[GSP] M.03.02 BREAST MALIGNANT CONDITIONS.pdf

PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.03.02 BREAST: MALIGNANT CONDITIONS GENERAL AND SYSTEMIC PATHOLOGY LECTURE LECTURER: ARLENE L. QUITASOL, MD, FPSP DATE: MARCH 20,2024 TOPIC OUTLINE Carcinoma of the Breast Incidence and Epidemiology Risk Factors Molecular Classification and Pathogenesis Pa...

PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.03.02 BREAST: MALIGNANT CONDITIONS GENERAL AND SYSTEMIC PATHOLOGY LECTURE LECTURER: ARLENE L. QUITASOL, MD, FPSP DATE: MARCH 20,2024 TOPIC OUTLINE Carcinoma of the Breast Incidence and Epidemiology Risk Factors Molecular Classification and Pathogenesis Pathogenesis of Familial Breast Cancer Pathogenesis of Sporadic Breast Cancer Luminal (ER-positive/HER2-negative) HER2Positive Cancer Triple Negative Breast Cancer Types of Breast Carcinoma Carcinoma in Situ Ductal Carcinoma in Situ o Comedo DCIS o Cribriform DCIS o Micropapillary DCIS o Papillary DCIS o Paget Disease of the Nipple Lobular Carcinoma in Situ Invasive (Infiltrating) Carcinoma Nottingham Histologic Score Special Histologic Types of Invasive Carcinoma Lobular Carcinoma Carcinomas with Medullary Pattern Colloid Carcinoma Tubular Carcinoma Papillary Carcinoma Apocrine Carcinoma Micropapillary Carcinoma Metaplastic Carcinoma Secretory Carcinoma Inflammatory Carcinoma Prognostic and Predictive Factors for Invasive Carcinoma Major Prognostic factors Lymph Node Metastases Distant Metastases Tumor Size Locally Advanced Disease Lymphovascular Invasion Inflammatory Carcinoma Response to Neoadjuvant Chemotherapy Male Breast Cancer Stromal Cancer Fibroadenoma Phyllodes Tumor Lesions of Interlobular Stroma Malignant Tumors of Interlobular Stroma ▪ Angiosarcoma Other Malignant tumors of the breast NOTE TAKER: FERRER | NAMUHMUH | OLARTE | SANTIAGO CARCINOMA OF THE BREAST BREAST CARCINOMA - Most common and deadly malignancy of women globally - 1.7 million women are diagnosed yearly, and one in three of those afflicted die of disease - All breast cancers can be separated into three major groups defined by the expression of two proteins o ER (Estrogen Receptor) o HER2 (also known as ERBB2) 3 MAJOR GROUPS 1. “Luminal” cancers - Positive for ER - Negative for HER2 2. “HER2” cancers - Cancers overexpressing HER2 - Can be either ER-positive or ER-negative 3. “Triple negative breast cancers” (TNBCs) - Negative for ER and HER2 - Termed “triple negative” because they also fail to express progesterone receptor (PR), which is under the control of ER INCIDENCE AND EPIDEMIOLOGY - Breast cancer is rare in women younger than age 25 - Increases in incidence rapidly after age 30 - Incidence of TNBC and HER2 cancer plateaus in middle age, whereas the incidence of luminal cancer peaks later in life As a result, TNBCs and HER2 cancers comprise almost half of cancers in young women and fewer than 20% of cancers in older women - Risk of death in those who develop invasive breast cancer has gradually declined in both younger and older women, most recently by 1% to 2% per year - The current overall risk of death is about 20% RISK FACTORS Most important risk factors: - Gender (99% of those affected are female) - Age - Lifetime exposure to estrogen - Genetic inheritance - Environmental factor ▪ Environmental contaminants, such as organochlorine pesticides and certain plastics, have estrogenic effects on humans that may increase the risk of breast cancer - Lifestyle factor Major factors that decrease risk are: - Early pregnancy (prior to 20 years of age) - Prolonged breastfeeding Page 1 | 14 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.03.02 BREAST: MALIGNANT CONDITIONS Surgical and medical interventions also can decrease risk - Bilateral prophylactic mastectomy ▪ Decreases risk by about 90% - Chemoprevention using ER antagonists ▪ Decreases the incidence of ER-positive cancers - Interventions are mainly offered to women at very high risk for breast cancer MOLECULAR CLASSIFICATION AND PATHOGENESIS Pathogenesis of Familial Breast Cancer It is believed that one-quarter to one-third of breast cancers occur due to inheritance of a susceptibility gene or genes Single gene mutations with moderate to high penetrance o PENETRANCE ▪ Refers to the risk of an individual with the mutated gene developing cancer ▪ Accounts for 8% to 17% of breast carcinomas o INHERITANCE ▪ Seen in additional 15% to 20% of women based on a POSITIVE FAMILY HISTORY Defined as an affected first-degree relative (mother, sister, or daughter), cancer in multiple relatives, and earlyonset cancers