Context.—

The utility of immunohistochemistry (IHC) in breast lesions needs to be updated with exceptions among these lesions. Biomarker studies with IHC in triple-negative breast carcinoma may help develop targeted therapies for this aggressive breast cancer. The distinction of metastatic lung adenocarcinoma to the breast and invasive breast carcinoma has significant prognostic and therapeutic implications. The determination can be challenging because both primary tumors can express estrogen receptor and/or HER2 by IHC, creating a diagnostic dilemma.

Objectives.—

To provide a practical update on the use of IHC markers in differential diagnoses in breast lesions, including benign, atypical, precancerous, and malignant tumors; to highlight recently published research findings on novel IHC markers in triple-negative breast carcinoma cases; and to reinforce the importance of IHC use as an ancillary tool in distinguishing metastatic lung adenocarcinoma to the breast from primary breast carcinoma using real case examples.

Data Sources.—

PubMed (US National Library of Medicine, Bethesda, Maryland) literature review and authors' research data and personal experiences were used in this review.

Conclusions.—

Immunohistochemistry has an important role in making differential diagnoses in breast lesions in morphologically equivocal settings; recognizing IHC expression status in the exceptions among these lesions will aid in the correct diagnosis of challenging breast cases. Studies suggest that androgen receptor, p16, p53, GATA3, and PELP1 may have potential diagnostic, prognostic, and predictive value in triple-negative breast carcinoma cases; these findings may provide insight and a greater understanding of the tumor biology in triple-negative breast carcinomas. In distinguishing metastatic estrogen receptor–positive or HER2+ lung adenocarcinoma to the breast from primary breast carcinoma, napsin A, TTF-1, and GATA3 comprise a useful IHC panel.

Distinguishing Between Usual Ductal Hyperplasia and Atypical Ductal Hyperplasia/Low-Grade Ductal Carcinoma In Situ

Usual ductal hyperplasia (UDH) and atypical ductal hyperplasia (ADH)/low-grade ductal carcinoma in situ (LG-DCIS) are biologically distinct, intraductal, epithelial proliferations with different clinical implications. Usual ductal hyperplasia consists of a heterogeneous proliferation of mixed populations of cells, including luminal/epithelial and myoepithelial (MEP) cells. Usual ductal hyperplasia can even contain apocrine metaplastic cells. It has minimal subsequent risks of cancer development.1  In contrast, ADH/LG-DCIS comprises a proliferation of a low-grade, monotonous population of luminal cells with significantly greater risk (3–5 times greater risk than that of the general population) of subsequent cancer.2  Immunohistochemical (IHC) analysis for differential cytokeratin staining and estrogen receptor (ER) expression can be helpful in difficult cases, especially when UDH is associated with necrosis or mitosis (Table 1; Figure 1, A and B). Usual ductal hyperplasia shows a mixed phenotype for both low–molecular-weight cytokeratins (CK7, CK8, and CK18, the luminal cytokeratins) and high–molecular-weight cytokeratins (34βE12, CK5, CK5/6, CK14, and CK17, the basal cytokeratins) and a heterogeneous or mosaic staining pattern for ER.3  Atypical ductal hyperplasia/LG-DCIS typically shows restricted luminal cytokeratin expression and uniform, strong ER expression (Figure 1, C and D).

Table 1

Usual Ductal Hyperplasia (UDH) Versus Atypical Ductal Hyperplasia (ADH)/Low-Grade Ductal Carcinoma In Situ (LG-DCIS)

Usual Ductal Hyperplasia (UDH) Versus Atypical Ductal Hyperplasia (ADH)/Low-Grade Ductal Carcinoma In Situ (LG-DCIS)
Usual Ductal Hyperplasia (UDH) Versus Atypical Ductal Hyperplasia (ADH)/Low-Grade Ductal Carcinoma In Situ (LG-DCIS)
Figure 1

Examples of usual ductal hyperplasia (A and B), atypical ductal hyperplasia (C and D), and basal-like ductal carcinoma in situ (E and F) (hematoxylin-eosin, original magnification ×400 [A, C, and E]; CK5, original magnification ×400 [B, D, and F]).

Figure 1

Examples of usual ductal hyperplasia (A and B), atypical ductal hyperplasia (C and D), and basal-like ductal carcinoma in situ (E and F) (hematoxylin-eosin, original magnification ×400 [A, C, and E]; CK5, original magnification ×400 [B, D, and F]).

Noteworthy Exceptions.—

Basal-like DCIS can sometimes mimic UDH, and staining is positive for CK5, CK5/6, CK14, or CK17 in either a diffuse or patchy pattern. The neoplastic cells, however, are usually of a high nuclear grade—often with abundant mitoses and central necrosis—and can be negative for ER and progesterone receptor (PR).4 

Example 1.—

A 45-year-old woman presented with newly developed microcalcifications in the right breast on a screening mammogram. An ultrasound-guided core biopsy was performed. Sections of the tissues showed morphologic features of high-grade DCIS, as illustrated in Figure 1, E, with ER, PR, and HER2 staining and central necrosis. The tumor cells also stained positively for CK5, as shown in Figure 1, F, consistent with a diagnosis of basal-like DCIS.

Distinguishing Between Invasive and In Situ Carcinomas

In addition to morphologic features (Table 2), MEP markers (Table 3) serve as important adjuncts for distinguishing between radial scars, invasive ductal carcinoma, and DCIS involving sclerosing adenosis. Basal-type cytokeratins, smooth muscle myosin heavy chain, smooth muscle actin, calponin, and p63 that are the frequently used MEP markers with varying specificities and sensitivities that are used to make the distinction. Clinical practices often use more than one MEP marker.5  Collagen IV and laminin have been used for distinguishing invasive carcinoma from in situ carcinoma.6  Benign or in situ lesions should demonstrate positive staining for MEP markers, whereas invasive carcinomas should show a loss of MEP staining at the periphery of each glandular structure (Figure 2, A through F). Cytokeratin markers may be helpful in highlighting the presence of malignant cells of a microinvasive carcinoma (≤1 mm) arising in a background of DCIS.7 

Table 2

Radial Scar Versus Tubular Carcinoma Versus Ductal Carcinoma In Situ (DCIS) in Sclerosing Adenosis (SA)

Radial Scar Versus Tubular Carcinoma Versus Ductal Carcinoma In Situ (DCIS) in Sclerosing Adenosis (SA)
Radial Scar Versus Tubular Carcinoma Versus Ductal Carcinoma In Situ (DCIS) in Sclerosing Adenosis (SA)
Table 3

Myoepithelial (MEP) Markers

Myoepithelial (MEP) Markers
Myoepithelial (MEP) Markers
Figure 2

Examples of immunohistochemistry (IHC) in nonbasal-like ductal carcinoma in situ (DCIS) (A and B), invasive ductal carcinoma (C and D), basal-like DCIS (E and F), adenoid cystic carcinoma (G and H), and microglandular adenosis (I through L). ADH5 is a cocktail of IHC markers that includes CK8/18-pink, CK5/14-brown, and p63-brown (hematoxylin-eosin, original magnifications ×200 [A] and ×400 [C, E, G, and I]; p63, original magnifications ×200 [B] and ×400 [H and K]; ADH5, original magnification ×400 [D]; CK5, original magnification ×400 [F]; estrogen receptor, original magnification ×400 [J]; S100, original magnification ×400 [L]).

Figure 2

Examples of immunohistochemistry (IHC) in nonbasal-like ductal carcinoma in situ (DCIS) (A and B), invasive ductal carcinoma (C and D), basal-like DCIS (E and F), adenoid cystic carcinoma (G and H), and microglandular adenosis (I through L). ADH5 is a cocktail of IHC markers that includes CK8/18-pink, CK5/14-brown, and p63-brown (hematoxylin-eosin, original magnifications ×200 [A] and ×400 [C, E, G, and I]; p63, original magnifications ×200 [B] and ×400 [H and K]; ADH5, original magnification ×400 [D]; CK5, original magnification ×400 [F]; estrogen receptor, original magnification ×400 [J]; S100, original magnification ×400 [L]).

Noteworthy Exceptions.—

There are invasive carcinomas that express MEP markers; this group of cancers consist of tumor cells that stain positive for MEP markers. They include, among others, adenoid cystic carcinoma (Figure 2, G and H) and metaplastic carcinoma. In these cases, careful evaluation of the location (the nonperipheral, linear location) of the MEP marker–positive cells is critical for a correct diagnosis.8,9 

Benign lesions without MEP cells (Table 4) include microglandular adenosis, which is an infiltrative, benign breast lesion consisting of small, round, open glands formed by a single layer of flat to cuboidal epithelial cells with fibrous or fatty stroma. Microglandular adenosis, which is surrounded by an often-thickened basement membrane, lacks MEP cells and contains periodic acid–Schiff diastase–positive secretions. Microglandular adenosis is a mimic of tubular carcinoma. Microglandular adenosis is positive for collagen IV; negative for ER, PR, and p63; and often strongly positive for S100, whereas tubular carcinoma is ER+/PR+ and p63 and S100.10 

Table 4

Microglandular Adenosis (MGA) Versus Tubular Carcinoma (TC)

Microglandular Adenosis (MGA) Versus Tubular Carcinoma (TC)
Microglandular Adenosis (MGA) Versus Tubular Carcinoma (TC)

Example 2.—

A 56-year-old woman presented with an architectural distortion in the left breast on screening mammogram; a core biopsy revealed focal, flat epithelial atypia. A partial mastectomy revealed a 0.6-cm lesion with small, round, open glands, each lined with a single layer of cuboid cells, as illustrated in Figure 2, I, and those cells were negative for ER (Figure 2, J) and p63 (Figure 2, K) and were positive for S100 (Figure 2, L), consistent with a diagnosis of microglandular adenosis. No evidence of malignancy was identified.

