Chapter Notes: Genital System and Breast - 2

Table of Contents
1. Secondary Amenorrhea
2. Breast
3. Inflammation
4. Benign Epithelial Lesions
5. Breast Carcinoma
6. Classification of Breast Carcinoma
7. Invasive (Infiltrating) Carcinoma
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Secondary Amenorrhea

Secondary amenorrhea refers to the condition where a woman who previously had regular menstrual cycles experiences a cessation of her periods for a duration of 3 months or more. The common causes of secondary amenorrhea include:

• Pregnancy: This is the most frequent cause of secondary amenorrhea.
• Hypothalamic/Pituitary Abnormalities: Disorders affecting the hypothalamus or pituitary gland can disrupt the hormonal signals necessary for menstruation.
• Ovarian Disorders: Conditions affecting the ovaries can lead to irregularities in hormone production and menstrual cycles.
• Uterine Disease: Disorders affecting the uterus can also contribute to secondary amenorrhea.

To determine the specific causes of secondary amenorrhea, doctors typically assess gonadotropin levels (FSH and LH) and may perform a progesterone challenge test.

Progesterone Challenge Test

• If a woman experiences withdrawal bleeding after taking progesterone, it indicates that her endometrial lining has been prepared by estrogen. This suggests normal functioning of both the hypothalamus/pituitary axis and the ovaries.

Hypothalamic/Pituitary Disorders

• These disorders are characterized by low levels of FSH and LH.
• They may include functional gonadotropin deficiencies, often observed in individuals with significant weight loss.
• In such cases, a body weight reduction of more than 15% below the ideal weight leads to decreased GnRH secretion from the hypothalamus.
• Lower gonadotropin levels result in decreased estrogen levels, causing amenorrhea and increasing the risk of osteoporosis.
• Due to low estrogen levels, withdrawal bleeding does not occur after a progesterone challenge.

Ovarian Conditions

• Conditions such as surgical removal of the ovaries typically result in increased gonadotropin levels.
• This increase occurs due to the lack of negative feedback from estrogen and progesterone.
• Consequently, reduced estrogen levels mean that the progesterone challenge usually does not induce withdrawal bleeding.

Uterine Disorders

• Uterine (end organ) disorders are characterized by normal levels of FSH and LH.
• Asherman's syndrome is a notable example of this type of condition.
• A patient with Asherman's syndrome would not respond to progesterone due to the nature of the disorder.

Pregnancy can be confirmed through a clinical history and a pregnancy test measuring serum or urine beta-human chorionic gonadotropin (beta-hCG) levels.

Asherman's Syndrome

• Asherman's syndrome is a condition that results from multiple aggressive dilation and curettage (D&C) procedures performed to manage menorrhagia.
• These procedures lead to the removal of the stratum basalis of the uterus and are associated with the absence of glandular epithelium in the affected area.

Gestational Trophoblastic Diseases

This group of diseases includes: Benign hydatidiform mole (both partial and complete) Invasive mole Placental site trophoblastic tumor Choriocarcinoma

Hydatidiform Mole

• Complete Mole: All chorionic villi are abnormal, and there are no fetal parts.
• Partial Mole: Some villi are abnormal, and fetal parts may be present.
• Karyotype: Complete moles have a 46, XX diploid pattern (androgenesis). Partial moles have a triploid or tetraploid karyotype (fertilization by two sperm).
• Immunostaining for p57: Complete moles show negative results for p57.

Invasive Moles

• These moles invade the uterine wall and myometrium with hydropic chorionic villi.
• Characterized by the growth of cytotrophoblast and syncytiotrophoblast.
• Hydropic villi can travel to distant sites (e.g., lungs, brain) but do not grow there as true metastases.

Placental Site Trophoblastic Tumor (PSTT)

• Intermediate trophoblasts, located in the implantation site and placental membranes, can develop into PSTTs.
• PSTTs make up less than 2% of gestational trophoblastic neoplasms.
• Characterized by neoplastic polygonal cells infiltrating the endomyometrium.
• PSTTs may occur after a normal pregnancy in about half of the cases.

Gestational Choriocarcinomas

• Malignant growths of cytotrophoblasts and syncytiotrophoblasts without forming villi.
• Can develop from normal or abnormal pregnancies: 50% from hydatidiform moles, 25% from previous abortions, 22% from normal pregnancies, rest from ectopic pregnancies or teratomas.
• High levels of human chorionic gonadotropin (hCG), particularly in choriocarcinoma unless significant tumor necrosis is present.