Mutations in BRCA1 and BRCA2 - Responsible for 80% to 90% of single gene familial breast cancers - About 3% to 6% of all breast cancers - Penetrance, age of onset, and susceptibility to other types of cancers vary according to the specific BRCA1 and BRCA2 mutation that is inherited, but most carriers develop breast cancer by the age of 70 years Mutations in BRCA1 - Markedly increase the risk of ovarian carcinoma, which occurs in 20% to 40% of carriers BRCA2 - Confers a smaller risk for ovarian carcinoma (10% to 20%) - Associated more frequently with male breast cancer BRCA1 and BRCA2 carriers - Higher risk for other epithelial cancers, such as prostatic and pancreatic carcinoma BRCA1 (on chromosome 17q21) and BRCA2 (on chromosome 13q12.3) are both large genes, and hundreds of different mutations distributed throughout their coding regions have been associated with familial breast cancer NOTE TAKER: FERRER | NAMUHMUH | OLARTE | SANTIAGO BRCA1-associated breast cancers - Commonly poorly differentiated - Usually fall in the TNBC subgroup BRCA2-associated breast carcinomas - Also tend to be poorly differentiated - More often ER-positive than BRCA1 cancers Other tumor suppressor genes associated with germline mutations that convey a high risk for breast cancer, often as part of well-described syndromes, include: TP53 (LiFraumeni syndrome) PTEN (Cowden syndrome) STK11 (Peutz-Jeghers syndrome) CDH1 (Hereditary diffuse gastric cancer syndrome) PALPB2 (Hereditary breast cancer) Moderately penetrant (10% to 30% risk) mutations occur in the tumor suppressor genes ATM (a cause of ataxia telangiectasia when homozygous mutations are present) and CHEK2 Pathogenesis of Familial Breast Cancer A. LUMINAL (ER-POSITIVE/HER2-NEGATIVE) CANCERS Arise via the dominant pathway of breast cancer development, constituting 50% to 65% of case By gene expression profiling, ER-positive cancers fall into the “luminal” subgroup o A pattern of gene expression that is dominated by a large number of genes that are regulated by estrogen Widest spectrum of histologic grades and proliferation rates Cancers with high expression of ER usually also express high levels of PR, which is itself upregulated by estrogen and ER; such ER-positive/PR-positive tumors → Well differentiated → Slow-growing Carcinomas with low ER and absent PR tend to lie at the other end of the spectrum → Typically poorly differentiated → High proliferative rate ESTROGEN EXPOSURE ✓ Major risk factor for luminal breast cancer ✓ May promote the development of breast cancer through several mechanisms ✓ Estrogen: - Increases the local production of growth factors, such as transforming growth factor α, plateletderived growth factor, and fibroblast growth factor - Regulates the expression of dozens of genes in breast epithelial cells that may directly contribute to tumor growth and development Page 2 | 14 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.03.02 BREAST: MALIGNANT CONDITIONS ESTROGEN EXPOSURE ✓ Stimulates the proliferation of breast epithelial cells during puberty, menstrual cycles, and pregnancy, thereby increasing the number of cells that are “at risk” for transformation ✓ A clear measure of the importance of estrogen is found in the therapeutic benefits of estrogen antagonists - Reduce the development of luminal cancers in women at high risk - Increased incidence of luminal cancers in women treated with postmenopausal hormone therapy ER-positive precursor lesions include: o FLAT EPITHELIAL ATYPIA o ATYPICAL DUCTAL AND LOBULAR HYPERPLASIA o Associated with genomic changes found in invasive carcinomas, including: ▪ Gains of chromosome 1q ▪ Losses of chromosome 16q ▪ Activating mutations in PIK3CA, the gene that encodes phosphoinositide-3 kinase (PI3K), which you will recall is an important component of signaling pathways downstream of growth factor receptors o Considered the earliest recognizable precursors of luminal breast cancers “Luminal A” Subgroup - Mainly associated the precursor lesions mentioned - Luminal cancers with low growth fractions and indolent clinical behavior; such tumors by gene expression profiling “Luminal B” Subgroup - More aggressive, high-grade luminal cancers - Defined by high levels of expression of genes associated with proliferation - Share some genomic changes with low-grade carcinomas but tend to have a greater burden of chromosomal aberrations - Sometimes arise from low-grade luminal cancers following the acquisition of mutations in genes that regulate genomic stability such as TP53 and also frequently occur in patients