Seminomatous vs Non-Seminomatous Germ Cell Tumours (GCTs)

Gross Pathology

Figure: Seminoma of the testis - Bailey & Love's 28th Ed

1. Classification

2. Histology

• Oval cells with clear cytoplasm and large, rounded nuclei with prominent acidophilic nucleoli
• Sheets of cells resembling spermatocytes, separated by fine fibrous stroma
• Active lymphocytic infiltration = good host response, better prognosis
• May contain syncytiotrophoblastic cells (which can secrete hCG, but AFP is never elevated)

• Embryonal carcinoma - most undifferentiated subtype; highly malignant; can differentiate into other subtypes; may invade cord structures; secretes AFP, hCG, both, or neither
• Yolk sac tumour - loose stroma; secretes AFP; commonest childhood testicular malignancy (rare pure form in adults); part of mixed tumour in adults
• Choriocarcinoma - highly malignant; early haematogenous + lymphatic spread; secretes hCG (often at very high levels); extremely rare as pure form
• Teratoma - derived from ≥2 germinal layers (ectoderm, mesoderm, endoderm); may be mature, immature, or malignant; all can metastasise; importantly, teratomas are chemotherapy resistant and must be treated surgically

3. Tumour Markers

AFP is never secreted by seminoma. A seminoma patient with elevated AFP must be managed as NSGCT. - Harrison's 22E, p. 749; Smith & Tanagho's General Urology 19th Ed, p. 394

4. Pattern of Spread

• Both initially spread via lymphatics to para-aortic nodes (lymphatic drainage of the testes follows the gonadal vessels, not inguinal nodes - inguinal nodes are involved only if scrotal skin is breached)
• Seminoma - predominantly lymphatic spread; haematogenous spread is uncommon
• Choriocarcinoma (NSGCT) - early haematogenous spread (lungs most common distant site); most aggressive of all subtypes
• Subsequent spread: retrocrural → mediastinal → supraclavicular nodes, then haematogenous to lungs, liver, bone, brain

5. Sensitivity to Treatment

6. Staging

• Stage I - confined to testis
• Stage II - retroperitoneal lymph node involvement
• Stage III - beyond retroperitoneum and/or distant metastases

Importantly, seminoma has no "poor risk" IGCCCG category. - Harrison's 22E, p. 749

7. Stage-Based Management

• ~70% of seminomas present at Stage I
• ~15% have occult retroperitoneal micrometastases
• Options: active surveillance (preferred), adjuvant paraaortic radiotherapy, or carboplatin monotherapy (1-2 cycles)
• Active surveillance is the standard as the vast majority are cured by orchiectomy alone

• Options: active surveillance, nerve-sparing retroperitoneal lymph node dissection (RPLND), or adjuvant BEP chemotherapy x1 cycle
• RPLND is both diagnostic and therapeutic

• BEP chemotherapy (bleomycin, etoposide, cisplatin) is the backbone
• Post-chemotherapy residual masses in NSGCT require surgical resection (teratoma is chemo-resistant; viable cancer may be present)
• Post-chemotherapy residual masses in seminoma: PET scan is used (FDG-avid = residual disease; PET-negative masses can be observed as they may be necrosis/fibrosis)

Quick Reference Summary

Syphilitic Aneurysm

Epidemiology & Historical Context

Pathogenesis - Step by Step

1. Spirochetemic seeding: During the spirochetemic phase of primary/secondary syphilis, T. pallidum organisms lodge in the adventitia of the vasa vasorum (the small vessels supplying the aortic wall)
2. Inflammatory response: A perivascular lymphocytic and plasma cell infiltrate develops around the vasa vasorum
3. Obliterative endarteritis: The vasa vasorum undergo obliterative endarteritis, compromising blood supply to the aortic media
4. Medial ischemia and destruction: Ischemic injury causes destruction of collagen and elastic fibers - loss of the structural skeleton of the aortic wall. There is patchy medial necrosis and elastic fiber fragmentation
5. Aneurysm formation: The weakened wall dilates, scar tissue forms, and calcification occurs
6. Characteristic linear calcification: These changes account for the linear calcification of the ascending aorta visible on chest X-ray - a hallmark radiographic sign

