Systematic review of lung cancer with breast metastasis

Introduction

Lung cancer is the leading cause of cancer-related death in adults and caused an estimated 1.8 million deaths worldwide in 2020 (1). In 2022, the American Cancer Society estimated 236,740 new lung cancer cases and 130,180 associated deaths, which is approximately 355 deaths per day (2). Most patients with lung cancer have advanced disease at initial evaluation, and the 5-year overall survival rates remain low at 22%. Although advances in lung cancer screening have improved early detection rates, 53% of all patients present with metastatic disease (3). The most common sites of lung cancer spread are the lymph nodes, brain, bone, liver, and adrenal glands. Dissemination to the breast is rare, with a reported incidence of 0.5–3% (4). More commonly, patients with primary breast cancer develop lung metastasis in 21–32% of cases (5). Metastatic involvement of the breast is relatively infrequent, ranging from 0.5% to 6.6% (6). Common sources of metastases to the breast include melanoma, lymphoma, lung cancer, ovarian carcinoma, and soft tissue sarcoma. Management typically involves palliative systemic therapy, as metastases to the breast from non-mammary primaries are indicative of disseminated disease, with less than a 10% 5-year survival rate for non-small cell lung cancer (NSCLC) (2,3). Distinguishing lung cancer with breast metastasis from primary breast cancer raises a consequential clinical dilemma. Awareness of these metastatic patterns is crucial for appropriate management due to their distinct treatment pathways. Our study offers a comprehensive review of lung cancer with breast metastasis in the current literature to raise awareness and assist in accurate diagnosis and treatment of affected individuals with the goal of improving their prognoses. We present this article in accordance with the PRISMA reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2040/rc).

Methods

The PubMed database was searched in February 2024 and included results ranging from 1962 to 2024 to include all available publications on this topic. The following search terms were used: (“lung squamous cell” AND “breast”), (“lung adenocarcinoma” AND “breast”), (“metastasis to breast” AND “lung”), (“small cell lung cancer” AND “breast” NOT “non-small cell lung cancer”), (“lung neuroendocrine tumor” AND “breast”), (“non-small cell lung cancer” AND “breast”), (“breast” AND “lung cancer” AND “metastasize”). The search results were independently reviewed by two authors (I.W. and M.R.), and discrepancies were mitigated by discussion and consensus among all authors. Further, these two authors continued to review articles independently during the full-text review phase and the data extraction phase. Additional articles were identified by reviewing the references of the articles in the initial search and were selected if they met the inclusion criteria. Duplicates were excluded, and the remaining articles were screened by title and abstract. Inclusion criteria included: (I) case studies of lung cancer with breast metastasis, (II) English language availability; and (III) availability of full text. Articles were excluded if any of the following criteria were met: (I) lung cancer with breast metastasis was not described; (II) full texts were unavailable or studies with only abstracts; (III) insufficient clinical data reported; (IV) non-original cases; (V) study was not published in a peer-review journal; or (VI) study was written in a non-English language. The variables collected comprised of epidemiologic factors, clinical disease characteristics, tumor immunohistochemistry (IHC), molecular biomarker profile, interventions/treatments, and clinical outcomes. IHC and molecular biomarkers collected were thyroid transcription factor 1 (TTF-1), estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (Her-2), cytokeratin 7 (CK7), cytokeratin 20 (CK20), Napsin A, GATA binding protein 3 (GATA3), gross cystic disease fluid protein 15 (GCDFP15), epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) mutation, repressor of silencing 1 (ROS1) proto-oncogene mutation, and programmed death-ligand 1 (PD-L1). Features of disease management and clinical outcomes collected were misdiagnosis of breast mass as primary breast disease, the use of chemotherapy or immunotherapy in management, the use of radiotherapy in management, the use of excisional breast surgery in management, the use of excisional thoracic surgery in management, length of follow up after initial diagnosis, and patient mortality.

Two reviewers independently assessed the risk of bias for each study using Rayyan, employing a combination of multiple tools to evaluate the overall quality of evidence. Discrepancies were resolved through discussion. During data extraction, missing significant amount of missing data resulted in study exclusion, ensuring the robustness of synthesized findings. Articles underwent title and abstract screening, and duplicates were removed. Tabulated data highlighted key epidemiologic and clinical variables, providing a comprehensive overview. No meta-analysis was performed or intended due to the type of data collected. Heterogeneity of the data was addressed by focusing on the most common markers and data reporting and statistics accounted for reporting heterogeneity amongst reports. Sensitivity analyses were not applicable due to the case report nature of included studies. However, the robustness of findings was enhanced through rigorous exclusion criteria and independent multi-author review. To mitigate reporting bias, only peer-reviewed articles with full texts were included. Certainty in the body of evidence was assessed by evaluating clinical data comprehensiveness, publication recency, and study peer-review status.