with germline BRCA2 mutations B. HER2-POSITIVE CANCERS Arise through a pathway that is strongly associated with amplification of the HER2 gene on chromosome 17q HER2 (also known as ERBB2) - Receptor tyrosine kinase that promotes cell proliferation and opposes apoptosis by stimulating the RAS- and PI3K-AKT signaling pathways NOTE TAKER: FERRER | NAMUHMUH | OLARTE | SANTIAGO Cancers with HER2 amplification constitute approximately 20% of all breast cancers and may be either ER-positive or ER-negative Most common subtype of breast cancer in patients with germline TP53 mutations (Li-Fraumeni syndrome) Diagnosed by detecting HER2 overexpression by immunohistochemistry or HER2 gene amplification by in situ hybridization Before the implementation of HER2-targeted therapy, HER2-positive cancers had a poor clinical outcome However, greater than half of patients with HER2 carcinomas have complete remissions when treated with antibodies that bind and block HER2 activity; such patients have an excellent prognosis The remarkable efficacy of this form of therapy proves the importance of HER2 as an oncogenic “driver.” C. TRIPLE NEGATIVE BREAST CANCERS (TNBCS) Arise through an estrogen-independent pathway that is not associated with HER2 gene amplification Comprise about 15% of breast cancers Have a “basal-like” gene expression profile, so-called because many of the genes that comprise this signature are normally expressed in basally located myoepithelial cells A possible precursor lesion has been identified that consists of lobular epithelial cells that are ER-negative and p53-positive, the latter being a feature that correlates with the presence of TP53 mutations These lesions resemble serous tubal intraepithelial carcinoma, the proposed precursor to serous carcinoma that is seen in the fallopian tubes of women with germline BRCA1 mutations Compared with luminal cancers, TNBC is more likely to present as a palpable mass and is less likely to be detected by mammographic screening Cytotoxic therapy combined with agents that are selectively active against cancers with defective homologous recombination results in complete or almost complete responses in about a third of cases Recur usually do so in the first 8 years after diagnosis Metastases are often to visceral sites and brain and frequently result in death Patients who survive 10 years are likely cured, as late recurrences are unusual Development of more effective treatments for this breast cancer subtype has been challenging, as obvious drug targets (such as ER or HER2) are lacking In addition, the genomic instability of these tumors leads to profound genetic heterogeneity, increasing the likelihood of emergence of more aggressive, therapy-resistant subclones Page 3 | 14 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.03.02 BREAST: MALIGNANT CONDITIONS Based on the resemblance of the involved spaces to normal ducts or lobules, but it is now recognized that these growth patterns are not related to the cell of origin, but rather reflect differences in tumor cell genetics and biology “LOBULAR” - Refers to invasive carcinomas that are biologically related to LCIS “DUCTAL” - Used more generally for adenocarcinomas that cannot be classified as a special histologic type Literally, “carcinoma in its original place” Cancer cells confined within ducts and lobules by a basement membrane No capacity to metastasize, as the location precludes access to blood vessels and lymphatics DUCTAL CARCINOMA IN SITU Clonal proliferation of epithelial cells limited to ducts and lobules by the basement membrane Myoepithelial cells are preserved in involved ducts/lobules, although they may be diminished in number Can spread throughout the ductal system and produce extensive lesions involving an entire sector of a breast Almost always detected by mammography Without mammography, fewer than 5% of carcinomas detected are in situ lesions, but this rises to 15% to 30% in screened populations Most are identified as a result of calcifications associated with secretory material or necrosis; less commonly, periductal fibrosis surrounding DCIS results in a mammographic density or creates a vaguely palpable mass DCIS (often of micropapillary or papillary types) rarely produces a nipple discharge or is detected as an incidental finding upon biopsy for another lesion TYPES OF BREAST CARCINOMA Almost all breast malignancies are adenocarcinomas Terms ductal and lobular are still used to describe subsets of both in situ and invasive carcinomas Most evidence suggests all breast carcinomas arise