with stable pulmonary nodules, as evidenced by bilateral breast MRI and chest CT surveillance, respectively.

Discussion

According to epidemiologists from the American Cancer Society, 279 100 new cases of breast cancer will occur in 2020 in USA.¹ MBC is rare, accounting for 0.25%–1% of breast cancers diagnosed annually, or approximately 700–2790 new cases.³ Metaplastic breast cancer is classified as a distinct pathologic entity by the WHO and characterised by mixed epithelial and sarcomatoid histology.⁴ Only two other case reports of MBC synchronous with another primary cancer have been reported in the literature, which are summarised in table 1. Li and Wei presented a 55-year-old woman who was diagnosed with synchronous MBC and an ovarian teratoma.⁵ She underwent modified radical mastectomy of the affected breast, excision of the ovarian teratoma and chemotherapy, after which she remained relapse-free for 10 months of follow-up. Klairmont et al presented a 74-year-old woman with four synchronous primary malignancies: MBC, lung, colon and oesophagus.⁶ She underwent single-stage breast lumpectomy and wide wedge resection of the lung adenocarcinoma, followed by sigmoidectomy and eventually oesophagectomy. She received chemotherapy intentionally tailored to target multiple malignancies and remained clinically disease-free for 18 months of follow-up.

Table 1.

Summary of case reports of MBC synchronous with another cancer

Case report	Lane and Yan et al (present study)	Klairmont et al6	Li and Wei5
Patient characteristics	66-year-old woman PMH: unremarkable SH: current smoker (35 pack-years) FH: negative for cancer	74-year-old woman PMH: basal cell carcinoma SH: former smoker (40 pack-years, quit 17 years prior) FH: breast cancer (sister, died, age 35 years), lung cancer (father, died, age 76 years)	55-year-old woman PMH: unremarkable FH: negative for breast cancer
Clinical presentation	Cyst-like lesion of the right breast discovered by self-exam, otherwise asymptomatic	Lesion of the right breast discovered during routine screening mammogram	Hard mass of the right breast discovered by self-exam, otherwise asymptomatic
Primary diagnosis	MBC, stage I*, pT1cN0M0	MBC, likely stage IIB*, T2N1M0	MBC, stage IIA*, pT2N0M0
Synchronous cancer(s)	Lung adenocarcinoma	Lung squamous cell carcinoma, colonic adenocarcinoma, oesophageal adenocarcinoma	Ovarian teratoma
Staging modalities	PET–CT, sentinel lymph node biopsy	CXR, CT chest/abdomen/pelvis, PET–CT	CT abdomen, axillary lymph node dissection
Treatment for MBC	R breast lumpectomy followed by chemotherapy	R breast lumpectomy followed by chemotherapy	R breast modified radical mastectomy followed by chemotherapy
Outcome	Cancer-free ×24-month follow-up	Cancer-free ×18-month follow-up	Cancer-free ×10-month follow-up

*based on AJCC staging

CT, computed tomography; CXR, chest X-ray; FH, family history; MBC, metaplastic breast carcinoma; PET, positron emission tomography; PMH, past medical history; R, right; SH, social history.

While certain cancer syndromes have been well established, for example BRCA1/2 and Li–Fraumeni syndrome, there is no well-recognised relationship between breast cancer and lung cancer in the US population. However, Lin et al recently reported an association between breast cancer and synchronous lung cancer in women in a large Taiwanese cohort.⁷

Our patient’s clinical presentation was unusual. MBC typically presents as a rapidly growing, large breast mass.^{3 4} Our patient’s MBC presented as a relatively small cyst-like lesion. Despite a history of smoking and the presence of primary lung cancer, she did not experience pulmonary symptoms and despite the presence of two primary malignancies, our patient had no constitutional symptoms.