Results

Overall, 3,468 articles were identified through the initial literature search. Figure 1 demonstrates a flowchart summarizing the selection of included studies in accordance with PRISMA guidelines. After duplicates were excluded and articles were screened based on the title and abstract, 358 articles underwent full-text review, and 57 fulfilled the inclusion criteria. An additional 26 articles were identified by reviewing the references of the included articles. Thus, 83 (found in Table S1) studies were included for final analysis (Figure 1). Case reports (n=70) comprised 84.3% of the included studies, and 15.7% were case series (n=13), with case series defined as including three or more patient-specific reports.

Figure 1 PRISMA diagram of the process of included and excluded studies.

Data from 145 patients were included (Table 1). One patient’s (0.7%) data was reported from our institution. Seventy-seven patients (53.1%) were described in case reports, and the remaining 67 patients (46.2%) were described in case series. The mean patient age across the studies was 55.5 years with a range of 28–84 years; 130 (89.7%) were female and 15 were male (10.3%); 27/53 (51.9%) reported patients had a history of smoking. The histological types of lung cancer were 95 (65.1%) adenocarcinoma, 22 (15.2%) small cell lung cancer (SCLC), 20 (13.8%) neuroendocrine carcinoma, 4 (2.8%) squamous cell carcinoma (SCC), and 1 (0.7%) adenosquamous carcinoma. Two patients were described as having “carcinoma”, and 1 patient was described only as NSCLC. The mortality was 62.5% of those with reported survival outcomes and an average follow up of 15.0 months (range of 1 week to 19 years).

A proportion of 50.4% developed as a metachronous lesion with an average time to breast diagnosis of 24.2 months (range, 2–87 months); 70.5% reported patients had a single breast lesion; 40.8% of patients had ipsilateral metastatic breast disease relative to the site of the primary lung cancer; 19.4% patients had breast metastases contralateral to the primary lung cancer; and the remaining 39.8% patients were reported as having unilateral breast disease with unspecified laterality relative to the site of primary lung cancer. Of the patients, 29.5% had more than one metastatic breast lesion; 27.3% patients had multiple lesions in a single breast ipsilateral to the primary lung cancer; 15.2% patients had contralateral disease; and 12.1% had unilateral breast metastasis with unspecified laterality relative to the site of the primary lung cancer. Additionally, 45.4% of patients had bilateral breast metastases. The remaining 8 patients did not have laterality recorded. The most common additional site of metastatic disease was bone, present in 21.4%, followed by pleura (20.7%), brain (17.9%), liver (17.2%), axillary lymph nodes (15.9%), contralateral lung (9%), adrenal glands (6.2%), N3 or contralateral mediastinal lymph nodes (4.8%), and supraclavicular lymph nodes (2.8%). Twenty-nine patients had other extramammary sites of metastasis, including the peritoneum, omentum, and mesentery, scrotum, trachea, stomach, ovaries, retroperitoneum, skin, cervix, pancreas, kidney, spleen, and abdominal wall. Of note, 74 (51.0%) patients presented with an additional site of extrathoracic metastatic disease, not including disease spread to lymph nodes. 11 patients had isolated metastasis to lymph nodes.

Lung resection was performed in 11 (22.4%) patients, which included lobectomy (n=8), lobectomy plus segmentectomy (n=1), and pneumonectomy (n=2) (Table 1). All patients who underwent lung resection developed metachronous breast metastasis after the initial operation with an average time to breast metastasis of 31.3 months (range, 3–57 months). Six (54.5%) patients underwent additional breast resection after lung resection, including partial mastectomy (n=3), simple mastectomy (n=1), and modified radical mastectomy (n=2). A total of 24 (34.8%) patients underwent a breast resection, including partial mastectomy (n=18), simple mastectomy (n=4), and modified radical mastectomy (n=2). Chemotherapy and/or immunotherapy (neoadjuvant or adjuvant) were administered in 91.4% (74/81) of those reported. Radiotherapy was administered in 84.2% (32/38) of reported cases, 10 (31.3%) of which were administered for treatment of the primary lung carcinoma. Many case descriptions did not report whether chemoimmunotherapy or radiotherapy was used in management of lung versus breast cancer, nor what the specific regimens entailed.