Distinguishing Between Lobular and Ductal Lesions

Because lobular and ductal carcinomas have different clinical behaviors and different clinical implications, differentiating between these lesions is important for patient management. Loss of E-cadherin expression is one of the most consistent molecular alterations in lobular lesions reported in the literature. However, E-cadherin stains not only epithelial (luminal) cells but also MEP cells. p120 catenin (p120) demonstrates membranous staining in ductal lesions and diffuse cytoplasmic staining in lobular lesions.11  p120 can be helpful in the diagnoses of some invasive lobular carcinomas, especially when they consist of sparse single-tumor cells, because of its cytoplasmic staining. In addition, the positive staining pattern of p120 is helpful in the diagnosis of lobular lesions when an internal, positive control for E-cadherin staining is lacking.

In Situ Lobular Lesions.—

Two variants of lobular carcinoma in situ (LCIS)—pleomorphic lobular carcinoma in situ (Figure 3, A and B)12  and florid LCIS with central necrosis (Figure 3, C and D)13—can mimic high-grade DCIS and low-grade DCIS with central necrosis, respectively. Loss of E-cadherin in IHC analysis is critical for differentiating the 2 variants of LCIS and DCIS. Sometimes, atypical lobular hyperplasia/LCIS in collagenous spherulosis can mimic low-grade cribriform DCIS. A loss of IHC staining for E-cadherin and p63 in lesional cells, but with staining present around small cribriform spaces, is helpful in differentiating lobular neoplasia from DCIS. On rare occasions, LCIS can demonstrate aberrant E-cadherin staining (Figure 3, E and F). p120 and E-cadherin double stains can be helpful in such situations (Figure 3, G and H).

Figure 3

Examples of pleomorphic lobular carcinoma in situ (A and B), florid lobular carcinoma in situ (C and D), and lobular carcinoma in situ (LCIS) (E through G). H, LCIS with associated invasive lobular carcinoma (hematoxylin-eosin, original magnifications ×200 [A] and ×400 [C and E]; E-cadherin, original magnifications ×200 [B] and ×400 [D and F]); p120-catenin (pink) and E-cadherin (brown) double stain, original magnification ×400 [G and H]).

Figure 3

Examples of pleomorphic lobular carcinoma in situ (A and B), florid lobular carcinoma in situ (C and D), and lobular carcinoma in situ (LCIS) (E through G). H, LCIS with associated invasive lobular carcinoma (hematoxylin-eosin, original magnifications ×200 [A] and ×400 [C and E]; E-cadherin, original magnifications ×200 [B] and ×400 [D and F]); p120-catenin (pink) and E-cadherin (brown) double stain, original magnification ×400 [G and H]).

Noteworthy Exceptions.—

Occasionally, E-cadherin can show aberrant expression in lobular lesions,14  even though these lesions carry a mutated E-cadherin gene and/or dysfunctional E-cadherin protein. Thus, interpretation of the staining results in such cases must be correlated with the corresponding hematoxylin-eosin morphology.

Invasive Lobular Carcinomas.—

Any cell type that can cause increased stromal cellularity can mimic invasive lobular carcinoma, although careful morphologic evaluation is usually sufficient for a correct diagnosis. Occasionally, IHC analysis of stromal cells with AE1/AE3, CD68, CD34, desmin, smooth muscle actin, ER, and PR is helpful in determining the diagnosis (Table 5).

Table 5

Invasive Lobular Carcinoma and Its Mimics

Invasive Lobular Carcinoma and Its Mimics
Invasive Lobular Carcinoma and Its Mimics

Distinguishing Between Papillary Lesions

A papillary lesion of the breast is characterized by an epithelial proliferation arising within the ductal/lobular system, supported by fibrovascular cores, with or without an intervening MEP cell layer. Papillary lesions consist of a range of benign, atypical, in situ, and even invasive lesions. Papillary lesions are among the most challenging in diagnostic breast pathology, and IHC analysis is often used in making the diagnosis.15,16  The most commonly used markers are CK5 (or CK5/6) for the presence or absence of UDH and MEP cells, and p63 for the presence or absence of MEP cells. Table 6 summarizes the distinguishing histologic and immunophenotypic features of papillary lesions of the breast.

Table 6. 

Distinguishing Histologic and Immunophenotypic Features of Papillary Lesions of the Breast

Distinguishing Histologic and Immunophenotypic Features of Papillary Lesions of the Breast
Distinguishing Histologic and Immunophenotypic Features of Papillary Lesions of the Breast

Intraductal Papilloma.—

Intraductal papilloma (IP) is a benign papillary lesion characterized by fibrovascular cores lined by MEP and epithelial layers. Immunohistochemistry analysis for MEP markers highlights the presence of MEP cells along the fibrovascular cores and at the periphery of the lesions (Figure 4, A through D).

Figure 4

Examples of immunohistochemistry in intraductal papilloma [A through D] and intraductal papilloma with low-grade ductal carcinoma in situ [E through H]. ADH5 is a cocktail of immunohistochemical markers that includes CK8/18-pink, CK5/14-brown, and p63-brown (hematoxylin-eosin, original magnifications ×40 [A], ×200 [B], ×100 [E], and ×400 [G]; CK5, original magnifications ×200 [C] and ×100 [F]; p63, original magnification ×200 [D]; ADH5, original magnification ×400 [H]).

Figure 4

Examples of immunohistochemistry in intraductal papilloma [A through D] and intraductal papilloma with low-grade ductal carcinoma in situ [E through H]. ADH5 is a cocktail of immunohistochemical markers that includes CK8/18-pink, CK5/14-brown, and p63-brown (hematoxylin-eosin, original magnifications ×40 [A], ×200 [B], ×100 [E], and ×400 [G]; CK5, original magnifications ×200 [C] and ×100 [F]; p63, original magnification ×200 [D]; ADH5, original magnification ×400 [H]).

IP With ADH/LG-DCIS.—

Intraductal papilloma can contain areas of atypia that are diagnostic of ADH or LG-DCIS. Intraductal papilloma with atypia is characterized by the presence of a population of monotonous cells with cytologic and architectural features of LG-DCIS. The MEP cells are typically scant or absent in atypical areas. Lack of CK5 or ADH-5 (the breast marker cocktail) staining (Figure 4, E through H) and uniform ER expression are helpful clues for the diagnosis of IP with ADH/LG-DCIS.17  An IP with atypia can be classified as IP with ADH or IP with LG-DCIS, depending on the size of the atypical proliferation. If the size of the atypical area within an IP is smaller than 3 mm, the lesion is classified as IP with ADH; if the atypical area is 3 mm or larger, it is called IP with LG-DCIS.16 

Intraductal Papillary Carcinoma.—

Intraductal papillary carcinoma lesions are considered a de novo, in situ papillary malignant process without a recognizable benign IP in the background. Intraductal papillary carcinoma consists of slender fibrovascular cores covered by a single layer of monotonous neoplastic cells without the presence of MEP cells; however, the MEP cells are retained at the periphery of the lesions but, often, in a more-attenuated form (Figure 5, A through D). The neoplastic cells are usually low to intermediate nuclear grade and are often strongly positive for ER, PR, and luminal cytokeratins.

Figure 5

Examples of immunohistochemistry in intraductal papillary carcinoma (A through D), encapsulated papillary carcinoma (E through H), and solid papillary carcinoma (I through L). ADH5 is a cocktail of IHC markers that includes CK8/18-pink, CK5/14-brown, and p63-brown (hematoxylin-eosin, original magnifications ×40 [A, E, and I], ×100 [B], ×200 [G], and ×400 [J]; CK5, original magnifications ×200 [C] and ×100 [K]; p63, original magnifications ×200 [D] and ×100 [L]; ADH5, original magnifications ×40 [F] and ×200 [H]).

Figure 5

Examples of immunohistochemistry in intraductal papillary carcinoma (A through D), encapsulated papillary carcinoma (E through H), and solid papillary carcinoma (I through L). ADH5 is a cocktail of IHC markers that includes CK8/18-pink, CK5/14-brown, and p63-brown (hematoxylin-eosin, original magnifications ×40 [A, E, and I], ×100 [B], ×200 [G], and ×400 [J]; CK5, original magnifications ×200 [C] and ×100 [K]; p63, original magnifications ×200 [D] and ×100 [L]; ADH5, original magnifications ×40 [F] and ×200 [H]).

Encapsulated Papillary Carcinoma.—

Encapsulated papillary carcinoma (EPC) is a variant of intraductal papillary carcinoma and is characterized by fine fibrovascular cores covered by neoplastic cells surrounded by a fibrous capsule. Encapsulated papillary carcinoma lacks MEP cells, both at the periphery of the lesion and within the fibrovascular cores.18,19  Most of the EPCs are low- to intermediate-grade, usually have a favorable prognosis, and are currently staged and managed as in situ carcinoma (pTis).16  Some authors consider EPCs to be slow-growing, invasive lesions or lesions in transition from in situ to invasion.18  High-grade EPCs are rare and account for approximately 3% of the EPCs. A high-grade EPC is defined by marked nuclear pleomorphism and increased mitotic activities. It is also often negative for hormone receptor, tends to be larger, and is more frequently associated with stromal invasion as compared with low- to intermediate-grade EPCs. A recent study reported that 1 of 10 patients with pure, high-grade EPC developed recurrence and died of the disease.20  Because of its aggressive clinical behavior, those authors suggest managing high-grade EPC in a similar fashion to invasive breast carcinoma. Figure 5, E through H, shows an example of EPC with negativity of ADH-5 immunostaining.

