Female Genital System, Breast & Endocrine Pathology

Systematic Notes

Cervical Tumors Breast Carcinoma Gestational Trophoblastic Disease Thyroid Neoplasms

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Part 1 — Tumors of the Cervix

Epidemiology & Risk Factors

Parameter	Details
Peak age — CIN	30 years
Peak age — Invasive carcinoma	45 years
Most important risk factor	High-risk HPV infection (especially HPV 16, 18)
Behavioural risk factors	Early age at first intercourse, multiple sexual partners
Other risk factors	Cigarette smoking, immunodeficiency
Predilection site	Squamocolumnar junction (transformation zone) of cervix

How HPV Causes Cervical Cancer

📌 Mechanism — Must Know Nearly all CINs and carcinomas are caused by high-risk HPV (especially HPV 16 & 18). Persistent infection → integration into host genome → ↑ expression of E6 and E7 proteins.

E6 protein → inactivates p53 tumor suppressor → suppresses apoptosis
E7 protein → inactivates RB tumor suppressor → increases cell proliferation
Together → progression to high-grade CIN → invasive cancer
HPV vaccine prevents infection by high-risk HPV → prevents cervical carcinoma

CIN — Cervical Intraepithelial Neoplasia

📖 Terminology CIN = Cervical Intraepithelial Neoplasia | SIL = Squamous Intraepithelial Lesion
LSIL = CIN I (NOT a precancerous lesion) | HSIL = CIN II + CIN III (precancerous lesions)

CIN I — Mild Dysplasia

Atypical cells in basal 1/3 only
Koilocytotic change in superficial layers (HPV cytopathic effect)
= LSIL; rarely progresses to cancer

CIN II — Moderate Dysplasia

Atypical cells up to middle 1/3
Nuclear size variation, heterogeneous chromatin
Mitoses present
= HSIL (precancerous)

CIN III — Severe Dysplasia / CIS

Severe dysplasia: > lower 2/3 but not full thickness
Carcinoma in situ: all layers involved; basement membrane intact
May extend into endocervical glands (still CIS if BM intact)
= HSIL (precancerous)

⚠️ Key Concept Even when CIN III cells extend into endocervical glands, as long as they do not break through the basement membrane, it remains CIN III (carcinoma in situ) — NOT invasive carcinoma.

Diagnosis of CIN

CIN is clinically asymptomatic — detected only by screening.

🔬 Pap Smear (Papanicolaou Smear)

Cells scraped from transformation zone with a small brush
Examined microscopically for SIL changes
Most successful cancer-screening test — dramatically lowered incidence of invasive carcinoma

🧬 HPV Test

Used in conjunction with Pap smear
Detects high-risk HPV types (most important risk factor)

🔎 Colposcopy + Biopsy

Colposcopy: magnified view of cervix → identify abnormal areas
Biopsy: tissue sample for histological (definitive) diagnosis

Treatment of CIN

CIN Grade	Treatment
CIN I	Monitoring — Pap smear + HPV test in 1 year (rarely progresses)
CIN II & III	LEEP — thin looped wire with electric current removes thin layer of cervix including CIN lesion Cold knife conization — surgical cone-shaped excision of cervix including CIN lesion

Invasive Carcinoma of Cervix

Gross Morphology — 4 Types

Type	Gross Features
Erosive	Reddened, moist, granular surface
Fungating Most Common	Papillary, cauliflower-like protruding mass; superficial ulcer and necrosis
Ulcerative	Large, irregular cancerous crater with necrosis
Infiltrative	Grey tumour invades cervical tissue, no clear border; cervical wall thickened

Histological Types

Squamous cell carcinoma — 75% (most common)
Adenocarcinoma — HPV18 associated; involves columnar epithelium
Mixed adenosquamous carcinoma
Small cell neuroendocrine carcinoma — <5% (rare)

Squamous Cell Carcinoma — Subtypes

Subtype	Criteria	Treatment
Microinvasive	Invasion depth <5 mm AND <7 mm horizontal	Conization or simple hysterectomy
Invasive	Invasion depth >5 mm	Hysterectomy + lymph node dissection

Differentiation of Invasive Squamous Cell Carcinoma

Well differentiated (Keratinizing) — keratin pearls present
Moderately differentiated (Non-keratinizing) — keratinocytes without keratin pearls
Poorly differentiated — highly atypical cells