The percentages of the positive IHC stains and molecular tests are listed in Table 2. TTF-1 was positive in 88.1% (96/109) of cases, CK7 in 91.7% (44/48), CK20 in 8.0% (2/25), Napsin A in 67.7% (21/31), ER in 7.1% (7/98), PR in 2.5% (2/81), Her-2 in 5.3% (2/38), GATA3 in 3.7% (1/27), and GCDFP15 in 0% (0/34). Molecular testing showed EGFR was positive in 55.6% (15/27), ALK in 31.3% (5/16), and ROS1 in 60.0% (3/5).

Management and outcomes of patients misdiagnosed as primary breast cancer is listed are Table 3. Overall, 24.5% (25/102) of reported patients were initially diagnosed and managed as primary breast cancer: 16 (64.0%) were adenocarcinoma, 1 SCC, 1 adenosquamous, 4 neuroendocrine, and 3 SCLC. Fifteen patients had synchronous lesions and 5 had metachronous breast lesions. Fourteen patients received chemotherapy, with 4 patients receiving breast cancer regimens during initial treatment. Two patients received radiation therapy. Seven (28.0%) patients underwent surgical resection, including partial mastectomy (n=2), simple mastectomy (n=3), lobectomy and partial mastectomy (n=1), and pneumonectomy (n=1). The mortality rate of patients misdiagnosed as primary breast cancer was 72.7% with an average follow-up of 8.25 months (range, 1–21 months).

All processes regarding the assessment of the characteristics of the data, including assessing study characteristics, risk of bias, statistical synthesis, heterogeneity, sensitivity analyses, reporting biases, and the certainty of evidence, were conducted to ensure a comprehensive and reliable synthesis of findings. Specific assessments and bias mitigation techniques have been summarized in Table S2. However, due to the nature and goals of this study and in the interest of providing a short, concise review, detailed descriptions of these methods were not included. This approach aligns with the study’s intent to focus on broader thematic insights rather than specific methodological intricacies.

Discussion

Lung cancers are diagnosed with varying proportions: 15% SCLC, 37–47% adenocarcinoma, 22% SCC, and 15–26% other (7,8). Our study of metastatic lung cancer found that 65.5% were adenocarcinoma, 15.2% SCLC, 13.8% neuroendocrine tumor, 2.8% SCC, and 0.7% adenosquamous carcinoma. The relative preponderance of adenocarcinoma in our study may be explained by the higher proportion of female patients, a population known to have a higher risk of lung adenocarcinoma specifically, which was 89.7% of our study’s patients, while only 47.5% of metastatic lung cancer patients are female (8,9). Site-specific metastatic spread for lung cancer has been reported as bone 19.2%, brain 13.3%, liver 12.2%, and distant lymph nodes 6.5% (10). In NSCLC specifically, the frequencies of metastatic sites are bone 34.3%, brain 28.4%, adrenals 16.7%, liver 13.4%, and 9.5% extrathoracic lymph nodes (11). Overall, these rates are lower compared to our study’s findings, likely due to all patients having breast metastasis. In particular, the rate of axillary lymph node spread is higher in our study, which may be related to the theory of metastatic spread to the breast via lymphatics (12-15). Metastatic spread from the lung to the ipsilateral breast may occur sequentially via invasion of the pleura, then drainage to the ipsilateral axillary or mediastinal lymphatics, and finally retrograde migration to the breast (15). This route is suggested by the presence of ipsilateral pleural effusion, axillary lymph node enlargement, and ipsilateral breast metastasis in affected patients (15-18). The absence of valves in the pulmonary venous system may facilitate a route that fosters a conducive environment for metastatic colonization (19). While hematogenous spread is generally accepted as the primary route of metastasis, the breasts’ limited blood supply and fibrous tissue make lung cancer metastasis to the breast rare compared to other tissues (13,14). Our study shows that most of the reported breast metastases (41.1%) occur in the ipsilateral breast; however, 19.4% of metastatic breast disease occurred in the contralateral breast. Thus, the laterality of breast metastases relative to the primary lung cancer site is uncertain in a considerable proportion of cases, potentially impacting the observed distribution of contralateral or ipsilateral breast disease.