from cells in the terminal duct lobular unit CARCINOMA IN SITU Classified as: o DUCTAL CARCINOMA IN SITU (DCIS) o LOBULAR CARCINOMA IN SITU (LCIS) NOTE TAKER: FERRER | NAMUHMUH | OLARTE | SANTIAGO MORPHOLOGY (Ductal Carcinoma in Situ) ✓ DCIS grows in several architectural patterns, which vary in nuclear grade and the presence and extent of necrosis ✓ Some cases of DCIS have a single growth pattern, but most are comprised of a mixture of patterns → COMEDO DCIS → CRIBRIFORM DCIS → MICROPAPILLARY DCIS → PAPILLARY DCIS ✓ Varying degrees of necrosis can be associated with each architectural pattern as well as calcifications, which develop in association with intraluminal secretions or necrosis Page 4 | 14 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.03.02 BREAST: MALIGNANT CONDITIONS COMEDO DCIS - Occasionally produce a vague nodularity, but more often is detected as clustered or linear and branching areas of calcification - It is defined by two features: 1. Tumor cells with pleomorphic, high-grade nuclei 2. Areas of central necrosis PAGET DISEASE OF THE NIPPLE Rare manifestation of breast cancer (1% to 4% of cases) Presents as a unilateral erythematous eruption with a scale crust Pruritus is common and the lesion may be mistaken for eczema Malignant cells (Paget cells) extend from DCIS within the ductal system via the lactiferous sinuses into nipple skin without crossing the basement membrane (A) Specimen radiograph reveals linear and branching calcifications within the ductal system. (B) High-grade proliferation associated with large central zones of necrosis and calcifications fills several ducts. Cribriform DCIS - Rounded (cookie cutter–like) spaces, often filled with calcified secretory material (C) Note the round, regular (“cookie cutter”) spaces containing calcifying secretory material. Micropapillary DCIS - Produces complex fibrovascular cores bulbous protrusions without Tumor cells disrupt the normal epithelial barrier, allowing extracellular fluid to seep out onto the nipple surface Paget cells are readily detected by nipple biopsy or cytologic preparations of the exudate Palpable mass is present in 50% to 60% of women with Paget disease, and almost all of these masses prove to be invasive carcinoma Usually ER-negative and overexpress HER2 In contrast, the majority of women without a palpable mass have only DCIS Prognosis depends on the features of the underlying carcinoma and is not affected by the presence or absence of Paget disease (D) The papillary projections lack fibrovascular cores. Papillary DCIS - Produces true papillae with fibrovascular cores that lack a myoepithelial cell layer NOTE TAKER: FERRER | NAMUHMUH | OLARTE | SANTIAGO Page 5 | 14 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.03.02 BREAST: MALIGNANT CONDITIONS CLINICAL FEATURES (Ductal Carcinoma in Situ) Current practice of surgical excision, usually followed by radiation, is largely curative If untreated, women with small, low-grade DCIS develop invasive cancer at a rate of about 1% per year When invasive cancer develops in the same breast quadrant, it tends to have a similar grade and expression pattern of ER and HER2 as the associated DCIS Patients with high-grade or extensive DCIS are believed to have a higher risk for progression to invasive carcinoma Overall death rate for women with DCIS - Lower than that for women in the population as a whole, possibly because mammographic screening is a “marker” for better access to medical care or other socioeconomic factors that are associated with longevity Death from metastatic breast cancer after a diagnosis of DCIS occurs in 1% to 3% of women The origin of metastatic disease may be from a subsequent invasive carcinoma in the ipsilateral or contralateral breast or occult foci of invasion that were not detected at the time of DCIS diagnosis Mastectomy is curative in greater than 95% of women Breast conservation is appropriate for most women but has a slightly higher risk of recurrence—about half of which are DCIS and half invasive carcinoma The major risk factors for recurrence are: 1. High nuclear grade and necrosis 2. Extent of disease 3. Positive surgical margins LOBULAR CARCINOMA IN SITU Clonal proliferation of cells within ducts and lobules that grow in a dyscohesive fashion Almost always an incidental biopsy finding, since it is rarely associated with calcifications or stromal reactions that produce mammographic densities Incidence of LCIS (1% to 6% of all carcinomas) has been unchanged by the introduction of mammographic screening When both breasts