Solid Papillary Carcinoma.—

Solid papillary carcinoma (SPC) is a distinctive variant of papillary carcinoma with a solid growth pattern and inconspicuous fibrovascular cores. It typically has a single, large, expansile mass or multiple solid, closely opposed nodules, and it may show spindle cell morphology and/or mucin production. The neoplastic cells are strongly positive for ER and PR and are negative for CK5, CK5/6, and MEP markers. Figure 5, I through L, shows an example of SPC with negative CK5 and p63 staining. A study21  reported that, of 20 SPC cases, at least 10 (50%) expressed one or more neuroendocrine markers. Solid papillary carcinoma should be differentiated from UDH, which is positive for CK5 and CK5/6.2224  Regardless of the presence or absence of peripheral MEP cells, SPC is staged as an in situ tumor (Tis) if it has a smooth, nodular tumor border. A lesion is considered invasive SPC only with the presence of a geographic “jigsaw” pattern with ragged, irregular borders in the absence of MEP cells.16 

Noteworthy Exceptions.—

IP With Diffuse, Florid UDH Versus IP With ADH/LG-DCIS or SPC.—

Florid UDH is commonly seen within IP (Figure 6, A and B). Distinguishing between florid UDH and ADH/LG-DCIS within IP or SPC can be challenging diagnostically. Immunohistochemistry analysis with CK5 can be helpful; CK5 stains positively in florid UDH (Figure 6, C) but is negative in ADH/LG-DCIS or SPC. p63 stain shows scattered positivity in florid UDH (Figure 6, D). In addition, ER and PR are diffusely and homogeneously positive in ADH/LG-DCIS and SPC but are variable expressed or show a mosaic expression in UDH.24 

Figure 6

Examples of immunohistochemistry in intraductal papilloma with florid usual ductal hyperplasia (A through D), intraductal papilloma with sclerosis (E through H), and adenomyoepithelioma (I through L; the arrow indicates a mitotic figure in [J]) (hematoxylin-eosin, original magnifications ×40 [A, E, and I] and ×400 [B and J]; CK5, original magnifications ×400 [C and K] and ×200 [F]; p63, original magnifications ×400 [D and L] and ×200 [G]; calponin, original magnification ×400 [H]).

Figure 6

Examples of immunohistochemistry in intraductal papilloma with florid usual ductal hyperplasia (A through D), intraductal papilloma with sclerosis (E through H), and adenomyoepithelioma (I through L; the arrow indicates a mitotic figure in [J]) (hematoxylin-eosin, original magnifications ×40 [A, E, and I] and ×400 [B and J]; CK5, original magnifications ×400 [C and K] and ×200 [F]; p63, original magnifications ×400 [D and L] and ×200 [G]; calponin, original magnification ×400 [H]).

IP With Sclerosis Versus Invasive Carcinoma.—

Intraductal papilloma with sclerosis (Figure 6, E) can be difficult to distinguish from invasive carcinoma. A benign cytology, strong CK5 positivity (Figure 6, F), and ER negativity are helpful clues in making a correct diagnosis. Immunohistochemistry analysis with additional MEP markers, such as p63, calponin, or smooth-muscle myosin heavy chain, can highlight the associated MEP cells within the lesion, confirming the benign nature of IP with sclerosis (Figure 6, G and H).

Adenomyoepithelial Lesion With a Papillary Growth Pattern Versus IP.—

Adenomyoepithelial lesion is a neoplasm that is characterized by a biphasic proliferation of ductal epithelial and MEP cells.25  Histologically, adenomyoepithelial lesions can exhibit lobulated, tubular, papillary, or mixed patterns. When a papillary pattern predominates, differentiating an adenomyoepithelial lesion from IP with MEP cell hyperplasia is difficult. Immunohistochemistry analysis for CK5 and MEP markers can highlight the dual populations of epithelial and MEP cells, respectively.26  The MEP cells are ER, PR, and HER2.27  Adenomyoepithelioma with a malignant transformation is extremely rare and when seen, is found in both ductal epithelial and MEP components. However, there are only few reports of that transformation in the literature.28 

Example 3.—

A 40-year-old woman presented with a solitary mass in the right breast. A diagnostic mammography revealed a 2.5-cm lesion with a well-demarcated border. An ultrasound-guided core biopsy was performed, which showed an IP with areas of MEP hyperplasia. A subsequent surgical-excision specimen showed a solid papillary lesion with focal necrosis; the morphologic features are shown in Figure 6, I. These cells present with nuclear atypia and increased mitotic activity (Figure 6, J). Immunophenotypically, the cells are positive for CK5 (Figure 6, K) and p63 (Figure 6, L) and are negative for ER, PR, and HER2. One positive right axillary lymph node was identified at the time of the surgery. The final diagnosis was malignant adenomyoepithelioma.

 Fibroepithelial lesions.—

Occasionally, fibroepithelial lesions show a prominent papillary-like growth pattern and mimic papillary lesions. Clinical information, such as the patient's age (younger for fibroepithelial lesions) and the lesion location in the breast (central location for papillary lesions), can be helpful. Immunohistochemistry analysis, especially for CD34, may be helpful as well; the stromal cells are often positive for CD34 in fibroepithelial lesions.29 

Overview of Clinicopathologic Characteristics of Triple-Negative Breast Carcinoma

Breast carcinomas are classified as ER+ (luminal A and luminal B), HER2+, or triple negative. The different types demonstrate different tumor biology, prognoses, and therapy responses based on their gene expression profiles.

Triple negative breast carcinomas (TNBCs) represent approximately 15% of all breast carcinomas and have the worst 5-year survival rate of any type of breast cancer.30  They do not drive their growth with the hormones estrogen or progesterone or with the oncogene HER2 and, correspondingly, are characterized by their lack of ER, PR, and HER2 expression in IHC. Without a known driver, there has been no “target” for developing targeted therapy. Women with TNBCs do not benefit from endocrine therapy or trastuzumab. Currently, conventional chemotherapy is the main treatment modality for TNBC in a neoadjuvant or adjuvant setting. However, more than one-half of TNBCs do not respond to chemotherapy.31  Predictably, patients who do not obtain a complete pathologic response have a high likelihood of disease relapse, frequent distant metastases, and a poorer prognosis compared with patients who have hormonal receptor–positive breast cancer. As compared with patients who have non-TNBCs, patients with TNBCs are younger at disease onset (<50 years) with a higher tumor grade at diagnosis and a higher rate of developing metastatic disease. These aggressive tumors also have different metastatic patterns compared with non-TNBC tumors. Distant metastases typically occur early in the disease course, with a propensity for visceral metastasis to the lung and brain, rather than the lymph nodes, bone, or liver as seen in non-TNBCs.30,3234  The development of targeted therapies is crucial to improve the clinical outcome for these patients. There is a need to further elucidate the molecular basis of TNBC to identify novel prognostic and predictive tumor biomarkers. These studies are vital to developing targeted therapies for patients with TNBC, particularly for those who do not respond to chemotherapy.

Histologically, TNBCs are usually high-grade, invasive ductal carcinomas. Triple-negative breast cancers can be divided into 2 subtypes by IHC: basal-like and nonbasal-like tumors. The basal-like TNBCs are defined by CK5 or CK5/6 and/or epidermal growth factor receptor (EGFR) positivity and have a worse prognosis than nonbasal-like TNBCs.30,34  Basal-like TNBCs, which comprise most of these tumors, have characteristic histologic features. The tumors are typically well circumscribed with pushing borders and often have central tumor necrosis. Highly atypical tumor cells are arranged in solid sheets or nests with a prominent lymphocytic infiltrate and brisk mitotic activity (Figure 7, A through C). The tumors commonly have high expression of Ki-67 (Figure 7, D), a high proliferation index, and high p53 expression, a tumor suppressor protein.

Figure 7

Examples of various stains in, and morphologic features of, basal-like triple-negative breast carcinoma (hematoxylin-eosin, original magnifications ×20 [A], ×200 [B], and ×400 [C]; Ki-67, original magnification ×100 [D]; CK5/6, original magnification ×100 [E]; EGFR, original magnification ×200 [F]).

Figure 7

Examples of various stains in, and morphologic features of, basal-like triple-negative breast carcinoma (hematoxylin-eosin, original magnifications ×20 [A], ×200 [B], and ×400 [C]; Ki-67, original magnification ×100 [D]; CK5/6, original magnification ×100 [E]; EGFR, original magnification ×200 [F]).

Tumor Heterogeneity of TNBCs

Recent studies by molecular analysis have demonstrated that TNBCs are a heterogeneous group of tumors. Six TNBC subtypes were identified using gene expression profiling: (1) basal-like carcinoma (BL1 and BL2), which is the major subtype; (2) immunomodulatory; (3) mesenchymal; (4) mesenchymal stemlike; (5) luminal androgen receptor; and (6) unstable subtypes.35  This further characterization of TNBCs has allowed for specific targeting of the unique biologic behavior of each subtype. For instance, the basal-like subtype was noted to have high expression of genes involved in cell cycle and division, and several studies have shown increased benefit in women with basal-like TNBC treated with mitotic inhibitors, such as taxanes.35  The molecular variation in TNBCs may result from differing tumor responses to chemotherapy, which requires different therapeutic approaches to these lesions.