Our findings additionally demonstrate a higher frequency of lung cancer metastasis to the breast in women compared to men. This observation prompts discussion, particularly considering statistics from the American Cancer Society indicating a higher and escalating incidence of lung cancer in men relative to women (20). Several hypotheses have been proposed regarding the pattern of breast metastasis. One factor that may elevate the risk includes the higher proportionate volume of breast tissue in women compared to men, which statistically offers a plausible explanation for the observed disparity in metastatic incidence between the sexes. Additionally, the higher concentration of estrogenic hormones in female breast tissue predisposes it to successful metastatic spread from ER-positive lung cancer, albeit uncommon. Future investigations for the potential pathways of metastatic spread in women may better inform our understanding of patterns of lung cancer spread.

Investigation of disease

The IHC panel for workup of the origin of carcinoma in the lung tissue includes many different biomarkers. CK7 is an epithelial biomarker present in lung cancer; CK20 is a cytokeratin detected in gastrointestinal tract tumors, which aids in differentiating the origin of metastatic adenocarcinoma; TTF-1 is a transcription factor tested for thyroid and lung cancer; Napsin A is seen in lung and gastrointestinal adenocarcinoma, metanephric adenoma, and endometrial and ovarian clear cell carcinomas; GATA3 is found in metastatic urothelial and breast carcinoma, SCC of skin, and mesothelioma; GCDFP15 was also collected as it is a marker of metastatic breast disease (21-29). As breast pathology, IHC stains often include ER, PR, and Her-2 receptor testing for prognostication and treatment guidance; this was collected as well. To note, 2–4% of lung cancers have a Her-2 mutation (30), which was consistent with the 5.3% positive rate recorded in our data. While markers classically associated with breast cancer, such as ER, PR, and Her-2 receptor, play a pivotal role in breast cancer, their significance in lung cancer remains less defined. Some studies have suggested associations between their positivity and poor prognosis in lung cancer (5,17,31,32). Increasing epidemiological evidence, preclinical in vitro and in vivo studies, and clinical trial data support ER positivity as a potentially clinically significant feature that may contribute to lung carcinogenesis, lung cancer growth and metastasis via interactions with the EGFR pathway. Although hormone receptor positivity has yet to influence treatment strategies in lung cancer, its assessment is part of the diagnostic evaluation for breast masses. However, these associations can further confound the ability to distinguish primary breast cancer vs. lung metastasis in breast tissue.

EGFR gene mutations are present in 10–50% of lung adenocarcinoma and ALK mutations are posed as driving development of 5–6% of NSCLC cases (33,34). ROS-1 mutations are found in 1–2% of lung adenocarcinoma and are associated with high response rates to c-MET/ALK inhibitors such as crizotinib but may also be found in angiosarcoma, cholangiocarcinoma, colorectal cancer, glioblastoma, ovarian cancer, and gastric adenocarcinoma (30,33-37). In recent years, PD-L1 has elicited increasing attention, particularly following the CheckMate 816 (Phase III trial of nivolumab plus chemotherapy in resectable NSCLC) and KEYNOTE-671 (Phase III trial of pembrolizumab plus chemotherapy in resectable NSCLC) trials, which demonstrated its efficacy in newer therapies (38,39). However, despite its growing popularity, PD-L1 IHC was not routinely performed in clinical practice until recently. Consequently, in our patient cohort, PD-L1 is significantly underreported, due to the majority of data being collected prior to the aforementioned trials and the incorporation of PD-L1 testing into routine clinical practice.

While TTF-1 remains a primary marker for diagnosing metastatic disease from the lung, its sensitivity is not all-inclusive. Our data indicate that approximately 88% of patients tested positive for TTF-1. As the majority (65.5%) of our cases were adenocarcinoma, it is consistent that the collection of the IHC markers was strongly indicative of lung adenocarcinoma. More specifically, TTF-1, CK7, and Napsin A were positive, as well as positive EGFR and ROS-1 mutations. Among the remaining 12% of patients who tested negative for TTF-1, diagnosis primarily relied on alternative characteristics. Histologic features such as tumor architecture and cell patterns, presence of metastasis to organs typical of lung cancer, and synchronous diagnosis of lung cancer with breast metastasis were key to lung cancer diagnosis.

Patients who initially present with synchronous breast and lung lesions created a scenario for misdiagnosis, particularly those with adenocarcinoma. Of the reported patients, 24.5% were misdiagnosed as having primary breast cancer in our review, of which 28.0% underwent surgical resection and 28.6% of those who received chemotherapy had regimens targeted toward breast cancer. These patients require careful evaluation of medical history, clinical presentation, and histopathological examination to achieve a correct diagnosis. Appropriately targeted management is critical, as patients misdiagnosed as primary breast cancer had a mortality rate of 72.7% in our review (see Table 3). Correct diagnosis and staging of metastatic lung cancer to the breast was made after further histopathologic analysis of a metastatic breast site. Thus, biopsy of suspected neoplasms and appropriate metastatic workup may help avoid unnecessary and incorrect interventions.

