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Pathology: Testicular & Ovarian Tumors + Fibroid Uterus

(Robbins Pathology - 2nd Year MBBS)

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PART 1: CLASSIFICATION OF TESTICULAR TUMORS

WHO Classification

1. Seminoma (~50%)
2. Embryonal carcinoma
3. Yolk sac tumor
4. Choriocarcinoma
5. Teratoma (malignant in adults)
6. Mixed GCTs (~30-40%; most common: teratoma + embryonal carcinoma)

• Yolk sac tumor (most common in children <3 yrs)
• Teratoma (prepubertal; benign)

• Leydig cell tumor, Sertoli cell tumor, Granulosa cell tumor

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Summary Table of Testicular GCTs (Robbins & Kumar Basic Pathology, Table 16.1)

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PART 2: SEMINOMA - GROSS AND MICROSCOPIC FEATURES + MORPHOLOGY + MODES OF SPREAD

Classical Seminoma - Pathogenesis

• Most common testicular GCT (~50% of all testicular GCTs)
• Virtually all arise from Germ Cell Neoplasia In Situ (GCNIS)
• Nearly all have isochromosome 12p [i(12p)] - extra copies of chromosome 12p short arm
• KIT oncogene mutations in up to 25%
• Risk factors: cryptorchidism (10% of cases), intersex syndromes, family history

GROSS FEATURES

• Soft, well-demarcated, lobulated gray-white homogeneous tumor
• Bulges prominently from the cut surface of the affected testis
• "Fish flesh" or "fleshy" appearance
• No hemorrhage (unlike embryonal carcinoma - key distinguishing feature)
• Large tumors may show foci of coagulative necrosis
• May be very large at diagnosis (remains confined to testis for long periods)

MICROSCOPIC FEATURES

• Large, uniform, polygonal cells with distinct cell borders
• Clear, glycogen-rich cytoplasm (PAS positive)
• Round nuclei with coarsely clumped chromatin
• Conspicuous nucleoli (1-2 prominent nucleoli per cell)
• Cells arranged in small lobules separated by delicate fibrous septa
• Lymphocytic infiltrate in the stroma (hallmark - T lymphocytes)
• May elicit granulomatous reaction (epithelioid cells, giant cells)
• In ~15% of cases, syncytiotrophoblast cells present (source of mildly elevated hCG)

Labeled Diagram - Classical Seminoma Histology

         CLASSICAL SEMINOMA - HISTOLOGICAL FEATURES
         ═══════════════════════════════════════════

    ┌──────────────────────────────────────────────────────┐
    │          FIBROUS SEPTUM                              │
    │   (divides tumor into lobules)                       │
    │   Contains: Lymphocytes (•) + Granulomas [G]        │
    └──────────────────┬───────────────────────────────────┘
                       │
    ┌──────────────────▼───────────────────────────────────┐
    │                 LOBULE OF TUMOR CELLS                │
    │                                                      │
    │    ○ ── ○ ── ○ ── ○ ── ○ ── ○ ── ○                  │
    │    │    │    │    │    │    │    │                   │
    │    ○    ○    ○    ○    ○    ○    ○                   │
    │                                                      │
    │    ○ = Large polygonal tumor cell:                   │
    │        - Distinct cell borders                       │
    │        - CLEAR glycogen-rich cytoplasm (PAS+)        │
    │        - Round nucleus                               │
    │        - 1-2 PROMINENT NUCLEOLI                      │
    │                                                      │
    │    • = Lymphocytes in stroma (HALLMARK)              │
    │    [G] = Epithelioid granuloma                       │
    │    *ST* = Syncytiotrophoblast (15% cases; hCG+)      │
    └──────────────────────────────────────────────────────┘

    IHC: PLAP (+), OCT3/4 (+), D2-40 (+), CD117/KIT (+)
         AFP (-), CD30 (-)
    hCG: mildly elevated in 10-15% (stage I)

MODES OF SPREAD of Seminoma

• First drains to iliac and para-aortic (retroperitoneal) lymph nodes
• This reflects the embryologic origin of the testis from the retroperitoneum
• NOT to inguinal nodes (unless scrotal skin is invaded - scrotal nodes only if skin infiltrated)
• Predictable, stepwise lymphatic progression

• Occurs late - distinguishes seminoma from NSGCTs
• Common metastatic sites: lungs, liver, bone, brain
• Seminoma characteristically spreads hematogenously much later than embryonal carcinoma

• Late involvement of epididymis, spermatic cord
• Usually well-contained by tunica albuginea early on

Clinical significance: Seminoma spreads in a predictable, stepwise lymphatic pattern and is exquisitely sensitive to radiation therapy and platinum-based chemotherapy. Stage I disease has ~99% cure rate.