are biopsied, LCIS is bilateral in 20% to 40% of cases compared with 10% to 20% of cases of DCIS Observed loss of cellular adhesion - usually due to dysfunction of E-cadherin, a transmembrane protein that contributes to the cohesion of normal epithelial cells in the breast and other glandular tissues E-cadherin functions as a tumor suppressor protein in such tissues and may be lost in neoplastic proliferations through a variety of mechanisms, including mutation of the E-cadherin gene (CDH1) NOTE TAKER: FERRER | NAMUHMUH | OLARTE | SANTIAGO In rare cases, there is dysregulation of other proteins, such as catenins, that are also needed for E-cadherin– mediated cellular cohesion. LCIS associated with invasive carcinoma shares the same mutations and, thus, in some cases is a true precursor lesion. MORPHOLOGY (Lobular Carcinoma in Situ) ✓ LCIS consists of a uniform population of cells with oval or round nuclei and small nucleoli involving ducts and lobules ✓ Mucin-positive signet ring cells are commonly present ✓ The lack of E-cadherin results in a rounded shape without attachment to adjacent cells ✓ Pagetoid spread, defined by the presence of neoplastic cells between the basement membrane and overlying luminal cells, is commonly seen in breast ducts, but Paget disease (involvement of nipple skin) does not occur ✓ Necrosis and secretory activity are not seen, and thus calcifications are absent ✓ LCIS almost always expresses ER and PR and is HER2negative (A) Monomorphic population of small, rounded, loosely cohesive cells fills and expands the acini of a lobule. The underlying lobular architecture can still be recognized. The cells extend into the adjacent duct by pagetoid spread. (B) Immunoperoxidase study shows E-cadherin–positive normal luminal cells that have been undermined by Ecadherin–negative LCIS cells spreading along the basement membrane. LCIS is a risk factor for developing invasive carcinoma in either breast, with a slightly higher risk to the ipsilateral breast Invasive carcinoma develops at a rate of about 1% per year, similar to that observed for untreated DCIS However, unlike DCIS, it is unclear if surgical removal of the identified lesion lowers risk Invasive carcinomas developing in women after LCIS are three-fold more likely to be lobular carcinoma; however, most are of other morphologies Treatment choices include: o Bilateral prophylactic mastectomy o Tamoxifen o Typically, close clinical follow-up and mammographic screening Page 6 | 14 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.03.02 BREAST: MALIGNANT CONDITIONS INVASIVE (INFILTRATING) CARCINOMA Breast carcinoma has a wide variety of morphologic appearances About one-third can be classified into special histologic types that merit discussion because they have important biologic and clinical associations MORPHOLOGY (Invasive Carcinoma) ✓ Majority of invasive breast cancers are ductal adenocarcinomas that are not classified further into a special type ✓ In the absence of mammographic screening, these carcinomas usually present as a mass of at least 2 to 3 cm in size ✓ Mammographic and gross appearance varies widely depending on the stromal reaction to the tumor ✓ Most commonly present as a hard, irregular radiodense mass associated with a desmoplastic stromal reaction ✓ When cut or scraped, such tumors typically produce a characteristic grating sound (similar to cutting a water chestnut) due to small, central pinpoint foci or streaks of chalky-white desmoplastic stroma and occasional foci of calcification ✓ Larger carcinomas may invade the pectoralis muscle and become fixed to the chest wall or invade the dermis and cause retraction (dimpling) of the skin ✓ When the tumor involves the central portion of the breast, retraction of the nipple may develop A subset of carcinomas grow as masses that appear to be well circumscribed or lobulated on imaging (D) and gross inspection (E). Microscopically, such cancers typically take on the appearance of expansile masses of cells with pushing borders; stromal response is often limited to a narrow zone of fibrosis at the tumor margin (F). Rarely, invasive cancers produce little or no stromal response. Such cancers may show only subtle architectural distortion on mammography (G) and may not produce palpable masses or be identifiable grossly (H). Microscopically, tumor cells are found scattered within normalappearing fibroadipose tissue (I). NOTTINGHAM HISTOLOGIC SCORE - Grading used in invasive carcinoma of the breast - Carcinomas are scored for: → Tubule formation → Nuclear pleomorphism → Mitotic rate Grade 1 (well differentiated) carcinomas Grow in a tubular or cribriform pattern Have small uniform nuclei Have a low proliferative rate Grade 2 (moderately differentiated) carcinomas Have areas where cells grow as solid clusters or single infiltrating cells Show greater nuclear pleomorphism High numbers of mitotic figures Invasive carcinoma of no special type. The majority of invasive carcinomas have a haphazard pattern of stromal invasion that produces masses with irregular margins on imaging (A) and gross examination (B). Microscopically, such tumors are marked by an exuberant desmoplastic stromal response (C). NOTE TAKER: FERRER | NAMUHMUH | OLARTE | SANTIAGO Grade 3 (poorly differentiated) carcinomas Invade as ragged nests or solid sheets of cells Have enlarged irregular nuclei High proliferative rate Areas of tumor necrosis are common in high-grade tumors Page 7 | 14 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.03.02 BREAST: MALIGNANT CONDITIONS ✓ Tubule formation is absent Invasive carcinomas are separated into three grades based on tubule formation, nuclear pleomorphism, and number of mitoses. (A) This example of a grade 1 well-differentiated carcinoma shows frequent tubules formed of cells with small monomorphic nuclei. Only rare mitoses are present. (B) In contrast, this grade 2 moderately differentiated carcinoma shows less tubule formation and some solid nests of cells with pleomorphic nuclei. Occasional mitotic figures are seen. (C) Grade 3 poorly differentiated carcinomas infiltrate as ragged sheets of cells with enlarged pleomorphic nuclei. SPECIAL HISTOLOGIC TYPES OF INVASIVE CARCINOMA Can be organized into molecular groups based on expression of ER and HER2, which carry their usual therapeutic implications Often harbor unique genetic aberrations, sometimes have distinct gene signatures, and frequently show associations with clinical behavior and prognosis that break the established “rules” for ductal carcinomas of no special type LOBULAR CARCINOMA Subtype with the clearest association of phenotype and genotype Like LCIS, most cases show biallelic loss of expression of CDH1, the gene that encodes E-cadherin Lobular carcinomas are dyscohesive, typically infiltrate as single cells, and sometimes fail to produce a desmoplastic response, making it difficult to detect these cancers by palpation and imaging Distinctive patterns of metastatic spread, often involving: → Peritoneum and retroperitoneum → Leptomeninges (carcinomatous meningitis) → Gastrointestinal tract → Ovaries and uterus Males and females with heterozygous germline mutations in CDH1 are at increased risk for developing lobular carcinoma and have a greatly increased risk for signet ring carcinoma of the stomach MORPHOLOGY (Lobular Carcinoma) ✓ Infiltrates the breast while producing minimal desmoplasia ✓ Histologic hallmark: presence of dyscohesive infiltrating tumor cells, often including signet ring cells containing intracytoplasmic mucin droplets NOTE TAKER: FERRER | NAMUHMUH | OLARTE | SANTIAGO (A) Lobular carcinoma CARCINOMAS WITH MEDULLARY PATTERN Over half of BRCA1-associated carcinomas have this appearance Better prognosis than other poorly differentiated carcinomas Notably, these tumors also have unusually large number of infiltrating T lymphocytes, suggesting that improved outcomes may be related to a host immune response to tumor antigens MORPHOLOGY (Carcinomas with medullary pattern) ✓ TNBC (ER-negative, HER2-negative) often corresponds to one of several special histologic types. Chief among these is carcinoma with medullary pattern ✓ These carcinomas are softer than other carcinomas (medulla is Latin for “marrow”) due to minimal desmoplasia and often form well-circumscribed masses ✓ DCIS is minimal or not seen ✓ Histologic features include: 1. Solid sheets of large cells with pleomorphic nuclei and prominent nucleoli 2. Frequent mitotic figures 3. A moderate to marked lymphoplasmacytic infiltrate surrounding and within the tumor 4. A pushing (non-infiltrative) border (G) Carcinoma with medullary pattern Page 8 | 14 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.03.02 BREAST: MALIGNANT CONDITIONS MUCINOUS (COLLOID) CARCINOMA Soft or rubbery and has the appearance and consistency of pale gray-blue gelatin Borders are pushing or circumscribed Tumor cells are arranged in clusters and small islands of cells within large lakes of mucin (E) Apocrine carcinoma MICROPAPILLARY CARCINOMA (a misnomer) forms hollow balls of cells that float within intercellular fluid, creating structures