Prognostic and Predictive Values of Androgen Receptor in TNBCs

Androgen receptor (AR) expression has been shown to have prognostic implications in breast cancers, and higher AR expression levels have been associated with higher expression of ER or PR, lower nuclear grade, and smaller tumors, with lower risk of recurrence and death.3637  Significant differences in AR protein expression have been detected in the various molecular subtypes of breast cancers. Triple-negative breast cancers, which are by nature ER, characteristically have much lower frequency of AR expression compared with ER+ breast cancers.33,3537 

A recent study revealed that only 38 (31.4%) of the 121 TNBC cases expressed AR when analyzed by IHC (Figure 8, A),33  which is similar to other studies reporting 25% to 35% positivity.36,3840  Genetic profiling analyses have demonstrated that AR-expressing TNBCs are the luminal androgen receptor subtype of TNBC.35  Previous studies on AR expression in TNBCs have shown that AR tumors are associated with shorter disease-free intervals and overall survival compared with AR+ TNBCs.4043  In 2012, a group reported that, among AR+ TNBCs, patients with distant metastases (pathologic staging: pM1) had tumors that were significantly associated with a lower intratumoral expression of AR protein as compared with patients without distant metastasis or who had only locoregional disease (pathologic staging: pM0).33  The study also demonstrated that the AR expression was inversely correlated with Ki-67. This result suggests that TNBCs with higher AR expression may be associated with a better prognosis, partly because decreased tumor cell proliferation caused by the increased antiproliferative effect of AR stimulation. These findings indicate AR could be used as a prognostic marker for TNBCs.

Figure 8

Examples of various immunohistochemistry markers in triple-negative breast carcinoma (TNBC) and benign breast tissue. A, Positive androgen receptor staining in TNBC. B, Positive p16 staining in TNBC. C, Negative p16 staining in paired, benign breast lobules. D, Positive PELP1 staining in TNBC. E, Reduced E-cadherin staining in TNBC. F, Normal E-cadherin staining in paired, benign breast ducts (original magnification ×200 [A]; original magnifications ×200 [B] and ×100 [C]; original magnification ×200 [D]; original magnification ×200 [E and F].

Figure 8

Examples of various immunohistochemistry markers in triple-negative breast carcinoma (TNBC) and benign breast tissue. A, Positive androgen receptor staining in TNBC. B, Positive p16 staining in TNBC. C, Negative p16 staining in paired, benign breast lobules. D, Positive PELP1 staining in TNBC. E, Reduced E-cadherin staining in TNBC. F, Normal E-cadherin staining in paired, benign breast ducts (original magnification ×200 [A]; original magnifications ×200 [B] and ×100 [C]; original magnification ×200 [D]; original magnification ×200 [E and F].

The AR signaling pathway may represent a molecular driver that can be therapeutically targeted in AR-expressing TNBCs by using an AR inhibitor as a novel therapeutic agent. Therefore, knowing the AR expression status of a TNBC is necessary for selecting patients who could benefit from antiandrogen therapy. Antiandrogen therapy may be of particular interest to those who do not respond to conventional chemotherapy, or it could even be used as an addition to first-line therapies. Several studies have shown positive results for AR antagonists. One such study demonstrated that luminal androgen receptor cell lines were uniquely sensitive to bicalutamide, an AR antagonist.35  In mouse models of TNBC with a low percentage of AR+ tumor cells, the antiandrogen drug enzalutamide was significantly effective at reducing proliferation, growth, migration, and invasion of the cancer cells. That study showed that only 1% of tumor cells in a TNBC must be AR+ to show benefit from AR-targeted therapies.44  In addition, multiple clinical trials currently underway for patients with TNBC have shown promising preliminary results with AR-targeted therapies against TNBCs with a higher percentage of AR+ cells.45  We, therefore, propose testing for AR expression in all metastatic/recurrent TNBCs and primary TNBCs that do not completely respond to chemotherapy to help guide management decisions.

Potential Diagnostic Utility of Basal Cytokeratins and EGFR in TNBCs

As previously mentioned, TNBCs can be divided into basal-like and nonbasal-like subtypes by IHC, with most categorized as the basal-like subtype.4647  Immunohistochemistry markers often used for identifying basal-like tumors include basal cytokeratins (CK5/6, CK5, CK14, and CK17) and/or EGFR (Figure 7, E and F). In particular, positivity of CK5/6 and/or EGFR can be helpful in diagnosing ER/PR/HER2 poorly differentiated or undifferentiated invasive carcinomas of the breast as basal-like TNBCs, especially in the core biopsy setting in which in situ lesions may be absent. In addition, a small proportion of high-grade DCIS cases demonstrate a triple-negative phenotype (ER/PR/HER2), and those lesions more commonly show expression of CK5/6 and/or EGFR.48  CK5/6 and EGFR positivity also helps in a diagnosis of basal-like DCIS, which may represent a precursor lesion to an invasive, basal-like TNBC.

It can be challenging for the pathologist to diagnose metastatic, basal-like TNBCs when present as unknown primary tumors. The tumors lack expression of ER, PR, and HER2 by IHC, and other commonly used markers for breast primary tumors, such as mammaglobin and gross cystic disease fluid protein 15 (GCDFP-15), have low sensitivity.49,50  Although not highly specific and/or sensitive, CK5/6 is expressed in 62.3% (43 of 69) of basal-like TNBCs, and EGFR is expressed in 91.3% (63 of the 69), making these 2 markers helpful when attempting to make a diagnosis of metastatic basal-like TNBC in the appropriate clinical setting.34  Historically, CK5/6 is the most commonly used basal cytokeratin in determining the basal-like phenotype of TNBC. However, a study4  reported CK5 positivity in 32 of 33 (97%) of basal-like TNBC tumors and suggested that CK5 is more sensitive than CK5/6 in identifying basal-like TN tumors. Importantly, negative CK5/6, CK5, or EGFR staining does not definitively rule out a basal-like TNBC. Comparison of morphologic characteristics with a known primary, if present, will aid in a correct diagnosis.

Potential Prognostic and Predictive Values of Basal Cytokeratins and EGFR in TNBCs

Several studies have demonstrated that, among the histologic subtypes, patients with basal-like TNBCs have significantly worse outcomes.30,47,51,52  A group of researchers34  reported that approximately one-third of basal-like TNBCs developed distant metastasis. They found that TNBCs with metastases had significantly higher expression of CK5/6 and EGFR than cases without metastases had.34  Their findings suggest that high-level expression of CK5/6 and EGFR may have a role in the development of nodal or distant metastases in basal-like TNBCs and may be predictive of metastatic disease. Although some reports show TNBCs respond well to adjuvant anthracycline-based chemotherapy, patients with the basal-like phenotype of TNBC have significantly poorer response to chemotherapy, making alternative therapy options desirable.53  Although the EGFR pathway is targetable for treatment in lung adenocarcinoma, targeted therapies for breast cancers, including TNBCs, have not proven effective.

Potential Prognostic and Predictive Values of p53 and p16 in TNBCs

Both p53 and p16 are tumor-suppressor proteins, which have an important role in cell cycle regulation. Triple-negative breast cancers can be divided into 2 subtypes based on their p16 and p53 expression status.

p53 acts to induce apoptosis and to arrest the cell cycle in response to cellular stresses, such as DNA damage. p53 overexpression has been reported to have a more significant prognostic value in patients with TNBC than in patients with non-TNBC tumors.54,55  A recent study56  demonstrated that p53 expression in TNBCs with nodal metastasis was significantly greater than it was in non-TNBCs with nodal metastasis. p53 expression had the strongest prognostic significance in patients with TNBC in a multivariate analysis.57  From the molecular perspective, a TP53 gene mutation has been reported in most TNBCs in recent publications and, as such, is a target of particular interest.54  TP53 mutations are strongly predictive for relapse-free and overall survival in patients with TNBC who have been treated with an adjuvant anthracycline-based chemotherapy regimen.58  Patients with p53+ TNBCs have worse overall and disease-free survival than do patients with p53 tumors.59  Because p53 overexpression is associated with poorer survival, it has been suggested that p53 can be used as a prognostic marker for TNBC.

p16 normally acts as a cyclin-dependent kinase (CDK) inhibitor by inactivating CDK4/6 and preventing the phosphorylation of retinoblastoma. p16 by IHC is widely used as a surrogate marker for high-risk human papilloma virus infection in diagnosing high-grade dysplasia and squamous cell carcinoma of the cervix. Of note, some basal-like TNBCs morphologically resemble poorly differentiated squamous cell carcinoma. Recent studies also demonstrated that p16 overexpression was found in TNBCs.6062 

To better understand TNBC tumor biology in the retinoblastoma/p16 and p53 pathways, researchers investigated the relationship of p16 expression with Ki-67 in p53+ and p53 TNBC cases.63  Ki-67 is widely used as a prognostic and predictive tumor biomarker for breast cancer, and greater Ki-67 expression is associated with a worse prognosis and more aggressive behavior. The case series showed that 45 of 60 TNBC tumors (75%) expressed the p16 protein, and that expression was significantly higher than that found in paired, benign breast ducts (Figure 8, B and C).63  In addition, the mean value of Ki-67 expression was high (>60%) in both p53+ and p53 triple-negative tumors, regardless of p16 expression status, and there was a significant, positive correlation between p16 and Ki-67 only in p53 tumors, not p53+ tumors. These findings suggest that p16 may have a role in the poor outcomes of p53 tumors, and they provide insights into the potential prognostic value of p16 for TNBC. The p16-related cell cycle pathway might be potentially targetable for treatment of TNBCs, particularly for p53 tumors. Another study64  reported that patients with TNBC whose tumors showed strong p16 immunoreactivity had complete pathologic responses, and that decreasing response correlated with decreasing expression of p16. This finding suggests that the status of p16 expression could have a predictive value for tumor response to chemotherapy.

