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1. Tumors of the Testis - Classification and Seminoma

Classification of Testicular Tumors

WHO 2022 Pathologic Classification (Robbins, Cotran & Kumar PBD)

• Germ cell neoplasia in situ (GCNIS) - the precursor lesion
• Gonadoblastoma

• Seminoma - most common (~50% of all GCTs), peak 4th decade

• Embryonal carcinoma
• Yolk sac tumor (postpubertal type)
• Choriocarcinoma
• Teratoma (postpubertal type)
• Teratoma with somatic-type malignancy
• Mixed germ cell tumor (more than one histologic type)

• Spermatocytic tumor
• Teratoma (prepubertal type)
• Yolk sac tumor (prepubertal type)
• Mixed teratoma and yolk sac tumor (prepubertal type)

• Leydig cell tumor
• Sertoli cell tumor

Clinical Division (for management purposes)

1. Seminoma - confined to testis for a long time, spreads mainly to para-aortic lymph nodes, rare distant spread, better prognosis
2. Nonseminomatous tumors - tend to spread earlier via both lymphatics and blood vessels

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Seminoma - Detailed Discussion

Incidence and Overview

• Most common type of GCT, making up about 50% of all GCTs
• Peak incidence: fourth decade of life
• An identical tumor in the ovary is called dysgerminoma; in the CNS (pineal gland) it is called germinoma
• Associated with undescended testes (cryptorchidism) and testicular dysgenesis

Gross Morphology

• Produces bulky masses, sometimes 10 times the size of the normal testis
• Homogeneous, gray-white, lobulated cut surface
• Usually devoid of hemorrhage or necrosis
• Tunica albuginea generally not penetrated
• Occasionally extends to epididymis, spermatic cord, or scrotal sac

Microscopic Morphology

• Sheets of uniform cells divided into poorly demarcated lobules by delicate fibrous septa
• Septa contain a prominent lymphocytic infiltrate
• In some tumors, ill-defined granulomas are present (host immune response)
• Classic seminoma cell features:
  • Round to polyhedral shape
  • Distinct cell membrane
  • Clear/watery-appearing cytoplasm (contains glycogen)
  • Large, central nucleus with one or two prominent nucleoli

Immunohistochemistry

• Positive: KIT, OCT3/4, podoplanin (D2-40)
• Negative: cytokeratin (distinguishes from embryonal carcinoma)
• ~15% of seminomas contain syncytiotrophoblasts → elevated serum hCG (not as high as choriocarcinoma)
• AFP is NOT elevated in pure seminoma

Precursor Lesion

• Arises from Germ Cell Neoplasia In Situ (GCNIS) - intratubular malignant germ cells that do not yet invade
• GCNIS cells are OCT3/4 and KIT positive; they line the basement membrane of seminiferous tubules

Molecular/Genetic Features

• Characteristic cytogenetic change: isochromosome 12p [i(12p)] - gain of short arm of chromosome 12
• Present in virtually all GCTs derived from GCNIS

Staging

• Stage I - confined to testis
• Stage II - retroperitoneal (para-aortic) lymph node involvement
• Stage III - distant metastases (lung, liver, brain)

Clinical Features & Prognosis

• Presents as painless testicular swelling/heaviness
• Serum markers: hCG elevated in ~15% (those with syncytiotrophoblasts); AFP always normal
• LDH may be elevated
• Radiosensitive - responds excellently to radiotherapy
• 5-year survival >95% for stage I; overall excellent prognosis compared to NSGCTs

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2. Endometrial Biopsy in Health and Disease

Overview

Indications for Endometrial Biopsy

1. Women with suspected endometrial pathology
2. All women >45 years in whom medical treatment has been unsuccessful
3. Persistent intermenstrual bleeding
4. Endometrial thickness >4 mm in postmenopausal women, or >7 mm in women with PCOS
5. Persistently thickened/abnormal endometrial appearance in premenopausal women
6. Irregular or unscheduled bleeding while on HRT after the initial 3 months
7. Younger women with major risk factors for endometrial hyperplasia/cancer:
   • Polycystic ovarian syndrome (PCOS)
   • Obesity
   • Treatment with tamoxifen
   • Irregular bleeding on unopposed estrogen
   • Family history of endometrial/colon cancer (hereditary non-polyposis colorectal cancer - HNPCC)
8. Lynch syndrome patients - lifetime risk of endometrial cancer up to 60%; annual screening with TVS + EMB from age 35