Spread of Cervical Carcinoma

Route	Structures Involved
Direct extension	Uterine body, peritoneum, urinary bladder, ureters, rectum, vagina
Lymphatic	Pelvic lymph nodes → eventually supraclavicular lymph nodes
Hematogenous	Lung, liver

Symptoms, Prognosis & Treatment

Symptoms of Invasive Cervical Carcinoma

Unexpected (abnormal) vaginal bleeding
Painful coitus (dyspareunia)
Leukorrhea (vaginal discharge)

📊 Prognosis — 5-Year Survival by Stage

Stage 0 (Preinvasive)

100%

Stage 1 (Cervix only)

90%

Stage 3

35%

Stage 4

10%

Treatment of Invasive Cervical Carcinoma

Primary: Hysterectomy + lymph node dissection
Small microinvasive: cone biopsy
Adjuvant: radiation and/or chemotherapy when surgery alone not curative

✅ Prevention Pap smear is a highly effective screening tool → significantly reduced incidence of cervical carcinoma.
HPV test used in conjunction with Pap smear.
HPV vaccination prevents high-risk HPV infection → prevents cervical carcinoma.

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Part 2 — Breast Carcinoma

📌 Epidemiology — Key Facts Most common malignant tumour in women globally · Causes majority of cancer deaths in women · 75% occur after age 50 · Arises from the terminal duct lobular unit (TDLU)

Breast Anatomy (Quick Recap)

Each breast has 15–20 lobes, each with many smaller lobules, connected by ducts
Ducts and lobules embedded in fibrous stroma + adipose tissue
TDLU = Terminal Duct Lobular Unit — the basic functional & histopathological unit
TDLU = terminal duct + cluster of lobules (effective secretory units)

Risk Factors of Breast Carcinoma

Risk Factor	Details
Endogenous estrogen excess	Long duration of reproductive life, nulliparity, late age at first child
Exogenous estrogen	Estrogen therapy
Genetic (5–10%)	BRCA1 mutation → 85% lifetime risk BRCA2 mutation → 30–40% lifetime risk
Other factors	Fibrocystic disease, radiation exposure, obesity

🎭 Clinical Note Actress Angelina Jolie had BRCA1 mutation and underwent prophylactic double mastectomy to reduce her breast cancer risk — a well-known example of BRCA1's 85% lifetime risk.

Pathological Classification of Breast Carcinoma

Category	Types	Frequency
A. Non-invasive (In Situ)	Ductal Carcinoma in Situ (DCIS)	—
A. Non-invasive (In Situ)	Lobular Carcinoma in Situ (LCIS)	—
B. Invasive	Invasive Ductal Carcinoma	70–80%
	Invasive Lobular Carcinoma	10–15%
	Special types (Medullary, Colloid/Mucinous, Tubular)	10–15%
	Other types	—

📖 Key Rule — In Situ Carcinomas Both DCIS and LCIS arise from TDLU lining. Tumor cells are confined by basement membrane — do NOT invade into stroma or lymphovascular channels.

Non-Invasive: DCIS (Ductal Carcinoma In Situ)

Histological Appearances of DCIS

Nuclear grade ranges from low (uniform, round, bland) to high (pleomorphic)
Varieties: Solid, Comedo, Cribriform, Papillary, Micropapillary, Clinging
Necrosis and calcification may be present in any type

DCIS Type	Key Feature
Comedo	Central toothpaste-like necrosis that extrudes from transected ducts; comedo necrosis + calcification
Cribriform	Sieve-like ("Swiss cheese") pattern with multiple lumina
Solid	Solid sheets of cells filling the duct lumen; may show calcification
Papillary	Papillae with a vascular fibrous axis (stalk)
Micropapillary	Small papillary projections without vascularized axis

⚠️ Special Entity — Paget's Disease of Nipple Caused by extension of DCIS up the lactiferous ducts into the skin of the nipple.
Presentation: Unilateral crusting exudate over nipple and areolar skin.