that mimic the appearance of true papillae (B) Mucinous carcinoma TUBULAR CARCINOMA Consists exclusively of well-formed tubules Sometimes mistaken for a benign sclerosing lesion Cribriform pattern may also be present Apocrine snouts are typical Calcifications may be present within the lumens (F) Micropapillary carcinoma METAPLASTIC CARCINOMA (C) Tubular carcinoma PAPILLARY CARCINOMA Produces true papillae, fronds of fibrovascular tissue lined by tumor cells (D) Papillary carcinoma Includes: → Spindle cell carcinomas → Matrix-producing carcinomas Often have gene expression profiles resembling those of myoepithelial cells Rare special histologic types of TNBC have a favorable prognosis compared to other carcinomas in this molecular group and include: SECRETORY CARCINOMA LOW-GRADE ADENOSQUAMOUS CARCINOMA ADENOID CYSTIC CARCINOMA SECRETORY CARCINOMA Mimics lactating breast by forming dilated spaces filled with eosinophilic material Rarely metastasize Two special histologic types frequently overexpress HER2 APOCRINE CARCINOMA MICROPAPILLARY CARCINOMA APOCRINE CARCINOMA Resemble the cells that line sweat glands Cells have enlarged round nuclei with prominent nucleoli and abundant eosinophilic, occasionally granular, cytoplasm NOTE TAKER: FERRER | NAMUHMUH | OLARTE | SANTIAGO (H) Secretory carcinoma Page 9 | 14 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.03.02 BREAST: MALIGNANT CONDITIONS INFLAMMATORY CARCINOMA Has a characteristic gross appearance caused by extensive plugging of the lymphovascular spaces of the dermis with carcinoma cells and carries a very poor prognosis, as most patients prove to have distant metastases Presents as breast erythema, swelling, and skin thickening Edematous skin is tethered to the breast by Cooper ligaments and mimics the surface of an orange peel, an appearance referred to as PEAU D’ORANGE The name “inflammatory” is a misnomer, as typically no inflammation is present Underlying carcinoma is usually diffusely infiltrative and typically does not form a discrete palpable mass Presentation can be confused with a breast infection, leading to delayed diagnosis Usually of high grade but do not belong to any particular molecular subtype PROGNOSTIC AND PREDICTIVE FACTORS FOR INVASIVE CARCINOMA The outcome for women with breast cancer depends on the biologic features of the carcinoma (the molecular or histologic type) and the stage of disease at the time of diagnosis Based on these factors, some women with breast cancer have a normal life expectancy, whereas others have only a 10% chance of being alive in 5 years Patients who present with distant metastasis (5% of patients) or with inflammatory carcinoma (1% to 5% of patients) have a particularly POOR PROGNOSIS For other cancers, prognosis is determined by pathologic evaluation of the primary tumor and the axillary lymph nodes Prognostic factors are important in counseling patients about the likely outcome of their disease, choosing the most appropriate treatment, and designing clinical trials Predictive factors help to determine the likely response of a cancer to a specific type of treatment Factors related to tumor biology are usually both prognostic and predictive (e.g., ER and HER2 expression, proliferation), whereas factors related to tumor extent (e.g., tumor size, lymph node metastases, distant metastases) are primarily prognostic THE MAJOR PROGNOSTIC FACTORS ARE AS FOLLOWS: Lymph node metastases Distant metastases Tumor size Locally advanced disease Lymphovascular invasion Inflammatory carcinoma NOTE TAKER: FERRER | NAMUHMUH | OLARTE | SANTIAGO LYMPH NODE METASTASES Axillary lymph node status - Most important prognostic factor for invasive carcinoma in the absence of distant metastases 10-year disease-free survival rate → 70% to 80% - With no nodal involvement → 35% to 40% - With one to three positive nodes → 10% to 15% - When more than 10 nodes are positive It is important to note that the presence of nodal metastases is correlated with the probability of distant metastasis, and that removal of involved lymph nodes does not lower the risk of future metastatic disease Lymphatic vessels in most breast carcinomas drain first to one or two SENTINEL NODES, which can be identified with radiotracer or colored dyes - If a biopsy of the sentinel nodes is negative for metastasis, it is unlikely that other, more distant nodes will be involved - This approach is used to spare patients the morbidity of a complete axillary dissection In these patients, metastasis may occur via the internal mammary lymph nodes or hematogenously