This study has limitations, including bias due to English-only full-text articles and selection bias in the analysis of case studies. Many studies lacked data on collected variables, such as survival, which may skew the findings. Heterogeneity among studies prevented meta-analysis. Despite limitations, our review provides the largest comprehensive summary of breast metastasis from lung neoplasms and emphasizes the importance of its clinical presentation.

In our temporal analysis of diagnostic patterns, we did not observe any trends in misdiagnosis rates across the study period. While notable technological advances in diagnostic capabilities have emerged during this timeframe, particularly in biomarker testing and molecular profiling (38,39), our study’s primary focus was on other disease patterns rather than quantifying the impact of these diagnostic improvements. Future studies specifically designed to evaluate the relationship between advancing diagnostic technologies and misdiagnosis rates may provide valuable insights into this important aspect of clinical practice.

Conclusions

Our systematic review sheds light on the diagnostic challenges posed by lung cancer metastasizing to the breast, a rare but significant clinical scenario. Despite the limitations inherent to the available literature, this study underscores the critical need for increased awareness among physicians regarding the possibility of metastatic lung cancer in breast masses, particularly when distinguishing between primary breast cancer and metastatic lung disease. By synthesizing current evidence, we emphasize the importance of accurate diagnosis in expediting appropriate treatment and improving patient outcomes. Moving forward, further research and enhanced understanding of specific clinical and pathological features are warranted to refine diagnostic approaches and optimize patient care.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2040/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2040/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2040/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7-33. [Crossref] [PubMed]
3. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Populations - Total U.S. (1969-2020) <Katrina/Rita Adjustment> - Linked To County Attributes - Total U.S., 1969-2020 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released January 2022.
4. 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;472:771-7. [Crossref] [PubMed]
5. Wu Q, Li J, Zhu S, et al. Breast cancer subtypes predict the preferential site of distant metastases: a SEER based study. Oncotarget 2017;8:27990-6. [Crossref] [PubMed]
6. Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma; analysis of 1000 autopsied cases. Cancer 1950;3:74-85. [Crossref] [PubMed]
7. Houston KA, Henley SJ, Li J, et al. Patterns in lung cancer incidence rates and trends by histologic type in the United States, 2004-2009. Lung Cancer 2014;86:22-8. [Crossref] [PubMed]
8. Wang X, Wang Z, Pan J, et al. Patterns of Extrathoracic Metastases in Different Histological Types of Lung Cancer. Front Oncol 2020;10:715. [Crossref] [PubMed]
9. Baiu I, Titan AL, Martin LW, et al. The role of gender in non-small cell lung cancer: a narrative review. J Thorac Dis 2021;13:3816-26. [Crossref] [PubMed]
10. Popper HH. Progression and metastasis of lung cancer. Cancer Metastasis Rev 2016;35:75-91. [Crossref] [PubMed]
11. Tamura T, Kurishima K, Nakazawa K, et al. Specific organ metastases and survival in metastatic non-small-cell lung cancer. Mol Clin Oncol 2015;3:217-21. [Crossref] [PubMed]
12. Zhao M, Xiang Y, Su F, et al. Male small-cell lung cancer with breast mass as the first manifestation: A rare case report. Asian J Surg 2023;46:2587-9. [Crossref] [PubMed]
13. Nakazawa K, Kurishima K, Tamura T, et al. Specific organ metastases and survival in small cell lung cancer. Oncol Lett 2012;4:617-20. [Crossref] [PubMed]
14. Lee SH, Park JM, Kook SH, et al. Metastatic tumors to the breast: mammographic and ultrasonographic findings. J Ultrasound Med 2000;19:257-62. [Crossref] [PubMed]
15. Huang HC, Hang JF, Wu MH, et al. Lung adenocarcinoma with ipsilateral breast metastasis: a simple coincidence? J Thorac Oncol 2013;8:974-9. [Crossref] [PubMed]