Potential Diagnostic Utility of p16 and p53 in TNBCs

A strong and diffuse p16 expression is seen in most TNBCs.60,6263  Although there are few reports in the literature, this finding is especially important for the pathologist when attempting to distinguish metastatic TNBCs from p16+ carcinomas originating from organs other than the breast, particularly those from female reproductive organs. In addition, p16 and p53 coexpression is commonly seen in TNBCs, similar to those of the gynecologic tract, in which most high-grade serous carcinomas of the ovary/fallopian tube (or peritoneum) are diffusely positive for p16 and p53 by IHC. Occasionally, both TNBC and high-grade serous carcinoma can occur in patients with BRCA mutations. Making a distinction between those 2 primary tumors has important prognostic and therapeutic implications.

Clinically, when dealing with an ER/PR high-grade carcinoma originating from the female reproductive tract in a patient with a history of TNBC, the differential diagnosis should include metastatic TNBC to the gynecologic site and serous carcinoma presenting as a second primary tumor. Conversely, metastatic high-grade serous carcinoma to the breast or axillary lymph nodes also occurs. However, the differential diagnosis can be problematic when these 2 different primary tumors have identical immunophenotypic profiles—ER/PR/HER2/p53+/p16+—and similar morphologic features. For such cases, we recommend a differential IHC panel that includes, among other stains, GATA3, PAX8, and WT1. Breast primary tumors are commonly GATA3+/PAX8/WT1, whereas serous carcinomas are GATA3/PAX8+/WT1+. Combining clinical, radiographic, and morphologic information is essential for making a correct diagnosis.

Diagnostic Utility of GATA3 in TNBCs

Triple-negative breast cancer metastases are a significant cause of morbidity and death and also present a diagnostic challenge. There are significant therapeutic implications in making a correct and timely diagnosis of metastatic TNBC because the tumors may respond to chemotherapy.

GATA3, a zinc-binding transcription factor that regulates the differentiation of many human tissue types, including the mammary gland, is a novel, sensitive, and specific marker for primary breast carcinomas with up to 94% sensitivity (138 of 147), especially for those that are ER+.65,66  Recent studies have demonstrated that GATA3 is a more sensitive marker for TNBC than mammaglobin and GCDFP-15. Of note, different clones of GATA3 antibodies have different sensitivities in breast ductal epithelium. In 2014, a study50  reported that GATA3-L (L50-823) was technically and diagnostically more sensitive than GATA3-H (HG3-31) in TNBC. Because of the high sensitivity and specificity of GATA3 for breast origin, GATA3 has been widely used as a breast marker in routine clinical practice. We recommend including it in a panel of immunostains that also includes mammaglobin and GCDFP-15, when attempting to identify a possible breast carcinoma presenting as a metastasis from an unknown primary. GATA3 is particularly useful in the workup of metastatic TNBCs because ER, PR, or HER2 by IHC cannot serve as markers for detection. However, the sensitivity of GATA3 in TNBCs was significantly lower than it was in non-TNBCs and ranged from 43% to 66%.49,50,67  Certainly, more-sensitive diagnostic markers for TNBCs are needed.

Potential Diagnostic Utility of PELP1 in TNBC

Example 4.—

A 44-year-old woman presented with a 2-cm mass in the right breast. Breast imaging examination showed the lesion was lobulated and had a circumscribed border. An ultrasound-guided core biopsy was performed. Sections of histology demonstrated a poorly differentiated, invasive carcinoma with high nuclear grade, brisk mitotic activity, and extensive necrosis; no in situ carcinoma was identified. To further characterize the malignancy, an IHC panel was performed. The tumor cells showed the following results: ER/PR/HER2, Ki-67 high (95%), CK7+, mammaglobin, and GCDFP-15, GATA3 completely negative, and PELP1 (proline glutamic acid and leucine-rich protein) diffusely and strongly positive in 100% of the cells (Figure 8, D). Other immunostains, including CK20, TTF-1, napsin A, and PAX8, were all negative. Further systemic-imaging workup revealed no mass lesions found in nonbreast sites. The final diagnosis was high-grade, invasive TNBC (grade III) that was GATA3 and PELP1+. Subsequently, the patient underwent neoadjuvant chemotherapy, and the tumor showed complete pathologic response.

PELP1 is a novel coregulator of nuclear hormone receptors that has a role in driving breast cancer and enhancing metastatic potential.6870  In 2015, researchers67  conducted a comparative study by IHC on the sensitivity of PELP1, compared with GATA3, in TNBC tissues. They found that, of the 70 TNBC tumors, 67 (96%) showed strong, diffuse nuclear staining for PELP1, whereas only 46% (32 of 69) of the tumors were positive for GATA3 (the tissue from one case did not survive processing) (P < .001).67  These findings indicated PELP1 was a more sensitive marker for TNBCs than GATA3 was. The group also demonstrated that PELP1 was strongly and diffusely positive in paired primary and metastatic TNBC cases. The frequency of PELP1 expression (100%; 10 of 10) in metastatic triple-negative tumors was significantly higher than that of GATA3 expression (40%; 4 of 10) in the same tumors.67 

The high frequency of diffuse, strong PELP1 staining suggests that PELP1 may have potential diagnostic utility for metastatic TNBC as a distant disease in an appropriate clinical context, such as a patient's history of primary TNBC, particularly in cases in which the primary tumor is negative for GATA3, mammaglobin, and GCDFP-15. In addition, PELP1 may also be used in diagnosing metastatic TNBC as a local or regional disease in the axilla. For example, metastatic TNBC in the axillary lymph node may initially present as an unknown primary tumor when mammogram and ultrasound breast imaging fails to detect any breast lesions and the carcinoma is positive for CK7 but negative for ER, PR, HER2, GATA3, mammaglobin, and GCDFP-15. In those cases, diffuse, strong PELP1 staining in the carcinoma may suggest a triple-negative tumor of breast origin; further breast-imaging examination should be recommended by the pathologist, such as magnetic resonance imaging, which is a more sensitive and expensive tool for detecting an occult, triple-negative tumor within the breast. Further work is needed to address the status of the specificity of this novel marker for breast lesions. In addition, the diffuse, strong nuclear immunoreactivity of PELP1 in TNBC suggests that PELP1 may be a potential molecular target for treatment of TNBC.70 

Recent Studies on Additional IHC Markers in TNBCs

E-cadherin.—

E-cadherin is a cell-adhesion molecule. Loss of E-cadherin is a fundamental event in the epithelial to mesenchymal transition, which is associated with carcinogenesis of TNBCs.71  Reduced E-cadherin expression may also have a role in the poor prognosis in TNBCs.72 

A semiquantitative H-score is a method for scoring biomarkers with nuclear staining, such as ER and PR. It provides an overall score (0–300) based on the sum of ordinal, weighted percentages of cells that stain weakly, moderately, and strongly. The H-score is considered to be a more accurate and reproducible scoring method than other commonly used systems because of its wide dynamic range and its use of weighted percentages. Recently, a pilot study73  used the H-score to evaluate E-cadherin membranous immunostaining, which showed its expression was significantly decreased in TNBCs when compared with paired, benign breast ducts (Figure 8, E and F). Furthermore, the researchers found a positive correlation between the reduction in E-cadherin expression and high Ki-67 expression. These findings suggest reduced E-cadherin expression may be associated with tumor aggressiveness, which may provide insight into the role of E-cadherin in TNBC tumor biology.

Cyclin E.—

Cancer proliferation is fundamentally related to an altered regulation of the cell cycle, and cyclin E is an important regulator of the cell cycle.74  Previous studies showed that cyclin E overexpression was associated with a poor prognosis in breast cancer.74,75  Recent studies have revealed that cyclin E protein expression was higher in TNBCs than in non-TNBCs, and it was positively correlated with Ki-67 expression in both TNBCs and non-TNBCs.7577  These findings suggest that cyclin E expression may be associated with tumor aggressiveness in TNBCs. Much work is needed to further define the role of cyclin E in tumor biology and its relation to prognosis in TNBCs.

Table 7 summarizes potential utility of various biomarker expression by IHC in TNBCs.

Table 7

Utility of Biomarker Expression by Immunohistochemistry (IHC) in Triple-Negative Breast Carcinoma (TNBC)

Utility of Biomarker Expression by Immunohistochemistry (IHC) in Triple-Negative Breast Carcinoma (TNBC)
Utility of Biomarker Expression by Immunohistochemistry (IHC) in Triple-Negative Breast Carcinoma (TNBC)

Breast carcinoma is one of the most common malignant tumors in women. However, metastases to the breast from extramammary carcinomas are extremely rare, with an incidence ranging from 0.2% to 2%.78  The primary sites of metastasis include several organs, and the lung is one of the most common sites.7980  Distinguishing metastatic carcinoma with a lung origin from primary breast carcinoma is critical clinically because each diagnosis bears a significantly different prognosis and has different management strategies. Achieving the optimal diagnosis requires a comprehensive approach that includes clinical history, radiographic findings, tumor morphology, IHC, and even molecular analysis in particularly difficult cases. Histologically, identification of in situ carcinoma of the breast with similar cellular atypia to invasive carcinoma supports a diagnosis of a primary breast carcinoma.

Most breast carcinomas express ER and/or PR by IHC and some overexpress the HER2 protein. GATA3 is a recently recognized sensitive and specific maker for breast primary tumors. TTF-1 and napsin A are sensitive and specific markers for lung primary tumors. A recent study81  reported that a simple IHC panel of GATA3 and TTF-1 correctly differentiated breast carcinoma from lung adenocarcinoma in 93.4% of cases examined.