DCIS — Clinical Importance

Precursor to invasive ductal carcinoma
Typically found on mammography as calcifications or a mass
Prognosis: excellent (>97% long-term survival)
If untreated → 1/3 will progress to invasive ductal carcinoma in the same breast

Non-Invasive: LCIS (Lobular Carcinoma In Situ)

Cells grow in lobules (milk-producing glands) without breaking through basement membrane
Uniform appearance — monomorphic cells with bland, round nuclei in loosely cohesive clusters
Low nuclear grade; necrosis is rare
Does NOT tend to produce a mass or calcification → hard to detect on mammogram
Increases risk of invasive ductal or lobular carcinoma in EITHER breast
Acts as both a risk marker and direct precursor of some carcinomas
Prognosis is excellent

Feature	DCIS	LCIS
Origin	Ducts of TDLU	Lobules of TDLU
Nuclear grade	Low to high	Low (uniform)
Necrosis	Common (esp. comedo)	Rare
Calcification	Common	Uncommon
Mammogram detection	Usually detectable	Often not detected
Precursor to	Invasive ductal ca.	Invasive ductal or lobular ca. (either breast)
If untreated	1/3 → invasive (same breast)	Risk marker (both breasts)

Invasive Ductal Carcinoma

Carcinomas that cannot be subclassified into any specialized type
Most common — 70–80% of all invasive breast carcinomas
Usually associated with DCIS
Morphology: varies from well-developed tubules + low-grade nuclei → sheets of high-grade nuclei
Desmoplastic response (fibrous reaction) replaces normal breast fat → stony hard, irregular palpable mass + mammographic density
Desmoplasia causes contraction → nipple retraction and skin dimpling
Shape: irregular, without capsule

Invasive Lobular Carcinoma

10–15% of breast carcinomas
Cells similar to LCIS morphology; 2/3 cases have adjacent LCIS
Cells are non-cohesive — invade stroma as linear cords ("Indian file" or bull's-eye pattern)
May induce little stromal response → clinically occult; appears as subtle irregular mass on mammogram
Unique metastasis pattern: CSF, serosal surfaces, GI tract, ovary, uterus, bone marrow

Clinical Features of Invasive Breast Carcinoma

Major Symptom

🔑 Classic Presentation Painless, hard, fixed mass — the classic presentation of invasive breast carcinoma

Direct Spread Effects

Invade skin → retraction or dimpling of skin, nipple retraction
Invade chest wall → fixation of breast
Orange peel (Peau d'orange) → tumour cells block lymphatics → localized lymphedema → skin thickened, edematous around hair follicles

Metastasis

Lymphatic: Axillary lymph nodes (most common first site)
Hematogenous: Lung, bone, liver, brain

Prognostic Factors

⚠️ Poor Prognostic Factors — Know All

Factor	Poor Prognosis If...
TNM Stage	Large tumour size, many lymph node metastases, distant metastases
Grade	Poorly differentiated: few tubules, high nuclear grade, high mitotic rate
Histological type	Ductal carcinoma has poorer prognosis than specialised types (tubular, medullary, mucinous)
Hormone receptors	ER negative / PR negative → no response to anti-estrogen therapy → poorer prognosis
Proliferative rate	High proliferative rate → poorer prognosis
HER2 overexpression	HER2 positive → poorer prognosis generally; BUT responds well to Herceptin (trastuzumab) → good prognosis with treatment

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Part 3 — Gestational Trophoblastic Diseases

Normal Placental Villi — Quick Recap

Chorionic villi contain blood vessels; maternal blood circulates between villi
Covered by two layers:
- Inner cytotrophoblast (CT) — cuboidal cells
- Outer syncytiotrophoblast (ST) — abundant pink cytoplasm, multinucleated
Third type: Intermediate trophoblast (IT)

Classification of Gestational Trophoblastic Disease

Category	Condition
Molar lesions	Hydatidiform moles (Complete & Partial) Invasive hydatidiform moles
Non-molar lesions	Choriocarcinoma

🔑 Key Diagnostic Marker Serum hCG (human chorionic gonadotropin) is markedly elevated in all molar conditions — higher than normal pregnancy. Monitor hCG levels to assess treatment response.

