---

MUSEUM SPECIMEN GUIDE: GIT / Hepatobiliary / FGT

Based on Robbins & Kumar — Pathologic Basis of Disease and Basic Pathology

---

SYSTEM 1: GASTROINTESTINAL TRACT (GIT)

---

BENIGN SPECIMEN: COLONIC ADENOMA (Tubular/Villous Adenoma / Neoplastic Polyp)

Definition

Types

Gross Features (Identifying Points)

• Tubular adenoma: pedunculated (on a stalk), smooth-surfaced, 0.5-2 cm, red-pink, lobulated or raspberry-like head
• Villous adenoma: typically sessile (broad base, no stalk), larger (up to 10 cm), soft, shaggy/velvety surface with frond-like projections; most common in rectosigmoid
• Cut surface: fleshy, glandular or papillary architecture visible
• May show focal areas of hemorrhage or mucus coating

Microscopy

• Tubular adenoma: branching, closely packed glands lined by pseudostratified columnar epithelium with nuclear enlargement, hyperchromasia, loss of polarity - features of low-grade dysplasia
• Villous adenoma: tall finger-like projections lined by dysplastic epithelium; high-grade dysplasia may be present
• Goblet cells reduced; mitoses increased

Pathogenesis

• APC/β-catenin pathway mutation (most sporadic cases - APC gene on chromosome 5q)
• In FAP (Familial Adenomatous Polyposis): germline APC mutation → hundreds of adenomas → near 100% risk of cancer by age 50
• Adenoma → Carcinoma sequence: normal epithelium → adenoma (APC mutation) → high-grade dysplasia (KRAS, SMAD4, TP53 mutations) → carcinoma

Clinical Features

• Usually asymptomatic; detected on colonoscopy screening
• Large villous adenomas may cause profuse watery diarrhea with hypokalemia (secretory diarrhea)
• Rectal bleeding possible

---

MALIGNANT SPECIMEN: COLORECTAL ADENOCARCINOMA

Epidemiology

• Third most common cancer worldwide; second leading cause of cancer deaths in Western countries
• Peak incidence 60-70 years; slight male predominance
• Risk factors: high-fat/low-fiber diet, adenomatous polyps, IBD (ulcerative colitis), hereditary syndromes (FAP, Lynch syndrome/HNPCC)

Location

• 25% in cecum/ascending colon; 25% in rectosigmoid; rest distributed throughout

Gross Features (Identifying Points)

• Polypoid, exophytic, cauliflower-like fungating mass projecting into the lumen
• Rarely causes obstruction (wide lumen)
• Often ulcerated surface; soft, friable, necrotic
• Presents with occult bleeding → iron deficiency anemia

• Annular, "napkin-ring" or "apple-core" encircling growth that constricts the lumen
• Firm, gritty consistency
• Cut surface: firm, grey-white, infiltrative
• Presents with change in bowel habits, pencil-thin stools, obstruction
• Gross ulceration with heaped-up, everted edges

• Overlying mucosa destroyed
• May show satellite deposits in mesentery (lymph node metastases)
• Peritoneal spread may be visible as small nodular seedlings

Microscopy

• Malignant glands invading through the muscularis mucosa into submucosa and beyond
• Glands lined by tall columnar cells with nuclear pleomorphism, prominent nucleoli, increased mitoses
• Mucin-secreting (mucoid) adenocarcinoma: abundant extracellular mucin lakes with floating malignant cells
• Signet-ring cell carcinoma: cells with large cytoplasmic mucin vacuoles pushing nuclei to periphery (rare in colon, more common in stomach)
• Desmoplastic stroma surrounds invasive glands

Staging (Modified Dukes / TNM)

• Stage I: confined to wall → >90% 5-year survival
• Stage II: through wall, no nodes → 70-80%
• Stage III: lymph node metastases → 30-60%
• Stage IV: distant metastases (liver most common) → <5%