Breast

• DCIS (Ductal Carcinoma In Situ) is the most prevalent type of breast condition.
• Acute mastitis during breastfeeding is commonly caused by the bacterium Staphylococcus aureus.
• Over 90% of individuals with periductal mastitis are smokers.
• Pain in the breast, also known as mastalgia or mastodynia, is the most common symptom reported.
• Discrete palpable masses in the breast are the second most frequent symptom.

Breast Masses

• A breast mass is typically not detectable until it reaches a size of approximately 2 cm in width.
• Around 50% of breast carcinomas develop in the upper outer quadrant of the breast.
• 10% of breast carcinomas occur in each of the other quadrants.
• Approximately 20% of breast carcinomas arise in the central or subareolar region of the breast.
• Nipple discharge is less common but raises concern, particularly when it occurs spontaneously and is unilateral (affecting one side).
• Discharges that are bloody or serous (clear or yellowish) are usually associated with benign conditions but can occasionally indicate a malignancy.
• Common causes of nipple discharge include:
  • A solitary large duct papilloma (a benign tumor in a milk duct)
  • Breast cysts
  • Carcinoma (breast cancer)
  • Infections in the breast

Mammographic Signs

• The primary mammographic indicators of breast carcinoma are densities (masses) and calcifications (calcium deposits).

Densities

• Most neoplasms (tumors) appear as solid masses on mammograms and are denser than the surrounding normal breast tissue.
• Mammography has the capability to detect these masses before they become palpable (able to be felt).
• Common lesions identified as densities on mammograms include:
  • Invasive carcinomas (a type of breast cancer that has spread beyond the ducts or lobules)
  • Fibroadenomas (benign tumors made up of glandular and fibrous breast tissue)
  • Cysts (fluid-filled sacs in the breast)
• Ductal carcinoma in situ (DCIS), a non-invasive form of breast cancer, rarely presents as a density on mammograms.

Calcifications

• Calcifications on mammograms are associated with secretory material, necrotic (dead) debris, and hyalinised (hardened) stroma (connective tissue).
• Calcifications that are indicative of malignancy tend to be small, irregular, numerous, and either clustered together or arranged in a branching pattern.

Inflammation

Acute Mastitis

• Acute Mastitis almost always occurs during lactation.
• It is usually caused by the bacteria Staphylococcus aureus.

Periductal Mastitis/Zuska Disease

• Periductal Mastitis, also known as Zuska disease, is characterized by recurrent subareolar abscesses or squamous metaplasia of the lactiferous ducts.
• This condition can affect both women and men.
• It presents as a painful, red mass beneath the areola.
• The main feature of Periductal Mastitis is the keratinizing squamous epithelium extending deeply into the nipple ducts.

Mammary Duct Ectasia

• Mammary Duct Ectasia typically occurs in women during their fifth or sixth decade of life and primarily affects multiparous women.
• It is not linked to cigarette smoking.
• Patients with this condition may feel a poorly defined mass around the areola.
• Symptoms may include skin retraction and thick, white nipple secretions.
• Mammary Duct Ectasia is characterized by duct dilation, thickened secretions, and chronic granulomatous inflammation.

Fat Necrosis

• Fat necrosis can present as a painless mass and may cause skin thickening or retraction.
• It can be detected through mammographic densities or calcifications.

Benign Epithelial Lesions

Nonproliferative Breast Changes. Fibrocystic Changes.

There are three main patterns of changes:

• Cyst formation, often with apocrine metaplasia;
• Fibrosis;
• Adenosis.

Cysts: Small cysts form when lobules enlarge and unfold. Larger cysts develop when smaller cysts merge. Unopened cysts appear brown to blue (known as blue-dome cysts. due to their cloudy, semi-transparent fluid. They are lined by either flattened, atrophic epithelium or by cells altered through apocrine metaplasia, which have a round nucleus and a rich, eosinophilic cytoplasm resembling that of sweat glands.

Fibrosis: Cysts often burst, releasing secretions into nearby tissue. This leads to chronic inflammation and scarring, making the breast feel firm.

Adenosis: Adenosis is when the number of acini (the small, milk-producing structures) in a lobule increases. The acini can be larger (known as blunt duct adenosis) and do not become distorted, unlike in sclerosing adenosis.

Proliferative Breast Disease without Atypia

This group includes conditions where there is an increase in ductal epithelium and/or stroma without signs of cancer. It consists of:

• Moderate or florid epithelial hyperplasia,
• Sclerosing adenosis,
• Complex sclerosing lesions,
• Papillomas, and
• Fibroadenoma with complex features.

Epithelial Hyperplasia: In a normal breast, only myoepithelial cells and one layer of luminal cells are present above the basement membrane. Epithelial hyperplasia is characterised by more than two cell layers.