Symptoms of Gestational Trophoblastic Disease

Peak ages: <20 years and >40 years
Excessive uterine size (larger than dates)
Markedly elevated serum hCG
Absence of fetal heart sounds on ultrasound
Vaginal bleeding in first trimester

Hydatidiform Moles

Key Definition

Mass of swollen, cystically dilated chorionic villi → grossly look like grapelike structures
Normal to highly atypical chorionic epithelium covers the swollen villi
Due to abnormal paternal chromosome contribution

Feature	Partial Mole	Complete Mole
Ploidy	Triploid	Diploid
Chromosomes	Two sets paternal + one maternal	All chromosomes paternal
Fetal tissue	Accompanied by fetal tissue	Rarely any embryonic/fetal tissue
Risk of persistent disease	Low	Higher — 10% become invasive; 2% → choriocarcinoma

Morphology of Hydatidiform Moles

Swelling of chorionic villi
Villi have edematous stroma with rare vascularization
Proliferation of atypical chorionic epithelium (both CT and ST)
Grossly: uterine cavity expanded by delicate, friable mass of thin-walled, translucent cystic grapelike structures
Limited to uterine cavity — does NOT invade myometrium (distinguishes from invasive mole)

Prognosis of Hydatidiform Moles

No recurrence after curettage

80–90%

Progress to invasive mole

10%

Progress to choriocarcinoma

Invasive Hydatidiform Mole

Complete hydatidiform mole that locally invades the uterine wall (endometrium → myometrium)
Can cause uterine wall rupture and hemorrhage
Lacks metastatic potential (unlike choriocarcinoma)
Molar villi invade deeply into myometrium with atypical epithelium and proliferation of both CT and ST cells
Difficult to remove by curettage alone
Serum hCG remains elevated after evacuation
Chemotherapy is highly effective

Gestational Choriocarcinoma

🔴 Aggressive Malignant Tumor — Key Facts Arises from gestational chorionic epithelium · hCG much higher than molar levels · Remarkably sensitive to chemotherapy — curable in most cases

Origins of Choriocarcinoma

50% arise after complete moles
25% arise after an abortion
Others follow a normal pregnancy

Morphology

Tumor infiltrates uterine myometrium and vessels
Chorionic villi are NOT formed (key difference from molar disease)
Composed of: anaplastic cytotrophoblasts (mononucleate, cuboidal) + syncytiotrophoblasts (multinucleate)
No tumor stroma or vasculature within the tumor
Obvious and extensive hemorrhage and necrosis due to vascular invasion

Behaviour & Prognosis

Highly invasive and frequently metastatic
Remarkably sensitive to chemotherapy → curable in most cases despite aggressive behavior

Feature	Hydatidiform Mole	Invasive Mole	Choriocarcinoma
Chorionic villi	Present (swollen)	Present (invade myometrium)	Absent
Myometrial invasion	No	Yes	Yes
Metastasis	No	No	Yes (frequent)
hCG	Elevated	Elevated (persists post-curettage)	Much higher
Chemosensitivity	—	Highly effective	Remarkably effective

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Part 4 — Thyroid Neoplasms (Chapter 16)

Normal Thyroid — Quick Recap

Normal weight: 20–40 g
Follicular lumens contain colloid (made mostly of thyroglobulin)
Parafollicular cells (C cells) secrete calcitonin

Tumor Type	Origin
Follicular adenomas, Follicular carcinoma, Papillary carcinoma, Anaplastic carcinoma	Follicular epithelium
Medullary carcinoma	Parafollicular (C) cells

Follicular Adenoma

Most common benign thyroid tumor
Derives from follicular epithelium
Presents as painless nodule
Age: 40–50 years; Female:Male = 7:1

Gross Features

Solitary, spherical, well-defined lesion with intact capsule
Compresses adjacent non-neoplastic thyroid
Cut surface: soft, paler than surrounding thyroid
Hemorrhage, fibrosis, and cystic change are common

Histological Types of Follicular Adenoma

Embryonal adenoma
Fetal adenoma — microfollicles with little or no colloid
Simple follicular adenoma — mature follicles with normal amount of colloid
Colloid adenoma

Thyroid Carcinomas — Overview

Account for 1% of all malignancies in developed countries
Most occur in adults; papillary carcinoma may occur in children
Female more likely in early/middle adult years
First symptom: nodule in neck or enlarged lymph node

Type	Frequency	Origin
Papillary carcinoma	80%	Follicular epithelium
Follicular carcinoma	15%	Follicular epithelium
Anaplastic carcinoma	<5%	Follicular epithelium
Medullary carcinoma	5%	Parafollicular (C) cells

Papillary Carcinoma

✅ Most Common Thyroid Carcinoma (80%) Indolent lesion · Painless mass in neck · Non-functional · 10-year survival rate >95%

Gross Features

Solitary or multifocal lesions
Often infiltrates adjacent parenchyma with ill-defined margins; sometimes encapsulated
May contain granular/papillary foci, fibrosis, calcification, or cystic areas

Microscopic Features

Branching papillae with a fibrovascular stalk covered by neoplastic epithelial cells
Ground-glass nuclei ("Orphan Annie eye") — central clear and empty appearance due to formaldehyde fixation
Pseudo-inclusions — invagination of cytoplasm appearing as intranuclear inclusion
Psammoma bodies — concentrically calcified structures within papilla cores

📌 Diagnostic Key Points — Papillary Carcinoma Nuclear features (ground-glass nuclei + pseudo-inclusions) are sufficient for diagnosis even without papillary structure.