Normal Endometrial Histology (Cyclic Changes)

Proliferative Phase (Days 5-14)

• Estrogen-driven
• Straight, tubular, elongated glands with pseudostratified columnar epithelium
• Mitotic figures present in glands and stroma
• Stroma: compact with small, oval to spindle-shaped cells

Secretory Phase (Days 15-28)

• Progesterone-driven (after ovulation)
• Glands become tortuous, saw-toothed ("corkscrew" glands)
• Subnuclear vacuoles appear first (day 16-17), then supranuclear secretion
• Predecidual change in stroma (days 23-24)
• Spiral arteries become prominent

Menstrual Phase

• Breakdown of stroma and glands
• Neutrophilic infiltration, fibrin thrombi
• "Blue balls" of stroma (dense stromal breakdown)

Endometrial Pathology Detected on Biopsy

1. Endometrial Hyperplasia

2. Endometrial Carcinoma

• Endometrioid adenocarcinoma (Type I) - most common; estrogen-related; mutations in PTEN, PIK3CA, KRAS, ARID1A, mismatch repair genes
• Serous carcinoma (Type II) - non-estrogen dependent; TP53 mutations; aggressive
• Grading: Grade 1 (well-differentiated), Grade 2 (moderately), Grade 3 (poorly)

3. Endometrial Polyp

• Focal overgrowth of endometrial glands and stroma with fibrous cores
• Irregular vascular channels
• Non-cycling glands (lack of secretory change)

4. Endometritis

• Acute: neutrophilic infiltration (postpartum, post-abortion, PID)
• Chronic: plasma cells in stroma (key diagnostic feature) - seen in PID, IUD use, tuberculous endometritis

5. Anovulatory Cycles / Irregular Shedding

• Out-of-phase endometrium
• Mixed proliferative and secretory pattern
• Common in perimenopause and PCOS

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3. Classification of Ovarian Tumors and Functional Ovarian Tumors

Classification

WHO Classification of Ovarian Neoplasms

• Serous tumors (benign cystadenoma, borderline, malignant)
• Mucinous tumors, intestinal and endocervical type
• Endometrioid tumors
• Clear cell tumors
• Brenner tumors (transitional cell type)
• Epithelial-stromal tumors (Adenosarcoma, Carcinosarcoma)

• Granulosa cell tumors
• Fibromas, Fibrothecomas, Thecomas
• Sertoli-Leydig cell tumors
• Steroid (lipid) cell tumors

• Teratoma (mature/immature; solid/cystic - dermoid cyst; monodermal - struma ovarii, carcinoid)
• Dysgerminoma
• Yolk sac tumor (endodermal sinus tumor)
• Choriocarcinoma
• Mixed germ cell tumors

• From colorectal, gastric, pancreaticobiliary, breast primaries
• Krukenberg tumor (bilateral mucin-secreting "signet-ring" cells, usually gastric origin)

Non-Neoplastic / Functional Lesions

• Follicular cysts
• Corpus luteum cysts
• Theca-lutein cysts
• Polycystic ovarian syndrome (PCOS)

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Functional Ovarian Tumors (Hormonally Active Tumors)

A. Granulosa Cell Tumors (Feminizing)

• Usually unilateral
• Vary from microscopic foci to large solid-cystic encapsulated masses
• Yellow coloration on cut surface (due to intracellular lipids in hormonally active tumors)

• Small cuboidal to polygonal cells in anastomosing cords, sheets, or strands
• Call-Exner bodies: small, distinctive gland-like structures filled with acidophilic material, resembling immature follicles - pathognomonic
• Express high levels of inhibin (IHC marker)

• Prepubertal girls: precocious sexual development (juvenile granulosa cell tumor)
• Reproductive age: menstrual irregularities, endometrial hyperplasia
• Postmenopausal: abnormal uterine bleeding, endometrial hyperplasia
• ~10-15% develop endometrial carcinoma (due to prolonged estrogenic stimulation)
• Occasionally may secrete androgens causing virilization