16. Vaughan A, Dietz JR, Moley JF, et al. Metastatic disease to the breast: the Washington University experience. World J Surg Oncol 2007;5:74. [Crossref] [PubMed]
17. Klingen TA, Klaasen H, Aas H, et al. Secondary breast cancer: a 5-year population-based study with review of the literature. APMIS 2009;117:762-7. [Crossref] [PubMed]
18. Maounis N, Chorti M, Legaki S, et al. Metastasis to the breast from an adenocarcinoma of the lung with extensive micropapillary component: a case report and review of the literature. Diagn Pathol 2010;5:82. [Crossref] [PubMed]
19. Reck M, Remon J, Hellmann MD. First-Line Immunotherapy for Non-Small-Cell Lung Cancer. J Clin Oncol 2022;40:586-97. Erratum in: J Clin Oncol 2022;40:1265. [Crossref] [PubMed]
20. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48. [Crossref] [PubMed]
21. Fei F, Li C, Cao Y, et al. CK7 expression associates with the location, differentiation, lymph node metastasis, and the Dukes' stage of primary colorectal cancers. J Cancer 2019;10:2510-9. [Crossref] [PubMed]
22. Su YC, Hsu YC, Chai CY. Role of TTF-1, CK20, and CK7 immunohistochemistry for diagnosis of primary and secondary lung adenocarcinoma. Kaohsiung J Med Sci 2006;22:14-9. [Crossref] [PubMed]
23. Agoff SN, Lamps LW, Philip AT, et al. Thyroid transcription factor-1 is expressed in extrapulmonary small cell carcinomas but not in other extrapulmonary neuroendocrine tumors. Mod Pathol 2000;13:238-42. [Crossref] [PubMed]
24. Weidemann S, Böhle JL, Contreras H, et al. Napsin A Expression in Human Tumors and Normal Tissues. Pathol Oncol Res 2021;27:613099. [Crossref] [PubMed]
25. Sharifai N, Abro B, Chen JF, et al. Napsin A is a highly sensitive marker for nephrogenic adenoma: an immunohistochemical study with a specificity test in genitourinary tumors. Hum Pathol 2020;102:23-32. [Crossref] [PubMed]
26. Liu H, Shi J, Wilkerson ML, et al. Immunohistochemical evaluation of GATA3 expression in tumors and normal tissues: a useful immunomarker for breast and urothelial carcinomas. Am J Clin Pathol 2012;138:57-64. [Crossref] [PubMed]
27. Higgins JP, Kaygusuz G, Wang L, et al. Placental S100 (S100P) and GATA3: markers for transitional epithelium and urothelial carcinoma discovered by complementary DNA microarray. Am J Surg Pathol 2007;31:673-80. [Crossref] [PubMed]
28. Miettinen M, McCue PA, Sarlomo-Rikala M, et al. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol 2014;38:13-22. [Crossref] [PubMed]
29. Ding Q, Huo L, Peng Y, et al. Immunohistochemical Markers for Distinguishing Metastatic Breast Carcinoma from Other Common Malignancies: Update and Revisit. Semin Diagn Pathol 2022;39:313-21. [Crossref] [PubMed]
30. Villalobos P, Wistuba II. Lung Cancer Biomarkers. Hematol Oncol Clin North Am 2017;31:13-29. [Crossref] [PubMed]
31. Valenza C, Porta FM, Rappa A, et al. Complex Differential Diagnosis between Primary Breast Cancer and Breast Metastasis from EGFR-Mutated Lung Adenocarcinoma: Case Report and Literature Review. Curr Oncol 2021;28:3384-92. [Crossref] [PubMed]
32. Liang Amy ST, Ryan C, O'Hern K, et al. Primary estrogen receptor-positive lung adenocarcinoma identified by immunohistochemical investigation of rare cutaneous metastasis to the breast in a patient with presumed recurrent estrogen receptor-positive breast cancer. JAAD Case Rep 2021;14:85-7. [Crossref] [PubMed]
33. Du X, Shao Y, Qin HF, et al. ALK-rearrangement in non-small-cell lung cancer (NSCLC). Thorac Cancer 2018;9:423-30. [Crossref] [PubMed]
34. Le T, Gerber DE. ALK alterations and inhibition in lung cancer. Semin Cancer Biol 2017;42:81-8. [Crossref] [PubMed]
35. Yoshida A, Kohno T, Tsuta K, et al. ROS1-rearranged lung cancer: a clinicopathologic and molecular study of 15 surgical cases. Am J Surg Pathol 2013;37:554-62. [Crossref] [PubMed]
36. Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 2013;18:865-75. [Crossref] [PubMed]
37. Davies KD, Le AT, Theodoro MF, et al. Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clin Cancer Res 2012;18:4570-9. [Crossref] [PubMed]
38. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
39. Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:491-503. [Crossref] [PubMed]