Molecular Pathogenesis

1. APC/WNT pathway (chromosomal instability, ~85%): APC → KRAS → SMAD4 → TP53 mutations
2. Microsatellite instability (MSI) pathway (~15%): MLH1/MSH2 defects (Lynch syndrome or sporadic methylation) → mismatch repair deficiency → better prognosis, responds to immunotherapy

---

SYSTEM 2: HEPATOBILIARY

---

BENIGN SPECIMEN: CAVERNOUS HEMANGIOMA

Definition

Gross Features (Identifying Points)

• Discrete, red-blue, spongy/soft nodule
• Usually less than 2 cm in diameter, but may be large (giant hemangioma up to 20 cm)
• Typically subcapsular in location
• Well-circumscribed, not encapsulated
• On cut section: blood-filled, honeycomb-like spaces; exudes blood when compressed
• May show central fibrosis/scarring (old lesions appear pale white and firm - "sclerosed hemangioma")
• Usually solitary

Microscopy (per Robbins PBD Fig. 18.50)

• Dilated thin-walled vascular channels lined by flat endothelial cells
• Channels separated by dense fibrous stroma
• No nuclear atypia; no mitotic figures
• Old lesions show organizing thrombi and fibrosis

Clinical Features

• Almost always asymptomatic - detected incidentally on imaging (US, CT, MRI)
• Clinically important: do NOT biopsy (risk of life-threatening hemorrhage)
• Rarely, Kasabach-Merritt syndrome (giant hemangioma → consumptive coagulopathy/thrombocytopenia)
• No malignant potential

Differential Diagnosis

• Hepatic adenoma (young women on OCP - uniform hepatocytes, no portal tracts)
• Focal nodular hyperplasia (central stellate scar, contains bile ducts)
• Angiosarcoma (malignant, atypia, infiltrative)

---

MALIGNANT SPECIMEN: HEPATOCELLULAR CARCINOMA (HCC)

Epidemiology

• Most common primary malignant tumor of the liver
• Worldwide: Southeast Asia, sub-Saharan Africa (endemic HBV areas); higher incidence
• USA/Europe: rising incidence due to HCV and MASLD (metabolic-associated steatotic liver disease)
• Male predominance; peak age 50-60 years

Risk Factors

• Chronic HBV infection (most important worldwide - may occur without cirrhosis)
• Chronic HCV infection
• Alcoholic cirrhosis
• MASLD/NASH → cirrhosis
• Aflatoxin B1 (Aspergillus flavus-contaminated grains) - causes TP53 R249S mutation
• Hereditary hemochromatosis, alpha-1 antitrypsin deficiency
• Anabolic steroid use

Gross Features (Identifying Points)

• Unifocal massive tumor: single large mass, most commonly in right lobe; pale yellow-green (bile-staining), soft and necrotic
• Multifocal: multiple nodules of varying sizes scattered throughout liver; typically in background of cirrhosis
• Diffuse: permeates entire liver as innumerable small nodules; difficult to distinguish from cirrhosis macroscopically

• Background of cirrhosis (nodular liver surface - firm, regenerative nodules separated by fibrous bands)
• Tumor shows portal vein invasion (tumor thrombus) - this is nearly pathognomonic
• Bile-stained (green) areas
• Satellite lesions/daughter nodules
• Necrosis and hemorrhage within tumor
• "Nodule-within-nodule" pattern (evolving cancer within a dysplastic nodule)
• Fibrolamellar variant (young adults, no cirrhosis): well-demarcated solitary nodule with central stellate scar, surrounded by dense fibrous bands (lamellar fibrosis)

Microscopy

• Well-differentiated: trabeculae 2-3 cells thick of polygonal cells resembling hepatocytes, with central nuclei, prominent nucleoli; bile production visible
• Moderately differentiated: thicker trabeculae, acinar (pseudoglandular) pattern, more nuclear pleomorphism
• Poorly differentiated: sheets of pleomorphic cells, giant cells; minimal hepatocytic differentiation
• Vascular invasion of portal/hepatic veins
• Fibrolamellar variant: oncocytic (eosinophilic granular) hepatocytes in nests and cords separated by dense parallel lamellae of collagen