B. Thecoma (Feminizing)

• Composed of lipid-laden theca cells
• Usually unilateral, solid, yellow-cut surface
• Almost always benign
• Estrogenic symptoms: endometrial hyperplasia/carcinoma risk
• Often associated with fibroma (fibrothecoma)

C. Fibroma

• Most common benign sex cord-stromal tumor
• Composed of fibroblasts
• Usually hormonally inactive
• Associated with Meigs syndrome: ovarian fibroma + ascites + pleural effusion (right-sided)
• Resolves with tumor removal

D. Sertoli-Leydig Cell Tumors (Androblastoma - Virilizing)

• Contain Sertoli cells (form tubular structures) and Leydig cells (with Reinke crystalloids)
• Secrete androgens → virilization in females:
  • Defeminization: amenorrhea, breast atrophy
  • Masculinization: clitoral enlargement, hirsutism, voice deepening
• Usually low-grade malignant; <5% recur or metastasize
• Most common in women of reproductive age

E. Leydig Cell Tumors (Hilus Cell Tumors - Virilizing)

• Located in ovarian hilus
• Large lipid-laden Leydig cells with Reinke crystalloids (cytoplasmic rod-shaped structures)
• Secrete testosterone → virilization
• Almost always benign

F. Steroid/Lipid Cell Tumors

• Contain lipid-rich cells resembling adrenal cortex, Leydig, or lutein cells
• May be virilizing or feminizing depending on hormone produced

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4. Endometriosis

Definition

Sites of Involvement (in descending frequency)

1. Ovaries (most common) - form "chocolate cysts" (endometriomas)
2. Uterine ligaments
3. Rectovaginal septum
4. Cul-de-sac (pouch of Douglas)
5. Pelvic peritoneum
6. Serosa of large/small bowel and appendix
7. Mucosa of cervix, vagina, fallopian tubes
8. Laparotomy scars (rare)

Epidemiology

• Affects ~10% of women of reproductive age
• Most common in 3rd and 4th decades
• Major cause of infertility (30-40% of infertile women)

Types

1. Superficial peritoneal endometriosis - implants on peritoneal surface
2. Ovarian endometriosis - "chocolate cyst" or endometrioma
3. Deep infiltrating endometriosis - penetrates >5 mm below peritoneum; rarely undergoes malignant transformation

Pathogenesis (Theories)

1. Regurgitation Theory (Sampson's Theory) - Most Accepted

• Retrograde flow of menstrual endometrium through fallopian tubes implants at ectopic sites in peritoneal cavity
• Explains pelvic endometriosis
• Limitation: retrograde menstruation occurs in 90% of women; only ~10% develop endometriosis

2. Benign Metastasis Theory

• Endometrial tissue "spreads" to distant sites (bone, lung, brain) via blood vessels and lymphatics
• Explains rare extrapelvic locations

3. Metaplastic Theory (Coelomic Metaplasia)

• Endometrium arises from metaplastic transformation of coelomic epithelium (mesothelium)
• Explains endometriosis in amenorrheic women and even in males (rare cases)

4. Extrauterine Stem/Progenitor Cell Theory

• Bone marrow-derived stem cells differentiate into endometrial tissue

Molecular Differences in Endometriotic Implants

• Increased aromatase activity (local estrogen production)
• Resistance to progesterone (progesterone receptor B downregulation)
• Increased inflammatory cytokines (IL-1, IL-6, IL-8, TNF-alpha)
• Reduced apoptosis
• ARID1A mutations in endometriosis-associated ovarian cancer

Morphology

Gross

• Superficial: red, blue, or black "powder burn" peritoneal spots
• Ovarian endometriomas ("chocolate cysts"): filled with thick, brown, altered blood; walls contain endometrial glands and stroma
• Fibrosis and adhesions cause organs to become matted together ("frozen pelvis")
• Rectosigmoid involvement: low-signal fibrotic plaques on MRI; contraction of bowel wall

Microscopic

• Endometrial glands + endometrial stroma
• Hemosiderin-laden macrophages (key feature in old lesions)
• Fibrosis in surrounding tissue
• Cyclic changes (proliferative/secretory) may be present