Sclerosing Adenosis: The number of acini per terminal duct doubles compared to unaffected lobules, while maintaining the normal lobular structure. In the centre of the lesion, acini are compressed, while they are typically dilated at the edges. Myoepithelial cells are usually visible.

Complex Sclerosing Lesion (Radial Scar): These are star-shaped lesions with a central area containing trapped glands within a hardened stroma.

Papillomas: These tumours consist of branching fibrovascular cores, each lined with luminal and myoepithelial cells. They grow within a dilated duct. Small duct papillomas are part of proliferative breast disease and can increase the risk of later cancer.

Proliferative Breast Disease with Atypia

This includes atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH).

ADH: This condition looks similar to ductal carcinoma in situ, featuring a uniform cell type and orderly cell arrangement, with round lumens. However, these lesions are limited in size, and the cells are not entirely uniform or fail to fill ductal spaces completely.

ALH: This refers to the growth of cells that resemble those in lobular carcinoma in situ (LCIS), but they do not fill more than half of the acini in a lobule.

The term 'Milk of calcium' refers to calcifications in large cysts that look like a lining at the bottom of a rounded cyst during a mammogram.

Atypical hyperplasia involves a cell proliferation that resembles ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) but lacks sufficient features for a diagnosis of carcinoma in situ.

Non-proliferative changes usually do not increase cancer risk, with some rare exceptions. Proliferative disease poses a slight risk increase, while proliferative disease with atypia (ADH and ALH) presents a moderate increase in risk.

Breast Carcinoma

• Breast cancer is the most prevalent cancer among women in India.
• The condition of axillary lymph nodes is the key factor in predicting outcomes for invasive carcinoma when there are no distant metastases.
• The triple assessment for breast cancer comprises clinical examination, radiological examination (mammography), and Fine Needle Aspiration Cytology (FNAC).
• BRCA2 is more commonly associated with male breast cancer compared to BRCA1.
• Carcinoma is the most common form of breast cancer and the most prevalent non-skin cancer among women.

Prognostic Factors

• Invasive carcinoma typically has a worse prognosis than in-situ carcinoma.
• Distant metastasis indicates a poor prognosis.
• Involvement of axillary lymph nodes is linked to a worse prognosis.
• Tumor size is a critical factor:
• Less than 1 cm suggests a good prognosis.
• Greater than 2 cm indicates a poor prognosis.
• Local invasion into skeletal muscle signifies a poor prognosis.
• Inflammatory carcinoma is associated with a poor prognosis.

Minor Prognostic Factors

• Histological type is important: Invasive ductal carcinoma (no special type; NST) has a poor prognosis, while special types generally have a good prognosis, except for medullary carcinoma.
• The Nottingham histological score (Scarff-Bloom-Richardson grade) reflects:
• Grade 1 - good prognosis.
• Grade 3 - poor prognosis.
• Positive estrogen and progesterone receptors indicate a good response to anti-estrogen therapy.
• HER2/neu overexpression is associated with a poor prognosis.
• Lymphovascular invasion indicates a poor prognosis.
• A high proliferative rate signifies a worse prognosis.
• Aneuploidy is a marker of poor prognosis.

Risk Factors for Breast Carcinoma

• Hormonal and genetic factors (family history) are the major risk factors for developing breast cancer.
• Breast carcinomas can be classified into:
• Sporadic cases, possibly linked to hormonal exposure.
• Hereditary cases, associated with family history or germ-line mutations.

Hereditary Breast Cancer

• Mutations in BRCA1 significantly increase the risk of ovarian cancer, ranging from 20% to 40%.
• BRCA2 carries a lower risk for ovarian cancer (10% to 20%) but is more frequently associated with male breast cancer.
• Carriers of BRCA1 and BRCA2 mutations are also at risk for other cancers, such as colon, prostate, and pancreatic cancer, albeit to a lesser extent.
• BRCA1-associated breast cancers are typically poorly differentiated, exhibit medullary features, and lack hormone receptors and HER2/neu expression (triple-negative phenotype).
• These cancers have a gene profile similar to basal-like breast cancers and often show loss of inactive X-chromosome and reduplication of active X, resulting in the absence of Barr body.
• BRCA2-associated cancers are also poorly differentiated but are more likely to be estrogen receptor-positive.

Sporadic Breast Cancer

• Risk factors for sporadic breast cancer are primarily related to hormone exposure, including gender, age at menarche and menopause, reproductive history, breast-feeding, and exogenous estrogens.
• Most sporadic breast cancers occur in postmenopausal women and often overexpress estrogen receptors (ER).