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PART 3: TERATOMA - DEFINITION, CLASSIFICATION & EXTRAGONADAL SITES

Definition

Classification

1. Mature teratoma - well-differentiated adult-type tissues
   • In ovary ("dermoid cyst"): mainly ectodermal (skin, hair, teeth, sebaceous glands) - almost always benign
   • In prepubertal testis: benign
   • In postpubertal testis: still malignant despite mature appearance
2. Immature teratoma - embryonal/fetal-type tissues
   • Most common immature element: primitive neuroepithelium
   • Graded 0-3 (based on amount of immature neural tissue per slide)
   • Grade 0 = all mature; Grade 3 = >2 low-power fields immature neuroepithelium per slide
   • More aggressive - can metastasize
3. Teratoma with somatic-type malignancy (rare)
   • A secondary non-germ cell malignancy arises within the teratoma
   • Examples: squamous cell carcinoma, adenocarcinoma, rhabdomyosarcoma, PNET

Gross Features of Testicular Teratoma

• Heterogeneous, variegated appearance - hallmark distinguishing from uniform seminoma
• Multiple cysts of varying sizes containing serous, mucinous, or sebaceous material, hair, teeth
• Solid areas with cartilage (white/grey), bone, or fibrous tissue
• Foci of hemorrhage and necrosis in postpubertal/malignant forms

Microscopic Features of Testicular Teratoma

• Tissues from all 3 germ layers in disorganized arrangement, embedded in fibrous/myxoid stroma:
  • Ectoderm: Squamous epithelium, skin adnexa (sebaceous glands, hair follicles), neural tissue
  • Mesoderm: Smooth/skeletal muscle bundles, islands of cartilage, bone, connective tissue
  • Endoderm: Bronchial epithelium, intestinal wall structures, thyroid gland-like tissue, glandular epithelium
• Elements may be mature (adult-type) or immature (fetal-type)

Extragonadal Sites of Teratoma

    EXTRAGONADAL TERATOMA SITES
    (Midline migration path of primordial germ cells)

         CRANIAL
            │
       [Intracranial]         - Pineal gland, suprasellar region
            │                   (germinoma = seminoma equivalent in CNS)
            │
       [Anterior Mediastinum] - Most common ADULT extragonadal site
            │                   (50% of mediastinal GCTs)
            │
       [Retroperitoneum]      - 2nd most common adult extragonadal site
            │
       [Sacrococcygeal]       - Most common in NEONATES/infants
            │                   Most common solid tumor of newborns!
         CAUDAL                  4:1 female predominance

    Other (rare): Neck, orbit, liver

• Sacrococcygeal teratoma - most common solid tumor of newborns; benign in neonates; malignant risk increases with age (if not excised early)
• Anterior mediastinal teratoma - most common in adults; right-sided; may be very large
• Intracranial teratoma - pineal region most common; may cause Parinaud syndrome
• Extragonadal teratomas arise because primordial germ cells migrate along the midline and may arrest at any site during migration

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PART 4: TESTICULAR GERM CELL TUMORS - DESCRIBE ANY ONE (Seminoma, with full description above)

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PART 5: FIBROID UTERUS (LEIOMYOMA) - GROSS, MICROSCOPIC, COMPLICATIONS

Definition

Pathogenesis

• Most have normal karyotypes; ~40% have simple chromosomal abnormalities
• MED12 gene mutations (~70%) - encodes a component of the Mediator transcription complex
• Chromosomal rearrangements at 12q14 and 6p (HMGC/HMGIY genes)
• Associated with HLRCC syndrome (germline FH gene mutations)

GROSS FEATURES

• Sharply circumscribed, discrete, round, firm, gray-white tumors
• Multiple in most cases ("bag of worms" feel on palpation)
• Vary from tiny nodules to massive tumors filling the pelvis
• Locations in myometrium:

    UTERINE LEIOMYOMA - LOCATIONS
    ══════════════════════════════

    ┌─────────────────────────────────────┐
    │         [ENDOMETRIUM]               │
    │      ┌────┐                         │
    │      │(SM)│ SUBMUCOSAL              │
    │      └────┘ (causes most bleeding)  │
    │ ─────────────────────────────────── │
    │    ┌──────────┐  ┌───┐              │
    │    │    (IM)  │  │(IM│ INTRAMURAL   │
    │    └──────────┘  └───┘ (most common)│
    │ ─────────────────────────────────── │
    │         [MYOMETRIUM]                │
    │     ┌──────────┐                    │
    │     │   (SS)   │ SUBSEROSAL         │
    │     └────┬─────┘                    │
    │          │ pedunculated             │
    │     ─────┼─────  SEROSA             │
    └──────────│─────────────────────────-┘
               ↓ (P) Pedunculated subserosal - can undergo torsion

