Breast

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 16, and is invasive breast carcinoma of no special type.

Invasive breast carcinoma of no special type (IBC) accounts for 75% of invasive breast cancers and includes all adenocarcinomas that are not classified as a special histologic type. In women younger than 40 (in whom screening is uncommon except in high-risk patients with a strong family history), 85% of cases are detected as a palpable mass, while 15% are detected by screening (mammogram, ultrasound, and/or MRI). In contrast, in women older than 40, 60% of cases are detected by screening and 40% as a palpable mass. Grossly, most IBCs form a white-tan firm mass with a stellate or spiculated contour.

In this case, H&E-stained sections reveal an infiltrative tumor comprised of large cells with pleomorphic large nuclei, prominent nucleoli, atypical mitotic figures, and abundant eosinophilic and granular cytoplasm. There is no overt tubule formation. Histologically, IBC is highly heterogeneous. Tumors may form glands, nests, and solid sheets. The Nottingham system (also termed the Elston-Ellis modification of the Scarff-Bloom-Richardson grading system) is utilized to determine histologic grade of IBC and includes tubule formation (1: >75%; 2: 10% - 75%; 3: <10%), nuclear grade (1: low; 2: intermediate; 3: high), and mitotic activity (determined by the number of mitotic figures found in 10 consecutive high-power fields [HPF] in the most mitotically active part of the tumor). Full details on mitotic counts are explained in the notes section of the CAP’s invasive breast carcinoma synoptic protocol.

The American Joint Committee on Cancer prognostic groups now also include biomarkers, which are required for all newly diagnosed breast cancers. While biomarker testing has been evolving over time, the most recent updated American Society of Clinical Oncology/College of American Pathologists estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer guideline made new reporting recommendations for cases with 1% to 10% ER expression, to acknowledge the more limited data on endocrine responsiveness in this group and overlapping features with ER-negative cancers.

In addition, there is admixed background ductal carcinoma in situ (DCIS) with high nuclear grade (pleomorphic nuclei and prominent nucleoli) and abundant eosinophilic granular cytoplasm. The DCIS is associated with comedo necrosis and calcifications. In this case, because of the nested invasive growth pattern, differentiation of the invasive from the in situ components can be difficult. Utilization of myoepithelial markers (such as p63 and smooth muscle myosin-heavy chain) are useful to distinguish extensive duct colonization or involvement of a sclerosing lesion (tubular adenosis, sclerosing adenosis, complex radial lesion) by DCIS from true invasion. Be aware that p63 can stain tumor cells in high-grade cases such as this. Of note, myoepithelial cell attenuation can be present in DCIS, especially when involving a sclerosing lesion. Fortunately, at least some myoepithelial cells can almost always be found in adjacent less sclerotic areas. Close observation of the background breast glandular growth patterns can be a very useful clue as well. This diagnostic distinction is critically important for treatment, as it drives surgical treatment (sentinel nodes, actionable margin distances) and oncologic therapy. The Society of Surgical Oncology–American Society for Radiation Oncology–American Society of Clinical Oncology Consensus Guidelines on Margins for Breast-Conserving Surgery with Whole Breast Irradiation suggests 2 mm as the standard for adequate margins for DCIS alone and “tumor on ink” for any tumor with invasion.

Invasive apocrine carcinoma is a group of breast carcinomas with apocrine differentiation in greater than 90% of tumor cells. Its clinical course, presentation, and gross pathology are similar to IBC of no special type. Microscopically, the tumor cells have abundant granular eosinophilic cytoplasm and prominent nucleoli. Apocrine carcinomas have a distinct immunoprofile that helps to differentiate them from IBC of no special type (which may have some apocrine features). Invasive apocrine carcinomas are usually ER/PgR-negative and androgen receptor-positive in 90% of cases. About 30% to 60% of cases will show HER2 positivity. There are ongoing efforts to develop therapeutic options to target androgen receptor in breast cancer. Although the histologic features in this case raise the possibility of invasive apocrine carcinoma, ER and PgR positivity and absence of androgen receptor expression support the diagnosis of IBC of no special type.