DISTANT METASTASES Once distant metastases are present, cure is unlikely, although long-term remissions and palliation can be achieved, especially in women with ER-positive tumors Molecular group influences the timing and location of metastases TUMOR SIZE Risk of axillary lymph node metastasis increases with the size of the primary tumor, but size also is an independent prognostic factor Women with node-negative carcinomas less than 1 cm in size have a 10-year survival rate of more than 90%, whereas survival drops to 77% for cancers greater than 2 cm LOCALLY ADVANCED DISEASE Carcinomas invading the skin or skeletal muscle are usually large, making it difficult to achieve local control Such cases are now rare in the United States but continue to be common in countries with limited access to care LYMPHOVASCULAR INVASION Tumor cells are present within vascular spaces (either lymphatics or small capillaries) in about half of all invasive carcinomas This finding is strongly associated with the presence of lymph node metastases Poor prognostic factor for overall survival in women without lymph node metastases and a risk factor for local recurrence Page 10 | 14 PCCSOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.03.02 BREAST: MALIGNANT CONDITIONS INFLAMMATORY CARCINOMA Characterized by extensive invasion of dermal lymphovascular channels and portends a poor outcome 3-year survival rate is only 3% to 10% Only 1% to 5% of cancers are in this group, but the incidence is higher in women of African descent and younger women - TNBC remains a therapeutic challenge - There is hope that the genetic instability of these cancers will make them susceptible to agents that inhibit DNA repair and to immune system–based therapies FEW OTHER PROGNOSTIC FACTORS ARE CLINICALLY USEFUL: A. Gene expression profiling - Most are heavily weighted toward inclusion of genes that are involved in proliferation - Greatest clinical value of these assays is to identify patients with slowly growing, antiestrogenresponsive cancers who can be spared the toxicity of chemotherapy B. Response to neoadjuvant chemotherapy (Treatment) - Treating patients prior to surgery provides the opportunity to observe the tumor response to chemotherapy - A third or more of TNBCs and HER2 cancers regress completely (termed a pathologic complete response) - Patients with responsive cancers belonging to these subtypes have a better prognosis than patients with nonresponsive cancers - In contrast, very few luminal cancers respond completely to chemotherapy. However, these tumors are typically slow-growing and can often be controlled with endocrine-based treatment for many years - The main goals of breast cancer therapy are to control local disease and to prolong survival by treating known or potential distant metastases - Local control is achieved in the majority of patients with breast-conserving surgery and radiation therapy - Mastectomy is generally only necessary for locally advanced disease or for women at high risk of a second primary cancer who wish to reduce the risk of recurrence - Systemic therapy is used to treat known or likely distant disease and also reduces the likelihood of local recurrence - The first effective systemic treatment for any cancer was the discovery that oophorectomy caused regression of breast cancer in the late 1800s - This remains a treatment modality, but there are now many other options to inhibit the growth of hormonally responsive cancers - For many luminal cancers, endocrine therapy is the best and most effective therapeutic option - Chemotherapy is used for highly proliferative carcinomas, regardless of molecular subtype - For HER2 cancers, targeted therapy with HER2 antagonists has markedly improved prognosis NOTE TAKER: FERRER | NAMUHMUH | OLARTE | SANTIAGO MALE BREAST CANCER Incidence of breast cancer in men is only 1% of that in women, which translates to a lifetime risk of 0.11% Risk factors are similar to those in women and include: → Increasing age → First-degree relatives with breast cancer → Exposure to exogenous estrogens or ionizing radiation → Alcohol consumption → Infertility → Obesity → Prior benign breast disease → Klinefelter syndrome → Residency in Western countries Germline mutation of the BRCA2 tumor suppressor gene - Most important familial factor conferring an increased risk for male breast cancer Germline mutations in BRCA1, PTEN, TP53, and PALB2 - Lower risk of male breast cancer More than 90% of breast cancers in males are of luminal type, while TNBCs and HER2 cancers are very rare (