• Cut section shows characteristic whorled pattern of smooth muscle bundles
• Large tumors show yellow-brown to red softening (degeneration)

MICROSCOPIC FEATURES

• Bundles of smooth muscle cells resembling normal myometrium
• Cells uniform: oval "cigar-shaped" nuclei, long slender bipolar cytoplasmic processes
• Scarce mitotic figures (key feature - distinguishes from leiomyosarcoma)
• Sharp demarcation from surrounding myometrium (pseudo-capsule)
• Hyalinization common in older/larger tumors

COMPLICATIONS

• Abnormal uterine bleeding (menorrhagia) - especially submucosal
• Urinary frequency / hydronephrosis from compression
• Pelvic pain and pressure
• Infertility (distortion of endometrial cavity)
• Pedunculated tumors - torsion, ischemic necrosis

1. Hyaline degeneration - most common; replacement by collagen
2. Cystic degeneration - liquefaction of hyalinized areas
3. Carneous (Red) degeneration - infarction with hemolysis; especially in pregnancy (painful)
4. Calcification - late, post-menopausal "womb stones"
5. Fatty degeneration - rare
6. Myxoid degeneration - gelatinous appearance

• Spontaneous abortion
• Fetal malpresentation
• Uterine inertia (failure to contract adequately during labor)
• Postpartum hemorrhage

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p.937

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PART 6: GERM CELL TUMORS OF OVARY - CLASSIFICATION + DYSGERMINOMA

Classification of Ovarian Germ Cell Tumors

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PART 7: DYSGERMINOMA - GROSS AND MICROSCOPIC FEATURES

Epidemiology

• Most common malignant ovarian GCT (30-40%)
• 75% occur between ages 10-30 years; 5% before age 10; rare after 50
• 20-30% of ovarian malignancies in pregnancy are dysgerminomas
• Histologically identical to testicular seminoma and CNS germinoma

GROSS FEATURES

• Usually 5-15 cm in diameter
• Slightly bosselated (lobulated) capsule
• Cut surface: fleshy, pale tan to gray-brown
• Principally solid with some cystic areas and necrosis
• Usually unilateral (bilateral in 10-15%)

MICROSCOPIC FEATURES

• Large, round/ovoid/polygonal "primitive germ cells"
• Abundant, clear, very-pale-staining cytoplasm
• Large, irregular nuclei with prominent nucleoli
• Numerous mitotic figures
• Cells in lobules and nests separated by fibrous septa
• Septa extensively infiltrated with lymphocytes, plasma cells, epithelioid granulomas with giant cells
• When necrosis is extensive, may mimic tuberculosis
• May contain syncytiotrophoblastic giant cells (→ precocious puberty/virilization; does not alter prognosis)
• Calcifications should prompt search for underlying gonadoblastoma

Labeled Diagram

         DYSGERMINOMA - HISTOLOGICAL FEATURES
         ══════════════════════════════════════

    ┌──────────────────────────────────────────┐
    │        FIBROUS SEPTUM                    │
    │   • = Lymphocytes                        │
    │   [G] = Epithelioid granuloma            │
    │   PC = Plasma cells                      │
    └──────────────┬───────────────────────────┘
                   │
    ┌──────────────▼───────────────────────────┐
    │           NEST / LOBULE                  │
    │                                          │
    │   ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○             │
    │   ○ = Large round primitive germ cell:  │
    │       - Clear/pale cytoplasm             │
    │       - Large irregular nucleus          │
    │       - 1-2 PROMINENT NUCLEOLI           │
    │       - Mitoses frequent                 │
    │                                          │
    │   *ST* = Syncytiotrophoblast (some cases)│
    │   [Ca] = Calcifications → gonadoblastoma?│
    └──────────────────────────────────────────┘

    IHC: PLAP (+), OCT3/4 (+), D2-40 (+), KIT/CD117 (+)
    Tumor markers: LDH elevated | hCG: only if ST cells present
    AFP: Negative

Behavior and Spread

• Spreads via lymphatics to para-aortic lymph nodes (similar to seminoma)
• Hematogenous metastases occur late
• Exquisitely radiosensitive and chemosensitive (BEP regimen)
• Fertility-sparing surgery appropriate for Stage I
• Prognosis: excellent (5-year survival >90% for localized disease)

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QUICK REVISION: TERATOMA vs. DYSGERMINOMA vs. SEMINOMA

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• Robbins & Kumar Basic Pathology - Chapter 16 (Male Genital System), Table 16.1, Figs. 16.3, 16.4, 16.9
• Robbins, Cotran & Kumar Pathologic Basis of Disease - Chapter 22 (Female Genital Tract), p.937
• Berek & Novak's Gynecology - Chapter 39 (Germ Cell Malignancies), Figs. 39-18, 39-19