Molecular Pathogenesis

• HBV: HBx protein inactivates TP53; viral DNA integration causes chromosomal instability
• Telomere shortening → chromosomal instability
• Key driver mutations: TP53, CTNNB1 (β-catenin), TERT promoter, ARID1A, AXIN1
• Aflatoxin B1: TP53 R249S point mutation (hotspot)

Prognosis

• Overall poor: 5-year survival ~5-10% with extrahepatic spread
• Fibrolamellar variant: better prognosis (no cirrhosis background; resectable); up to 40% survive 10 years
• Serum AFP elevated in ~70% of cases

---

SYSTEM 3: FEMALE GENITAL TRACT (FGT)

---

BENIGN SPECIMEN: UTERINE LEIOMYOMA (Fibroid)

Definition

Epidemiology

• Affects ~25-30% of women of reproductive age
• More common in Black women (3-9x higher incidence)
• Estrogen-dependent: grow during reproductive years, regress after menopause
• Rarely undergo malignant transformation (<1%)

Gross Features (Identifying Points) — Most important for museum specimen

• Firm, well-circumscribed, whorled/nodular masses with a distinct pseudo-capsule
• Cut surface: glistening white, whorled/trabeculated pattern of interlacing smooth muscle bundles - this is the single most characteristic gross feature
• May be solitary or multiple (most common presentation is multiple fibroids)
• Size ranges from millimeters to >20 cm ("football-sized")
• Location:
  • Intramural: within myometrium (most common)
  • Subserosal: project from outer surface, may become pedunculated
  • Submucosal: beneath endometrium, distort uterine cavity; cause most bleeding symptoms
• Secondary changes (degeneration): hyaline degeneration (most common; white, glassy areas), calcification (white gritty deposits - "womb stones"), red/carneous degeneration (hemorrhagic infarction, typically in pregnancy - painful; dark red/brown cut surface), cystic degeneration, myxoid change

Microscopy

• Interlacing fascicles/bundles of spindle-shaped smooth muscle cells
• Uniform, elongated nuclei with blunt ends ("cigar-shaped")
• Abundant pink cytoplasm
• No nuclear atypia; mitoses rare (<5 per 10 HPF)
• Hyalinized stroma in degenerated areas
• Well-defined border from surrounding myometrium

Molecular Features

• Most contain somatic mutations in MED12 gene
• Loss of fumarate hydratase (FH) in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome

Clinical Features

• Many asymptomatic (found incidentally)
• Symptoms: abnormal uterine bleeding (most common = heavy/prolonged periods from submucosal fibroids), pelvic pressure/pain, urinary frequency (pressure on bladder), infertility (distortion of uterine cavity)
• Treatment: GnRH analogs (shrink tumors), myomectomy, hysterectomy, UAE

---

MALIGNANT SPECIMEN: CARCINOMA OF THE CERVIX

Definition

HPV and Pathogenesis

• High-risk HPV types: 16 and 18 (most important; together account for ~70% of cases)
• HPV infects immature squamous metaplastic cells of the transformation zone (where squamocolumnar junction undergoes metaplasia)
• HPV E6 protein → binds and degrades p53 (tumor suppressor)
• HPV E7 protein → binds and inactivates Rb (retinoblastoma protein) → uncontrolled cell cycle progression
• Progression: HPV infection → CIN 1 → CIN 2 → CIN 3/CIS → invasive carcinoma (takes ~10-15 years)

Precursor Lesions: CIN (Cervical Intraepithelial Neoplasia)

• CIN 1 (mild dysplasia): koilocytes (HPV-infected cells with perinuclear halo and wrinkled/raisinoid nuclei) in lower 1/3 of epithelium; most regress
• CIN 2 (moderate dysplasia): lower 2/3 involvement
• CIN 3/CIS (severe dysplasia/carcinoma in situ): full-thickness involvement; high risk of progression