Clinical Features

• Dysmenorrhea (painful menstruation - most common)
• Dyspareunia (deep)
• Pelvic pain (chronic)
• Infertility (tube/ovary adhesions, impaired implantation)
• Abnormal uterine bleeding (menorrhagia, menometrorrhagia)
• Rectal bleeding, bowel symptoms if bowel involved
• Cyclical hematuria if bladder involved

Complications

• Infertility (30-40% of cases)
• Chocolate cyst rupture → acute abdomen
• Endometriosis-associated ovarian cancer (clear cell and endometrioid carcinoma; risk ~0.5%)
• Frozen pelvis from adhesions

Diagnosis

• Clinical history + examination
• Transvaginal ultrasound (homogeneous low-level echo in endometrioma)
• MRI (best for deep infiltrating disease; low signal fibrotic plaques)
• Definitive: Laparoscopy with biopsy

Treatment

• Medical: NSAIDs, combined OCP, progestogens, GnRH agonists, danazol, levonorgestrel IUS
• Surgical: Conservative (laparoscopic excision/ablation), definitive (hysterectomy + bilateral salpingo-oophorectomy for severe cases)

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5. Contrasting Features of Serous and Mucinous Tumors (Epithelial Ovarian Tumors)

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6. Placental Site Trophoblastic Tumor (PSTT)

Definition and Overview

Cell of Origin

• Derived from intermediate trophoblasts (extravillous trophoblasts)
• These cells have features overlapping with both cytotrophoblasts and syncytiotrophoblasts
• They are the cells that normally invade the myometrium at the placental implantation site

PSTT vs Epithelioid Trophoblastic Tumor (ETT)

• Small amounts of hCG production relative to tumor mass
• Tendency to remain confined to uterus
• Late metastasis
• Relative insensitivity to chemotherapy

Hormone Production

• hCG: LOW levels (in contrast to choriocarcinoma, which has very high hCG)
  • Intermediate trophoblasts do not produce hCG in large amounts
• Human Placental Lactogen (hPL): Elevated - key diagnostic marker
• Inhibin A may also be elevated

Pathology

Gross

• Usually infiltrates myometrium as a soft, tan-yellow mass
• May appear as an ill-defined intramural thickening
• No villi present (distinguishes from hydatidiform mole)

Microscopic

• Sheets and cords of intermediate trophoblastic cells infiltrating between smooth muscle fibers of myometrium
• Cells are mononucleate, with abundant eosinophilic cytoplasm
• Characteristic vascular invasion: tumor cells replace vascular smooth muscle (fibrinoid necrosis of vessel walls)
• No chorionic villi
• Focal syncytiotrophoblast cells may be present

IHC

• hPL positive (strongly)
• Mel-CAM (CD146) positive
• hCG: Weakly/focally positive (in contrast to choriocarcinoma which is diffusely positive)
• Ki-67: Low proliferative index in PSTT vs. high in choriocarcinoma
• p63: Negative in PSTT; positive in ETT (key distinction)

Karyotype

• Usually diploid, XX karyotype
• Arises from the trophoblastic component of a previous pregnancy

Clinical Features

• Usually arises months to years after a preceding pregnancy (most commonly a normal term delivery; less often after abortion or mole)
• Presents with:
  • Irregular vaginal bleeding
  • Amenorrhea
  • Uterine enlargement
  • Serum hCG mildly elevated (often <1000 mIU/mL)

Natural History

• Generally indolent course
• Usually confined to endometrium and myometrium initially
• Once extrauterine spread occurs, prognosis becomes poor
• NOT sensitive to chemotherapy (unlike choriocarcinoma, which responds dramatically to MTX/actinomycin-D)

Contrast with Choriocarcinoma

Metastatic Pattern of GTN (including PSTT)

• Lungs: 80% (most common) - "snowstorm" pattern on CXR
• Vagina: 30%
• Pelvis: 20%
• Liver: 10%
• Brain: 10%

Treatment

• Hysterectomy is the primary treatment (unlike other GTN where chemotherapy is first-line)
• Chemotherapy (EMA-CO or EP-EMA regimen) for metastatic disease, though less effective than in choriocarcinoma
• Complete surgical excision results in excellent prognosis when confined to uterus

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