Psammoma bodies are characteristic of papillary carcinoma — NEVER found in other thyroid carcinomas.

Metastasis

Often metastasises to cervical lymph nodes — but prognosis remains excellent
Hematogenous metastasis is rare → poorer prognosis when it occurs

Follicular Thyroid Carcinoma

Second most common type of thyroid carcinoma
More frequent in areas with dietary iodine deficiency (accounts for 25–40% in such areas)
Usually presents as solitary nodule
Composed of uniform cells forming small follicles
May be widely invasive or minimally invasive
Tendency to hematogenous metastasis → lungs, bone, liver (unlike papillary which goes to lymph nodes)

📌 How to Distinguish Follicular Adenoma vs. Carcinoma Both are composed of well-differentiated follicular epithelial cells that look similar histologically.
Distinguished ONLY by evidence of capsular invasion and/or vascular invasion — present in carcinoma, absent in adenoma.

Feature	Follicular Adenoma	Follicular Carcinoma
Capsule	Complete, intact	Capsular invasion present
Vascular invasion	Absent	Present (key diagnostic feature)
Cell appearance	Well-differentiated follicular cells	Well-differentiated follicular cells (same appearance)
Metastasis	None	Hematogenous (lungs, bone, liver)

Quick Comparison — All 4 Thyroid Carcinomas

Feature	Papillary	Follicular	Medullary	Anaplastic
Frequency	80%	15%	5%	<5%
Origin	Follicular epi.	Follicular epi.	C cells	Follicular epi.
Key micro feature	Ground-glass nuclei, psammoma bodies	Capsular + vascular invasion	Secretes calcitonin, amyloid stroma	Highly anaplastic
Spread	Lymphatic (cervical LN)	Hematogenous (lung, bone, liver)	Both	Aggressive local + distant
Prognosis	Excellent (>95% at 10 yr)	Intermediate	Intermediate	Very poor

💡 Mnemonic — Thyroid Carcinomas

Papillary — most common, excellent Prognosis, goes to lymph nodes via Papillae
Follicular — Found in iodine-Free areas, Fights its way into blood vessels
Medullary — from Marks parafollicular cells, produces calcitonin
Anaplastic — Awful prognosis, All cells de-differentiated

⭐ High-Yield Exam Points Summary

HPV 16/18 → E6 inactivates p53 (apoptosis suppressed), E7 inactivates RB (↑ proliferation) → CIN → cancer
CIN: cells confined to epithelium; basement membrane intact = NOT invasive
Pap smear = most successful cancer screening test ever developed
Fungating type = most common gross type of invasive cervical carcinoma
SCC = 75% of cervical carcinomas; HPV18 → adenocarcinoma
Breast carcinoma arises from TDLU; most common cancer in women worldwide
DCIS: 1/3 progress to invasive if untreated; Paget's disease = DCIS extending to nipple skin
LCIS: risk marker for both breasts; no mass/calcification; hard to see on mammogram
Invasive ductal carcinoma: desmoplasia → hard mass, nipple retraction, skin dimpling
Invasive lobular carcinoma: non-cohesive cells in linear cords; unique metastasis to GI/CSF/ovary
HER2+ breast cancer → treat with Herceptin (trastuzumab)
Hydatidiform mole = grapelike villi in uterine cavity; complete mole = all paternal chromosomes
2% of complete moles → choriocarcinoma; hCG levels guide follow-up
Choriocarcinoma: NO chorionic villi, extensive hemorrhage/necrosis, curable with chemotherapy
Papillary thyroid carcinoma: ground-glass nuclei + psammoma bodies = diagnostic; best prognosis
Follicular adenoma vs. carcinoma: distinguished ONLY by capsular/vascular invasion
Medullary carcinoma: from parafollicular C cells; secretes calcitonin