MBC is an aggressive breast cancer with increased likelihood of metastasis without involvement of regional lymph nodes due to haematogenous spread.3 4 8 9 For this reason, we performed a PET–CT as part of the staging process for our patient despite a negative sentinel lymph node biopsy. The presence of multiple lung lesions in our patient was initially concerning for metastasis. However, similar cases of synchronous breast cancer (all histological types) and multiple primary lung adenocarcinomas have been reported.^{10 11} Therefore, it is critical to consider biopsy of multifocal lesions rather than assuming they represent metastases, as our biopsy results drastically altered our patient’s treatment plan.

There is no standard treatment regimen for MBC. Remarkably, evidence regarding the surgical approach is similar to that of other types of breast cancer despite its more aggressive nature. For early and locally advanced disease, mastectomy for large tumours (typically >5 cm) or breast-conserving surgery for small tumours has demonstrated no difference in overall or disease-specific survival in a retrospective study of MBC patients.¹² In another retrospective study, adjuvant radiation therapy provided an overall survival benefit but not a disease-specific survival benefit in both mastectomy and lumpectomy patients.¹³

Standard chemotherapy treatment for breast cancer, including triple-negative breast cancer, consists of anthracycline-based/taxane-based regimens.¹⁴ In contrast, first-line treatment for advanced, non-small cell lung cancer (NSCLC) is platinum-based chemotherapy.¹⁵ Of note, a few randomised clinical trials have shown that adding platinum-based agents to neoadjuvant chemotherapy for triple-negative breast cancer improves the rate of pathologic complete response.^{16 17} Additionally, Takuwa et al presented a patient with stage IIA MBC who exhibited a near pathologic complete response to platinum-based preoperative chemotherapy.¹⁸ In contrast, Keramati et al presented a patient with stage IIIA MBC who received preoperative chemotherapy without a platinum agent (doxorubicin and cyclophosphamide followed by paclitaxel) which resulted in minimal tumour response.¹⁹ Our patient was treated with paclitaxel and carboplatin. Considering the evidence from these studies along with our case, platinum-based chemotherapy agents should be considered in the treatment of MBC. Because MBC tends to be triple-negative, hormonal therapies are rarely used and chemotherapy is a mainstay.⁴ Case series of patients with MBC suggest improved breast cancer-specific survival and overall survival in patients with MBC who received adjuvant chemotherapy compared with those who did not.⁴ MBC has a relatively low 5-year survival rate of 49%–69%.²⁰

Nivolumab immunotherapy has not been shown to be superior to platinum-based chemotherapy for the treatment of advanced NSCLC in a prospective, randomised clinical trial.²¹ However, NSCLC high tumour burden and a PD-L1 expression level ≥50% are hypothesised to predict a higher response rate to nivolumab, as was demonstrated in our patient.²¹ Vogt et al suggest basic principles when designing treatment plans for synchronous primary malignancies, including determining the most significant tumour in terms of prognosis, tumour profiling to identify common targets and selecting systemic therapy active against both malignancies.²²

In summary, this case emphasises the unusual presentation and successful management of a 66-year-old woman with metaplastic breast cancer and synchronous primary lung cancer. Evidence-based clinical guidelines are absent given the rarity of such cases; thus, we hope this report will serve as a useful adjunct to the current literature.

Patient’s perspective.

I am grateful for the research, innovative treatments and wonderful physicians that, today, enable me to feel good and lead an active life, at 68 years, 2 years after my initial diagnosis of MBC and subsequently, the separate lung cancer diagnosis. With ongoing monitoring of blood, PET and CT scans I look forward to continuing successful management.

Learning points.

• Early stage metaplastic breast cancer (MBC) may present as an asymptomatic cyst-like lesion.

• Multifocal pulmonary lesions should be biopsied rather than assumed to represent metastasis.

• Chemotherapy is a mainstay of treatment for patients with MBC and advanced non-small cell lung cancer.

• Platinum-based chemotherapy agents have potential to be considered in the treatment of MBC.

• Second-line immunotherapy with nivolumab for lung adenocarcinoma can be considered depending on the tumour’s PD-L1 status.