Classification of Breast Carcinoma

• Almost all breast cancers are a type of cancer that originates in glandular tissue (adenocarcinomas). Other rare types, including squamous cell carcinomas, phyllodes tumors, sarcomas, and lymphomas, account for less than 5% of cases.
• Breast carcinomas are categorized into in situ (non-invasive) and invasive carcinomas.
• Noninvasive carcinomas, also known as carcinoma in situ, can occur in the ducts (intraductal carcinoma) or lobules (lobular carcinoma in situ).
• Types of Intraductal Carcinoma:
  • Comedocarcinoma. Characterized by a solid sheet of cells in the duct, often with a central area of cell death (necrosis) that can calcify. It is commonly associated with the erb B2/neu oncogene and is linked to a poor prognosis.
  • Cribriform carcinoma. Features round, duct-like structures within the solid sheet of cells.
  • Intraductal papillary carcinoma. Displays a predominantly papillary growth pattern.
• Paget's Disease.
  • Diagnosis: Involves the identification of large cells with clear cytoplasm infiltrating the nipple. These cells are typically found singly or in small clusters within the epidermis.
  • Association: Paget's disease is always linked with an underlying intraductal carcinoma that begins to invade the skin of the nipple and areola.
  • Distinction from Melanoma. Paget cells may resemble cells found in superficial spreading melanoma. However, they can be differentiated because they are PAS-positive, diastase-resistant, and positive for mucopolysaccharide and mucin, unlike melanoma cells.

Invasive (Infiltrating) Carcinoma

Invasive breast carcinoma is primarily categorized into:

• No Special Type Carcinoma (Intraductal)
• Special Type Carcinoma

Invasive Carcinoma, No Special Type (NST; Invasive Ductal Carcinoma)

• Luminal A (40-55%). These cancers are ER positive and HER2/neu negative. They typically grow slowly and respond well to hormonal treatments.
• Luminal B (15-20%). These are triple-positive cancers, meaning they are positive for ER, PR, and HER2/neu. They are usually of a higher grade and have a greater likelihood of spreading to lymph nodes.
• Normal Breast-like (6-10%). These cancers are well-differentiated, ER positive, and HER2/neu negative.
• Basal-like (13-25%). These are triple-negative cancers, meaning they are negative for ER, PR, and HER2/neu. They express markers typical of myoepithelial cells and stem cells. Many breast cancers in women with BRCA-1 mutations fall into this category.
• HER2 Positive (7-12%). These cancers are ER negative but overexpress HER2/neu, often due to amplification of a segment of DNA on chromosome 17q21.

Lobular Carcinoma

• Invasive lobular carcinoma of the breast is one of the few carcinomas observed bilaterally.
• The histological hallmark is the presence of infiltrating tumour cells, often arranged in single file or in loose clusters.
• Tubule formation is absent.
• Signet ring cells with intracytoplasmic mucin droplets are common.
• It metastasises frequently to the peritoneum, retroperitoneum, leptomeninges, gastrointestinal tract and ovaries.
• The incidence of lobular carcinoma is increasing among postmenopausal females, likely due to the higher use of HRT.

Medullary Carcinoma

• The tumour has a soft, fleshy consistency (medulla is Latin for "marrow") and is well-defined.
• The carcinoma is characterised by:
• Solid, syncytium-like sheets (occupying more than 75% of the tumour) of large cells with vesicular, pleomorphic nuclei, containing prominent nucleoli.
• Frequent mitotic figures.
• A moderate to marked lymphoplasmacytic infiltrate surrounding and within the tumour.
• A pushing (non-infiltrative) border.
• Medullary carcinomas have a slightly better prognosis than NST carcinomas, despite the almost universal presence of poor prognostic factors.
• These show overexpression of E-cadherin and basal-like gene expression.

Mucinous (Colloid) Carcinoma

• The tumour cells are seen as clusters and small islands of cells within large lakes of mucin that push into the adjacent stroma.

Tubular Carcinoma

• These tumours consist exclusively of well-formed tubules.
• However, a myoepithelial cell layer is absent, and tumour cells are in direct contact with stroma.

Invasive Papillary Carcinoma

• Invasive carcinomas with a papillary architecture are rare, representing 1% or fewer of all invasive cancers.
• This architecture is more commonly seen in DCIS.

Metaplastic Carcinoma

Metaplastic carcinoma encompasses a diverse group of rare breast cancers, accounting for less than 1% of all cases. These include conventional adenocarcinomas with chondroid stroma, squamous cell carcinomas, and carcinomas with a significant spindle cell component, which can be challenging to differentiate from sarcomas. Certain metaplastic carcinomas express genes shared with myoepithelial cells, suggesting they may originate from this cell type.