Many metastatic lesions to the breasts may be similar histologically to primary breast carcinoma. The most frequent metastatic tumors include melanoma, lung adenocarcinoma, carcinoid tumors, and ovarian carcinoma. An unusual immunoprofile and history of primary tumor masses elsewhere should raise the possibility of a tumor of non-mammary origin. In dealing with this possibility, the most useful markers include ER, GATA3, and mammaglobin (which would highlight primary breast carcinoma), along with site-specific metastatic markers (eg, TTF1 for lung or thyroid carcinoma, WT1 for ovarian serous, PAX8 for ovarian or thyroid carcinoma). A definitive in situ component also can be a distinguishing feature.

Carcinoma arising in microglandular adenosis (MGA) is rare. These carcinomas will often have adjacent areas of more typical MGA, which is characterized by small, infiltrative-appearing round tubules lined by a single layer of bland cells and luminal eosinophilic secretions. The glands of MGA-associated invasive carcinoma are larger, solid, more irregular, and angulated; show increased cellular atypia and mitotic activity; and can be associated with stromal desmoplasia. While MGA lacks myoepithelial cells, it is surrounded by a basement membrane that can be highlighted with immunostains such as collagen IV; carcinomas, on the other hand, lack any surrounding collagen IV-positive basement membrane. The cells of MGA and the carcinomas that arise from them are usually negative for ER, PgR, and HER2 and are characteristically positive for S100. This case lacks both the biomarker pattern and any hint of background MGA.

1. Which marker is the most diagnostic for invasive apocrine carcinoma?
   
   
   1. Androgen receptor
   2. Estrogen receptor
   3. GATA3
   4. HER2
   5. PAX8
2. A 48-year-old woman presents with a palpable breast mass. Ultrasound-guided core biopsy reveals an infiltrative papillary neoplasm with cuboidal to columnar cells with marked cytologic atypia. The patient also has a history of a pelvic mass.
   What is the most appropriate next step in view of the patient’s history?
   
   
   1. Excision of the breast mass
   2. Immunostains for ER, PgR, and HER2
   3. Immunostains for GATA3 and WT1
   4. Immunostains for smooth muscle myosin and p63
   5. Whole body PET/CT scan
3. A 46-year-old woman presents with a 2 cm palpable right breast mass. Ultrasound-guided core biopsy reveals uniform small glands that seem to infiltrate fibrous and adipose stroma. The glands contain eosinophilic secretions and consist of a single layer of cuboidal epithelial cells with small, bland nuclei without stromal desmoplasia. Stains for collagen IV and S100 are positive.
   What is the most likely diagnosis?
   
   
   1. Apocrine carcinoma
   2. Ductal carcinoma in situ involving sclerosing adenosis
   3. Invasive breast carcinoma of no special type
   4. Metastatic serous carcinoma from the ovary to breast
   5. Microglandular adenosis

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2. Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual, 8th Ed. Springer: 2017.
   
3. Anestis A, Zoi I, Papavassiliou AG, Karamouzis MV. Androgen Receptor in Breast Cancer—Clinical and Preclinical Research Insights. Molecules. 2020; 25(2):358.
   
4. College of American Pathologists. Protocol for the examination of resection specimens from patients with invasive carcinoma of the breast. V4.9.0.1. Published Dec 2023. Accessed June 2024. https://documents.cap.org/protocols/Breast.Invasive_4.9.0.1.REL_CAPCP.pdf;
5. D’Arcy C, Quinn CM. Apocrine lesions of the breast: Part 2 of a two-part review. Invasive apocrine carcinoma, the molecular signature of the molecular apocrine signature and utility of immunohistochemistry in the diagnosis of apocrine lesions of the breast. J Clin Pathol. 2019;72(1):7-11.
6. Elston CW, Ellis IO. Pathologic prognostic factors in breast cancer. I. The value of histologic grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19(5):403-410.
7. Kravtsov O, Jorns JM. Microglandular adenosis and associated invasive carcinoma. Arch Pathol Lab Med. 2020;144(1):42-46.
8. Morrow M, Van Zee KJ, Solin LJ, et al. Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology Consensus Guideline on Margins for Breast-Conserving Surgery with Whole-Breast Irradiation in Ductal Carcinoma in Situ. J Clin Oncol. 2016;34(33):4040-4046.
9. WHO Classification of Tumours Editorial Board, eds. World Health Organization Classification of Tumours of the Breast, 5th ed. IARC Press: 2019.

1. Androgen receptor (a)
2. Immunostains for GATA3 and WT1 (c)
3. Microglandular adenosis (e)