It has, however, been reported that a subset of lung adenocarcinomas express breast tumor biomarkers by IHC, and a small portion of breast carcinomas express TTF-1. Estrogen receptor positivity was identified in approximately 5% to 27% of lung adenocarcinomas, and most of the ER-expressing lung tumors were positive for TTF-1.8284  HER2 protein overexpression or gene amplification was found in primary lung carcinomas as well.85  TTF-1+ staining was identified in about 2.5% of breast carcinomas, ranging from focal and weak to diffuse and strong.86  Of note, the presence of TTF-1 immunoreactivity cannot by itself be used to exclude a breast origin in a carcinoma with an unknown primary site because a few breast carcinomas express TTF-1.

Occurrence of this overlapping immunoprofile makes a distinction between these 2 primaries diagnostically challenging in patients with a prior history of breast carcinoma, particularly for cases in which the primary breast tumor is ER+ and/or HER2+.

Example 5.—

A 67-year-old woman had a prior right-breast lumpectomy for invasive ductal carcinoma (ER+ [100%, strong intensity], PR+ [100%, strong intensity], and HER2 by IHC). Subsequently, she underwent a prophylactic, bilateral total mastectomy after detection of a deleterious RAD51 mutation. Two years later, she was found to have a 2.4-cm breast mass at the right-mastectomy scar site. Sections of the breast mass biopsy revealed high-grade adenocarcinoma (Figure 9, A through C) and a small focus of residual benign breast lobules (lower, right section of Figure 9, A and B). The tumor was ER+ (20%, moderate intensity) (Figure 9, E and F), PR, and HER2 by IHC. Although a recurrent breast carcinoma was suspected, given the discordant ER and PR expression in this tumor when compared with her prior breast carcinoma, additional immunostains were performed. The tumor was diffusely positive for TTF-1 (Figure 9, D) and napsin A (Figure 9, G), and the residual breast lobules were completely negative for napsin A (Figure 9, H). The tumor was negative for GATA3, mammaglobin, and GCDFP-15, excluding a breast origin. The immunoprofile was highly suspicious for a lung adenocarcinoma, even though no lung lesions were seen on initial pulmonary imaging. The pathologist recommended further imaging workup, and a whole-body positron emission tomography scan revealed a 0.7-cm, left, upper-lobe lung lesion with accompanying enlarged hilar lymph nodes. Thus, primary ER+ lung adenocarcinoma with metastasis to the breast was established. This case represents a recently reported rare example of metastatic, ER+ lung adenocarcinoma to the breast.87 

Figure 9

Metastatic estrogen receptor-positive lung adenocarcinoma to the breast (from example 5 in text). Morphologic features of the lung tumor (A through C); with TTF-1 staining (D); with ER staining at low power (E) and high power (F); and with napsin A staining of the tumor (G) and in residual, benign breast lobules (H) (hematoxylin-eosin, original magnifications ×20 [A], ×40 [B], and ×100 [C]; original magnification ×40 [D]; original magnifications ×40 [E] and ×100 [F]; original magnification ×100 [G and H]).

Figure 9

Metastatic estrogen receptor-positive lung adenocarcinoma to the breast (from example 5 in text). Morphologic features of the lung tumor (A through C); with TTF-1 staining (D); with ER staining at low power (E) and high power (F); and with napsin A staining of the tumor (G) and in residual, benign breast lobules (H) (hematoxylin-eosin, original magnifications ×20 [A], ×40 [B], and ×100 [C]; original magnification ×40 [D]; original magnifications ×40 [E] and ×100 [F]; original magnification ×100 [G and H]).

Example 6.—

A 65-year-old woman with a family history of breast cancer presented with a solitary, right breast mass, and diagnostic mammography identified a 0.6-cm, hypoechoic, soft tissue density with ill-defined margins. An ultrasound-guided core biopsy was performed, and the morphologic features are illustrated in Figure 10, A through C. Biomarker studies indicated that the tumor was negative for ER and PR (Figure 10, D and E) and was equivocal for HER2 protein expression (Figure 10, F). Subsequently, a reflex HER2 fluorescence in situ hybridization test was performed, which showed HER2 gene amplification. Based on those findings, invasive ductal carcinoma of the breast with papillary features was reported initially. However, soon afterward, additional medical history was obtained. Two years prior, the patient had a 4.0-cm, left, lower-lobe lung mass with evidence of brain metastasis on computerized tomography scan. At that time, no pathologic diagnosis was attempted, and no other clinical intervention was recorded. Further IHC workup demonstrated the tumor to be positive for TTF-1 (Figure 10, G) and napsin A (Figure 10, H). The prior diagnosis was amended to metastatic HER2+ lung adenocarcinoma to the breast.

Figure 10

Metastatic HER2+ lung adenocarcinoma to the breast (example 6 in text), and morphologic features of the lung tumor (hematoxylin-eosin, original magnifications ×40 [A], ×100 [B], and ×200 [C]; estrogen receptor, original magnification ×100 [D]; progesterone receptor, original magnification, ×100 [E]; HER2, original magnification ×200 [F]; TTF-1, original magnification ×200 [G]; napsin A, original magnification ×200 [H]).

Figure 10

Metastatic HER2+ lung adenocarcinoma to the breast (example 6 in text), and morphologic features of the lung tumor (hematoxylin-eosin, original magnifications ×40 [A], ×100 [B], and ×200 [C]; estrogen receptor, original magnification ×100 [D]; progesterone receptor, original magnification, ×100 [E]; HER2, original magnification ×200 [F]; TTF-1, original magnification ×200 [G]; napsin A, original magnification ×200 [H]).

These 2 cases reinforce the importance of correlating clinical history and radiographic findings to make the correct diagnosis of metastatic lung adenocarcinoma to the breast. In general, an IHC panel that includes TTF-1, napsin A, GATA3, ER, and HER2 serves as a useful ancillary tool in the differential diagnosis between these 2 primary tumors in most cases. This distinction has significant prognostic and therapeutic implications. However, in distinguishing metastatic ER+ or HER2+ lung adenocarcinoma to the breast from a primary breast carcinoma, napsin A and GATA3 are more useful because napsin A has been reported to be negative in breast carcinomas,88  and TTF-1, ER, and HER2 can be positive in both primary tumors. Lung adenocarcinomas are commonly napsin A+/GATA3, and breast carcinomas are napsin A/GATA3+. Napsin A appears to be more specific for diagnosing lung primary tumors, when compared with TTF-1, in making the distinction between lung and breast origins.

We thank Sharon Jiang for assistance with proofreading the manuscript and editing the figures and tables.