Histologic Types

1. Squamous cell carcinoma (~80%): arises from ectocervix/transformation zone
2. Adenocarcinoma (~15-20%): arises from endocervical glandular epithelium; associated with HPV 18; increasing incidence; harder to detect on Pap smear
3. Adenosquamous carcinoma: mixed

Gross Features (Identifying Points)

• Early invasive carcinoma: may not be visible grossly - only detected on colposcopy/biopsy
• Established invasive carcinoma:
  • Exophytic type: fungating, papillary, cauliflower-like mass growing outward from the ectocervix; friable, bleeds easily on touch
  • Endophytic/infiltrating type: ulcerative, crater-like lesion; firm, indurated cervix (barrel-shaped cervix in advanced disease); invades cervical stroma
  • Grayish-white, firm, granular/necrotic surface
  • Advanced disease: involves adjacent vaginal fornices; parametrial extension palpable as firm "wings" on rectal examination

Microscopy

• Squamous cell carcinoma: invasive nests, cords, and sheets of squamous cells with keratin pearls (well-differentiated), intercellular bridges, nuclear pleomorphism; desmoplastic stroma
• Adenocarcinoma: irregular glands with tall columnar cells, nuclear atypia, mitoses; mucin production

Staging and Prognosis

• Stage I (confined to cervix): >80% 5-year survival
• Stage II (beyond cervix, not pelvic wall): 60-65%
• Stage III (to pelvic wall or lower 1/3 vagina): 30-40%
• Stage IV (bladder/rectum involvement, distant metastases): <15%

Prevention

• Pap smear (cervical cytology): detects CIN at pre-invasive stage
• HPV vaccine (Gardasil, Cervarix): active against HPV 16, 18 (and HPV 6, 11 for condyloma)

---

SUMMARY TABLE FOR QUICK REFERENCE

---

ADDITIONAL MALIGNANT OPTIONS (if needed)

• Intestinal type: elevated mass with heaped-up borders and central ulceration (ulcerofungating), located near antrum
• Diffuse type (Linitis plastica): entire stomach wall diffusely thickened, rubbery, leather-bottle appearance - rugal folds lost; composed of signet-ring cells (large cytoplasmic mucin vacuole pushing nucleus to periphery)

• Most common gynecologic malignancy in Western countries; peak age 55-65 years
• Associated with hyperestrogenism (obesity, exogenous estrogens, PCOS)
• Gross: polypoid, soft, gray-white mass filling and distending the uterine cavity, arising from endometrium; necrosis and hemorrhage common; invades into myometrium (depth of invasion is key prognostic factor)
• Type I (endometrioid adenocarcinoma, ~80%): estrogen-driven, arises from endometrial hyperplasia, PTEN mutations, microsatellite instability, better prognosis
• Type II (serous/clear cell carcinoma, ~15%): TP53 mutations, aggressive, occurs in atrophic endometrium, worse prognosis

---

• Robbins, Cotran & Kumar - Pathologic Basis of Disease (9780443264528), Chapters 18 (Liver/Hepatobiliary), blocks 9
• Robbins & Kumar Basic Pathology (9780323790185), Chapters 13 (GIT), 17 (FGT), blocks 6-7

---

GIT MALIGNANT TUMORS

From Robbins & Kumar - Basic Pathology (9780323790185) and Pathologic Basis of Disease

---

SPECIMEN 1: COLORECTAL ADENOCARCINOMA

---

Epidemiology

• The most common malignancy of the gastrointestinal tract and a major cause of morbidity and mortality worldwide
• In the United States (~2022): approximately 151,000 new cases per year; ~53,000 deaths - representing 15% of all cancer deaths, second only to lung cancer
• Incidence peaks at 60-70 years of age; males slightly more often than females
• Up to 30-fold variation in incidence worldwide - highest in the USA, Canada, Australia, Denmark; lowest in India, South America, Africa
• Japan: previously low incidence, now risen to intermediate levels - evidence that lifestyle and diet are the dominant drivers

---

Risk Factors

---

Pathogenesis - Two Major Molecular Pathways

Pathway 1: APC/β-catenin Pathway (Classic Adenoma-Carcinoma Sequence) - ~80% of sporadic cases

Normal mucosa → Early adenoma → Intermediate adenoma → Late adenoma → Carcinoma
    APC loss        β-catenin↑        KRAS mutation       SMAD2/SMAD4      TP53 mutation
   (Chr 5q)         WNT↑             (proliferation↑)       loss           (invasion)

• APC is the gatekeeper mutation: a key negative regulator of β-catenin
• With loss of APC function, β-catenin accumulates, translocates to nucleus, activates MYC and Cyclin D1 → proliferation
• KRAS mutation: present in <10% of adenomas <1 cm, 50% of adenomas >1 cm, 50% of invasive carcinomas - late event
• SMAD2/SMAD4 mutations (TGF-β pathway components) and TP53 mutations complete the progression
• Epigenetic silencing (methylation of promoters) enhances progression

Pathway 2: Microsatellite Instability (MSI) Pathway - ~15-20% of sporadic cases

• Caused by germline mutations in MLH1 or MSH2 (also MSH6, PMS1, PMS2) - this is Lynch syndrome (HNPCC) when hereditary
• Sporadic cases: epigenetic silencing (methylation) of MLH1 promoter
• Loss of mismatch repair → microsatellite instability (accumulation of mutations at short repeat sequences) at rates up to 1000x higher than normal
• Downstream: mutations in TGFβRII, BAX (anti-apoptotic), BRAF, IGF2R, TCF-4
• Better prognosis than APC pathway cancers; responds to immunotherapy (PD-1 inhibitors)

---

GROSS MORPHOLOGY (Identifying Points for Museum Specimen)

• Polypoid, exophytic, fungating mass - large cauliflower-like growth projecting into the lumen
• Extends along one wall of the large-caliber cecum/ascending colon
• Rarely causes obstruction (large lumen)
• Surface: friable, necrotic, may be ulcerated
• Consistency: soft, friable
• Clinical clue: presents as iron-deficiency anemia (occult bleeding) - "it is a clinical maxim that the underlying cause of iron deficiency anemia in an older male or postmenopausal female is gastrointestinal cancer until proven otherwise" (Robbins)

• Annular "napkin-ring" constriction - encircles the bowel wall circumferentially
• Produces luminal narrowing; sometimes complete obstruction
• Feels firm and palpable as a hard mass through the bowel wall
• Ulcerated centre with heaped-up, everted edges
• Clinical clue: change in bowel habits, pencil-thin stools, left lower-quadrant cramping, hematochezia

• Invade the bowel wall over time - felt as firm masses on palpation
• Background mucosa may show polyps (adenomas), especially in FAP
• Mesenteric lymph nodes may be enlarged (metastases)
• Liver (most common site of distant metastasis) may show secondary nodules

---

MICROSCOPY

• Well-differentiated: invasive glands lined by tall columnar cells, resembling dysplastic epithelium of adenomas; nuclear pseudostratification, hyperchromasia, prominent nucleoli
• Desmoplastic stroma: strong fibrous stromal response surrounding glands - responsible for the firm consistency of the tumor on gross
• Mucinous carcinoma: abundant extracellular mucin pools within the intestinal wall with floating malignant gland fragments - associated with poor prognosis
• Signet ring cell carcinoma: cells with large cytoplasmic mucin vacuoles pushing the nucleus to the periphery (less common in colon than stomach)
• Poorly differentiated: few glands; sheets of pleomorphic cells
• Evidence of muscularis mucosa invasion confirms malignancy (distinguishes from high-grade adenoma/dysplasia)

---

Staging and Prognosis (TNM/Modified Dukes)

---

SPECIMEN 2: GASTRIC ADENOCARCINOMA

---

Definition & Frequency

• Most common malignancy of the stomach, accounting for >90% of all gastric cancers
• Accounts for ~8% of all cancer deaths worldwide
• Incidence up to 20 times higher in Japan, Chile, Costa Rica, Eastern Europe vs. North America
• In the USA/Europe: incidence has dropped >85% since the early 20th century (due to reduced H. pylori exposure, refrigeration, less nitrosamines in food)
• Exception: cancer of the gastric cardia is rising - linked to Barrett esophagus, GERD, and obesity