1
Dupont
WD,
Page
DL.
Risk factors for breast cancer in women with proliferative breast disease
.
N Engl J Med
.
1985
;
312
(
3
):
146
151
.
2
Fitzgibbons
PL,
Henson
DE,
Hutter
RV.
Benign breast changes and the risk for subsequent breast cancer: an update of the 1985 consensus statement: Cancer Committee of the College of American Pathologists
.
Arch Pathol Lab Med
.
1998
;
122
(
12
):
1053
1055
.
3
Bánkfalvi
A,
Ludwig
A,
De-Hesselle
B,
Buerger
H,
Buchwalow
IB,
Boecker
W.
Different proliferative activity of the glandular and myoepithelial lineages in benign proliferative and early malignant breast diseases
.
Mod Pathol
.
2004
;
17
(
9
):
1051
1061
.
4
Bhargava
R,
Beriwal
S,
McManus
K,
Dabbs
DJ.
CK5 is more sensitive than CK5/6 in identifying the “basal-like” phenotype of breast carcinoma
.
Am J Clin Pathol
.
2008
;
130
(
5
):
724
730
.
5
Dewar
R,
Fadare
O,
Gilmore
H,
Gown
AM.
Best practices in diagnostic immunohistochemistry: myoepithelial markers in breast pathology
.
Arch Pathol Lab Med
.
2011
;
135
(
4
):
422
429
.
6
Charpin
C,
Andrac
L,
Habib
MC,
et al.
Correlation between laminin and type IV collagen distribution in breast carcinomas, and estrogen receptors expression, lymph node and vascular involvement
.
Med Oncol Tumor Pharmacother
.
1990
;
7
(
1
):
43
54
.
7
Prasa
ML,
Osborne
MP,
Giri
DD,
Hoda
SA.
Microinvasive carcinoma (T1mic) of the breast: clinicopathologic profile of 21 cases
.
Am J Surg Pathol
.
2000
;
24
(
3
):
422
428
.
8
Mastropassqua
MG,
Maiorano
E,
Prunei
G,
et al.
Immunoreactivity for c-kit and p63 as an adjunct in the diagnosis of adenoid cystic carcinoma of the breast
.
Mod Pathol
.
2005
;
18
(
10
):
1277
1282
.
9
Adem
C,
Reynolds
C,
Adlakha
H,
Roche
PC,
Nascimento
AG.
Wide spectrum screening keratin as a marker of metaplastic spindle cell carcinoma of the breast: an immunohistological study of 24 patients
.
Histopathology
.
2002
;
40
(
6
):
556
562
.
10
Clement
PB,
Azzopardi
JG.
Microglandular adenosis of the breast—a lesion simulating tubular carcinoma
.
Histopathology
.
1983
;
7
(
2
):
169
180
.
11
Dabbs
DJ,
Bhargave
R,
Chivukula
M.
Lobular versus ductal breast neoplasms: the diagnostic utility of p120
.
Am J Surg Pathol
.
2007
;
31
(
3
):
427
437
.
12
Sneige
N,
Wang
J,
Baker
BA,
Krishnamurthy
S,
Middleton
LP.
Clinical, histopathologic, and biologic features of pleomorphic lobular (ductal-lobular) carcinoma in situ of the breast: a report of 24 cases
.
Mod Pathol
.
2002
;
15
(
10
):
1044
1050
.
13
Shin
SJ,
Lal
A,
De Vries
S,
et al.
Florid lobular carcinoma in situ: molecular profiling and comparison to classic lobular carcinoma in situ and pleomorphic lobular carcinoma in situ
.
Hum Pathol
.
2013
;
44
(
10
):
1998
2009
.
14
Da Silva
L,
Parry
S,
Reid
L,
et al.
Aberrant expression of E-cadherin in lobular carcinomas of the breast
.
Am J Surg Pathol
.
2008
;
32
(
5
):
773
783
.
15
Hill
CB,
Yeh
IT.
Myoepithelial cells staining patterns of papillary breast lesions: from intraductal papillomas to invasive papillary carcinomas
.
Am J Clin Pathol
.
2005
;
123
(
1
):
36
44
.
16
Lakhani
SR,
Ellis
IO,
Schnitt
SJ,
Tan
PH,
van de Vijver
MJ,
eds
.
WHO Classification of Tumours of the Breast. 4th ed
.
Lyon, France
:
IARC Press;
2012
.
World Health Organization Classification of Tumours
, vol 4.
17
Mulligan
AM,
O'Malley
FP.
Papillary lesions of the breast: a review
.
Adv Anat Pathol
.
2007
;
14
(
2
):
108
119
.
18
Collins
LC,
Carlo
VP,
Hwang
H,
Barry
TS,
Gown
AM,
Schnitt
SJ.
Intracystic papillary carcinomas of the breast: a reevaluation using a panel of myoepithelial cell markers
.
Am J Surg Pathol
.
2006
;
30
(
8
):
1002
1007
.
19
Esposito
NN,
Dabbs
DJ,
Bhargave
R.
Are encapsulated papillary lesion carcinomas of the breast in situ or invasive?: a basement membrane study of 27 cases
.
Am J Clin Pathol
.
2009
;
131
(
2
):
228
242
.
20
Rakha
EA,
Varga
Z,
Elsheik
IS,
Ellis
IO.
High-grade encapsulated papillary carcinoma of the breast: an under-recognized entity
.
Histopathology
.
2015
;
66
(
5
):
740
746
.
21
Otsuki
Y,
Yamada
M,
Shimizu
S,
et al.
Solid-papillary carcinoma of the breast: clinicopathological study of 20 cases
.
Pathol Int
.
2007
;
57
(
7
):
421
429
.
22
Rabban
JT,
Koerner
FC,
Lerwill
MF.
Solid papillary ductal carcinoma in situ versus usual ductal hyperplasia in the breast: a potentially difficult distinction resolved by cytokeratin 5/6
.
Hum Pathol
.
2006
;
37
(
7
):
787
793
.
23
Monitani
S,
Ichihara
S,
Kushima
R,
et al.
Myoepithelial cells in solid papillary carcinoma of the breast: a potential diagnostic pitfall and a proposal of an immunohistochemical panel in the differential diagnosis with intraductal papilloma with usual ductal hyperplasia
.
Virchows Arch
.
2007
;
450
(
5
):
539
547
.
24
Tse
GM,
Ni
YB,
Tsang
JY,
et al.
Immunohistochemistry in the diagnosis of papillary lesions of the breast
.
Histopathology
.
2014
;
65
(
6
):
839
853
.
25
Rosen
PP.
Adenomyoepithelioma of the breast
.
Hum Pathol
.
1987
;
18
(
12
):
1232
1237
.
26
Tamura
S,
Enjoji
M,
Toyoshima
S,
Terasaka
R.
Adenomyoepithelioma of the breast: a case report with an immunohistochemical study
.
Acta Pathol Jpn
.
1988
;
38
(
5
):
659
665
.
27
Hayes
MM.
Adenomyoepithelioma of the breast: a review stressing its propensity for malignant transformation
.
J Clin Pathol
.
2011
;
64
(
6
):
477
484
.
28
Han
JS,
Peng
Y.
Multicentric adenomyoepitheliomas of the breast with atypia and associated ductal carcinoma in situ
.
Breast J
.
2010
;
16
(
5
):
547
549
.
29
Lee
AH.
Recent developments in the histological diagnosis of spindle cell carcinoma, fibromatosis and phyllodes tumor of the breast
.
Histopathology
.
2008
;
52
(
1
):
45
57
.
30
Foulkes
WD,
Smith
IE,
Reis-Filho
JS.
Triple-negative breast cancer
.
N Engl J Med
.
2010
;
363
(
20
):
1938
1948
.
31
Oakman
C,
Moretti
E,
Galardi
F,
et al.
Adjuvant systemic treatment for individual patients with triple negative breast cancer
.
Breast
.
2011
;
20
(
suppl 3
):
S135
S141
.
32
Rakha
EA,
Chan
S.
Metastatic triple-negative breast cancer
.
Clin Oncol (R Coll Radiol)
.
2011
;
23
(
9
):
587
600
.
33
Sutton
LM,
Cao
D,
Sarode
V,
et al.
Decreased androgen receptor expression is associated with distant metastases in patients with androgen receptor-expressing triple-negative breast carcinoma
.
Am J Clin Pathol
.
2012
;
138
(
4
):
511
516
.
34
Sutton
LM,
Han
JS,
Molberg
KH,
et al.
Intratumoral expression level of epidermal growth factor receptor and cytokeratin 5/6 is significantly associated with nodal and distant metastases in patients with basal-like triple-negative breast carcinoma
.
Am J Clin Pathol
.
2010
;
134
(
5
):
782
787
.
35
Lehmann
BD,
Bauer
JA,
Chen
X,
et al.
Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies
.
J Clin Invest
.
2011
;
121
(
7
):
2750
2767
.
36
Loibl
S,
Müller
BM,
von Minckwitz
G,
et al.
Androgen receptor expression in primary breast cancer and its predictive and prognostic value in patients treated with neoadjuvant chemotherapy
.
Breast Cancer Res Treat
.
2011
;
130
(
2
):
477
487
.
37
Park
S,
Koo
JS,
Kim
MS,
et al.
Androgen receptor expression is significantly associated with better outcomes in estrogen receptor-positive breast cancers
.
Ann Oncol
.
2011
;
22
(
8
):
1755
1762
.
38
Hu
R,
Dawood
S,
Holmes
MD,
et al.
Androgen receptor expression and breast cancer survival in postmenopausal women
.
Clin Cancer Res
.
2011
;
17
(
7
):
1867
1874
.
39
Park
S,
Koo
J,
Park
HS,
et al.
Expression of androgen receptors in primary breast cancer
.
Ann Oncol
.
2010
;
21
(
3
):
488
492
.
40
Rakha
EA,
El-Sayed
ME,
Green
AR,
Lee
AH,
Robertson
JF,
Ellis
IO.
Prognostic markers in triple-negative breast cancer
.
Cancer
.
2007
;
109
(
1
):
25
32
.
41
He
J,
Peng
R,
Yuan
Z,
et al.
Prognostic value of androgen receptor expression in operable triple-negative breast cancer: a retrospective analysis based on a tissue microarray
.
Med Oncol
.
2012
;
29
(
2
):
406
410
.
42
Tang
D,
Xu
S,
Zhang
Q,
Zhao
W.
The expression and clinical significance of the androgen receptor and E-cadherin in triple-negative breast cancer
.
Med Oncol
.
2012
;
29
(
2
):
526
533
.
43
Luo
X,
Shi
YX,
Li
ZM,
Jiang
WQ.
Expression and clinical significance of androgen receptor in triple negative breast cancer
.
Chin J Cancer
.
2010
;
29
(
6
):
585
590
.
44
Barton
VN,
D'Amato
NC,
Gordon
MA,
et al.
Multiple molecular subtypes of triple-negative breast cancer critically rely on androgen receptor and respond to enzalutamide in vivo
.
Mol Cancer Ther
.
2015
;
14
(
3
):
769
778
.
45
Gucalp
A,
Tolaney
S,
Isakoff
SJ,
et al
Translational Breast Cancer Research Consortium (TBCRC 0111). Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer
.
Clin Cancer Res
.
2013
;
19
(
19
):
5505
5512
.
46
Rakha
E,
Reis-Filho
JS.
Basal-like breast carcinoma: from expression profiling to routine practice
.
Arch Pathol Lab Med
.
2009
;
133
(
6
):
860
868
.
47
Cheang
MC,
Voduc
D,
Bajdik
C,
et al.
Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype
.
Clin Cancer Res
.
2008
;
14
(
5
):
1368
1376
.
48
Bryan
B,
Schnitt
S,
Collins
L.
Ductal carcinoma in situ with basal-like phenotype: a possible precursor to invasive basal-like breast cancer
.
Mod Pathol
.
2006
;
19
(
5
):
617
621
.
49
Cimino-Mathews
A,
Subhawong
AP,
Illei
PB,
et al.
GATA3 expression in breast carcinoma: utility in triple-negative, sarcomatoid, and metastatic carcinomas
.
Hum Pathol
.
2013
;
44
(
7
):
1341
1349
.
50
Krings
G,
Nystrom
M,
Mehdi
I,
Vohra
P,
Chen
YY.
Diagnostic utility and sensitivities of GATA3 antibodies in triple-negative breast cancer
.
Hum Pathol
.
2014
;
45
(
11
):
2225
2232
.
51
Dawson
SJ,
Provenzano
E,
Caldas
C.
Triple negative breast cancers: clinical and prognostic implications
.
Eur J Cancer
.
2009
;
45
(
suppl 1
):
27
40
.
52
Nogi
H,
Kobayashi
T,
Suzuki
M,
et al.
EGFR as paradoxical predictor of chemosensitivity and outcome among triple-negative breast cancer
.
Oncol Rep
.
2009
;
21
(
2
):
413
417
.
53
Tan
DS,
Marchió
C,
Jones
RL,
et al.
Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients
.
Breast Cancer Res Treat
.
2008
;
111
(
1
):
27
44
.
54
Dang
D,
Peng
Y.
Roles of p53 and p16 in triple-negative breast cancer
.
Breast Cancer Manag
.
2013
;
2
(
6
):
537
544
.
55
Peng
Y.
Potential prognostic tumor biomarkers in triple-negative breast carcinoma
.
Beijing Da Xue Xue Bao
.
2012
;
44
(
5
):
666
672
.
56
Han
JS,
Cao
D,
Molberg
KH,
et al.
Hormone receptor status rather than HER2 status is significantly associated with increased Ki-67 and p53 expression in triple-negative breast carcinomas, and high expression of Ki-67 but not p53 is significantly associated with axillary nodal metastasis in triple-negative and high-grade non-triple-negative breast carcinomas
.
Am J Clin Pathol
.
2011
;
135
(
2
):
230
237
.
57
Lee
DS,
Kim
SH,
Suh
YJ,
Kim
S,
Kim
HK,
Shim
BY.
Clinical implication of p53 overexpression in breast cancer patients younger than 50 years with a triple-negative subtype who undergo a modified radical mastectomy
.
Jpn J Clin Oncol
.
2011
;
41
(
7
):
854
866
.
58
Hudis
CA,
Gianni
L.
Triple-negative breast cancer: an unmet medical need
.
Oncologist
.
2011
;
16
(
suppl 1
):
1
11
.
59
Biganzoli
E,
Coradini
D,
Ambrogi
F,
et al.
p53 status identifies two subgroups of triple-negative breast cancers with distinct biological features
.
Jpn J Clin Oncol
.
2011
;
41
(
2
):
172
179
.
60
Subhawong
AP,
Subhawong
T,
Nassar
H,
et al.
Most basal-like breast carcinomas demonstrate the same Rb−/p16+ immunophenotype as the HPV-related poorly differentiated squamous cellcarcinomas which they resemble morphologically
.
Am J Surg Pathol
.
2009
;
33
(
2
):
163
175
.
61
Laurinavicius
A,
Laurinaviciene
A,
Ostapenko
V,
Dasevicius
D,
Jarmalaite
S,
Lazutka
J.
Immunohistochemistry profiles of breast ductal carcinoma: factor analysis of digital image analysis data
.
Diagn Pathol
.
2012
;
7
:
27
.
62
Bohn
OL,
Fuertes-Camilo
M,
Navarro
L,
Saldivar
J,
Sanchez-Sosa
S.
p16INK4a expression in basal-like breast carcinoma
.
Int J Clin Exp Pathol
.
2010
;
3
(
6
):
600
607
.
63
Sugianto
J,
Sarode
V,
Peng
Y.
Ki-67 expression is increased in p16-expressing triple-negative breast carcinoma and correlates with p16 only in p53-negative tumors
.
Hum Pathol
.
2014
;
45
(
4
):
802
809
.
64
Arima
Y,
Hayashi
N,
Hayashi
H,
et al.
Loss of p16 expression is associated with the stem cell characteristics of surface markers and therapeutic resistance in estrogen receptor-negative breast cancer
.
Int J Cancer
.
2012
;
130
(
11
):
2568
2579
.
65
Liu
H,
Shi
J,
Wilkerson
ML,
Lin
F.
Immunohistochemical evaluation of GATA3 expression in tumors and normal tissues: a useful immunomarker for breast and urothelial carcinomas
.
Am J Clin Pathol
.
2012
;
138
(
1
):
57
64
.
66
Asch-Kendrick
R,
Cimino-Mathews
A.
The role of GATA3 in breast carcinomas: a review
.
Hum Pathol
.
2016
;
48
:
37
47
.
67
Dang
DN,
Raj
G,
Sarode
V,
Molberg
KH,
Vadlamudi
RK,
Peng
Y.
Significantly increased PELP1 protein expression in primary and metastatic triple-negative breast carcinoma: comparison with GATA3 expression and PELP1's potential role in triple-negative breast carcinoma
.
Hum Pathol
.
2015
;
46
(
12
):
1829
1835
.
68
Daniel
AR,
Gaviglio
AL,
Knutson
TP,
et al.
Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes
.
Oncogene
.
2015
;
34
(
4
):
506
515
.
69
Roy
S,
Chakravarty
D,
Cortez
V,
et al.
Significance of PELP1 in ER-negative breast cancer metastasis
.
Mol Cancer Res
.
2012
;
10
(
1
):
25
33
.
70
Krishnan
SR,
Nair
BC,
Sareddy
GR,
et al.
Novel role of PELP1 in regulating chemotherapy response in mutant p53-expressing triple negative breast cancer cells
.
Breast Cancer Res Treat
.
2015
;
150
(
3
):
487
499
.
71
Jiang
Z,
Jones
R,
Liu
JC,
et al.
RB1 and p53 at the crossroad of EMT and triple-negative breast cancer
.
Cell Cycle
.
2011
;
10
(
10
):
1563
1570
.
72
Kashiwagi
S,
Yashiro
M,
Takashima
T,
et al.
Significance of E-cadherin expression in triple-negative breast cancer
.
Br J Cancer
.
2010
;
103
(
2
):
249
255
.
73
Dang
D,
Saluja
K,
Sarode
V,
Molberg
K,
Leitch
M
and
Peng
Y.
Significantly reduced E-cadherin protein expression (H-score) in triple negative breast cancer and its correlation with Ki67
.
Am J Clin Pathol
.
2015
;
144
(
suppl 2
):
A280
.
74
Keyomarsi
K,
Tucker
SL,
Buchholz
TA,
et al.
Cyclin E and survival in patients with breast cancer
.
N Engl J Med
.
2002
;
347
(
20
):
1566
1575
.
75
Boström
P,
Söderström
M,
Palokangas
T,
et al.
Analysis of cyclins A, B1, D1, and E in breast cancer in relation to tumour grade and other prognostic factors
.
BMC Res Notes
.
2009
;
2
:
140
.
76
Torgbe
K,
Sutton
LM,
Cao
D,
Sarode
V,
Molberg
K,
Peng
Y.
Cyclin E expression correlates positively with Ki67 expression in triple-negative basal-like breast carcinoma
.
Am J Clin Pathol
.
2012
;
138
(
suppl 2
):
A157
.
77
Lund
MJ,
Trivers
KF,
Porter
PL,
et al.
Race and triple negative threats to breast cancer survival: a population-based study in Atlanta, GA
.
Breast Cancer Res Treat
.
2009
;
113
(
2
):
357
370
.
78
Klingen
TA,
Klassen
H,
Aas
H,
Chen
Y,
Aksen
LA.
Secondary breast cancer: a 5-year population-based study with review of the literature
.
APMIS
2009
;
117
(
10
):
762
767
.
79
Williams
SA,
Ehlers
RA,
Hunt
KK,
et al.
Metastases to the breast from nonbreast solid neoplasms
.
Cancer
.
2007
;
110
(
4
):
731
737
.
80
Georgiannos
SN,
Chin
J,
Goode
AW,
Sheaff
M.
Secondary neoplasms of the breast: a survey of the 20th century
.
Cancer
.
2001
;
92
(
9
):
2259
2266
.
81
Kawaguchi
KR,
Lu
FI,
Kaplan
R,
et al.
In search of the ideal immunopanel to distinguish metastatic mammary carcinoma from primary lung carcinoma: a tissue microarray study of 207 cases
.
Appl Immunohistochem Mol Morphol
.
2014
;
22
(
4
):
266
274
.
82
Gomez-Fernandez
C,
Mejias
A,
Walker
G,
Nadji
M.
Immunohistochemical expression of estrogen receptor in adenocarcinomas of the lung: the antibody factor
.
Appl Immunohistochem Mol Morphol
.
2010
;
18
(
2
):
137
141
.
83
Dabbs
DJ,
Landreneau
RJ,
Raab
SS,
Maley
RH,
Tung
MY,
Silverman
JF.
Detection of estrogen receptor by immunohistochemistry in pulmonary adenocarcinoma
.
Ann Thorac Surg
.
2002
;
73
(
2
):
403
405
.
84
Lau
SK,
Chu
PG,
Weiss
LM.
Immunohistochemical expression of estrogen receptor in pulmonary adenocarcinoma
.
Appl Immunohistochem Mol Morphol
.
2006
;
14
(
1
):
83
87
.
85
Mar
N,
Vredenburgh
JJ,
Wasser
JS.
Targeting HER2 in the treatment of non-small cell lung cancer
.
Lung Cancer
.
2015
;
87
(
3
):
220
225
.
86
Robens
J,
Goldstein
L,
Gown
AM,
Schnitt
SJ.
Thyroid transcription factor-1 expression in breast carcinomas
.
Am J Surg Pathol
.
2010
;
34
(
12
):
1881
1885
.
87
Saluja
K,
Peng
Y.
Metastatic ER positive lung adenocarcinoma to liver and breast mimicking recurrent breast carcinoma
.
Am J Clin Pathol
.
2015
;
144
(
suppl 2
):
A258
88
Bishop
JA,
Sharma
R,
Illei
PB.
Napsin
A
and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma
.
Hum Pathol
.
2010
;
41
(
1
):
20
25
.

Author notes

The authors have no relevant financial interest in the products or companies described in this article.

Competing Interests

Presented in part at the First Chinese American Pathologists Association Diagnostic Pathology Course: Best Practices in Immunohistochemistry in Surgical Pathology and Cytopathology; August 22–24, 2015; Flushing, New York.