---

Risk Factors

---

Classification: Two Major Types

Type 1 - Intestinal Type (~50-60%)

• Associated with: H. pylori, atrophic gastritis, intestinal metaplasia, environmental/dietary factors
• Predominantly affects: older males, 55+ years
• Geography: high-incidence regions (Japan, Korea)
• Molecular: APC/β-catenin pathway, acquired mutations in β-catenin and TP53; H. pylori-related
• Precursor: gastric adenoma, intestinal metaplasia

Type 2 - Diffuse Type (~30-40%)

• No identified precursor lesions; no geographic variation
• Affects males and females equally; often younger patients
• Molecular: CDH1 mutation (loss of E-cadherin - somatic in ~50% of sporadic diffuse cases; methylation of CDH1 promoter in the rest)
• Both types: TP53 mutations in majority; HER2 amplification in ~10-20%

---

GROSS MORPHOLOGY (Identifying Points for Museum Specimen)

Intestinal Type:

• Elevated, polypoid/fungating mass with heaped-up borders and central ulceration
• Located predominantly near the antrum/pylorus (lesser curvature)
• Surface: irregular, necrotic, hemorrhagic ulcerated center with raised margins
• Compare with benign peptic ulcer: peptic ulcer has smooth, punched-out edges and clean base; carcinoma has irregular, heaped-up, everted edges with indurated base

Diffuse Type (Linitis Plastica):

• Leather-bottle stomach / Linitis plastica: the entire gastric wall is diffusely thickened, rigid, inelastic
• Stomach does not distend; wall feels rubbery/firm throughout
• Rugal folds are partially or completely lost - smooth inner surface
• Cut section: thick white/grey rubbery wall infiltrated by tumor cells within the stroma
• Due to: signet ring cells spreading diffusely through the wall with extensive desmoplastic reaction → fibrosis → rigidity
• Stomach looks shrunken, with narrowed lumen

• Background mucosa: atrophic gastritis (loss of rugal folds, pale thin mucosa), intestinal metaplasia
• May show adjacent polypoid gastric adenomas (precursor lesions)
• Regional lymph nodes involved: perigastric nodes → celiac axis nodes

• Virchow's node: left supraclavicular lymph node metastasis (Troisier's sign)
• Krukenberg tumor: bilateral ovarian metastases (signet ring cells from diffuse type) - ovaries appear enlarged, solid, white, firm
• Sister Mary Joseph nodule: periumbilical nodule = peritoneal metastasis

---

MICROSCOPY

• Well-formed malignant glands lined by columnar cells with nuclear pleomorphism, mitoses
• Gland-forming pattern with mucin production
• Invades through muscularis into serosa

• Composed of signet ring cells: individual cells with a large mucin vacuole occupying the cytoplasm, pushing the nucleus to the periphery to form a crescent/half-moon shape
• Cells infiltrate diffusely through gastric wall - no gland formation
• Desmoplastic fibrous stroma throughout wall (explains rigidity)
• Poorly cohesive cells - due to loss of E-cadherin

---

Clinical Features and Prognosis

• Early symptoms: resemble chronic gastritis → dyspepsia, dysphagia, nausea - cancer often missed at this stage
• Late symptoms (when diagnosed in most Western patients): weight loss, anorexia, anemia, altered bowel habits, hemorrhage
• Early gastric cancer (limited to mucosa/submucosa): detected by endoscopic screening in Japan - 5-year survival >90% even with lymph node mets
• Advanced cancer (most cases in USA): overall 5-year survival <30% - current chemotherapy has limited impact
• HER2-positive tumors (~10-20%) benefit from targeted therapy (trastuzumab)

---

COMPARISON TABLE: GIT MALIGNANT TUMORS

---