"The initial lesion is an obliterative endarteritis of the vasa vasorum, especially in the adventitia... Destruction of collagen and elastic tissues leads to dilation of the aorta, scar formation, and calcification." - Harrison's Principles of Internal Medicine 22E

Morphology

Cardiovascular Complications

1. Aortic regurgitation (most common - 20-30%): Results from aortic root dilatation, not cusp disease (valve cusps are normal but the annulus dilates). The decrescendo murmur is often loudest along the right sternal margin (rather than the typical left sternal border), due to the ascending aortic involvement
2. Coronary ostial stenosis (25-30%): Syphilitic inflammation narrows the ostia of the coronary arteries, causing angina pectoris. Historically more common than coronary atherosclerosis as a cause of angina. MI is rare
3. Aneurysm formation (least frequent - 5-10% of those with syphilitic aortitis): Typically saccular; may compress or erode adjacent mediastinal structures (e.g., trachea, bronchus, esophagus, superior vena cava, recurrent laryngeal nerve). An aneurysm may present as a pulsating mass bulging through the anterior chest wall

Clinical Presentation

• Usually asymptomatic for years; often found incidentally on CXR
• Symptom onset: 15-30 years after initial infection
• Symptoms may arise from:
  • Aortic regurgitation (dyspnoea, wide pulse pressure, diastolic murmur loudest at right sternal border)
  • Coronary ostial stenosis (angina)
  • Compression of adjacent structures: dysphagia (esophagus), stridor/dyspnoea (trachea/bronchus), hoarseness (recurrent laryngeal nerve), SVC syndrome
  • Rupture (major complication - high mortality)
• Between 10-20% of patients with cardiovascular syphilis have coexistent neurosyphilis - always screen

Diagnosis

Treatment

1. Antibiotics: Penicillin G remains first-line for the underlying syphilitic infection. Whether this retards progression once aortitis is established is not clearly proven
2. Surgery: Surgical excision and repair is required for symptomatic aneurysms. Without surgery, symptomatic syphilitic aortic aneurysms carry a high mortality rate. Early antibiotic treatment of primary syphilis is the most important preventive measure
3. The prognosis for uncomplicated syphilitic aortitis is comparable to the general population, but becomes poor once aneurysms become symptomatic

Key Distinguishing Points (vs. Other Aortic Aneurysms)

Duchenne Muscular Dystrophy (DMD) vs Becker Muscular Dystrophy (BMD)

The "Reading Frame Rule" - The Core Concept

"Whereas dystrophin is absent in patients with the Duchenne phenotype, it is present but structurally abnormal in the Becker type. Moreover, phenotypes that fall between the classic Duchenne and Becker forms exist and are characterized by a lower-than-normal amount of dystrophin." - Adams and Victor's Principles of Neurology 12th Ed

Pathogenesis

1. Normal function: Dystrophin anchors the sarcomere F-actin cytoskeleton to the sarcolemma (cell membrane) via the dystrophin-associated protein (DAP) and dystroglycan complex, which in turn connects to the extracellular matrix via merosin/laminin
2. Loss of dystrophin disrupts this mechanical link
3. Sarcolemmal breaks and tears occur during muscle contraction
4. Extracellular calcium leaks into the fiber
5. Calcium activates proteases, increases protein degradation, causes myofiber necrosis
6. CK and other muscle enzymes leak into the serum
7. Repeated cycles of necrosis → fibrosis → fat replacement → muscle wasting

"Loss of dystrophin leads to a parallel loss of DAPs and to disruption of the dystroglycan-protein complex. This change renders the sarcolemma susceptible to breaks and tears during muscle contraction." - Adams and Victor's Principles of Neurology 12th Ed

Genetics

Clinical Features

Age of Onset

Motor Features

• Delayed motor milestones; falls frequently, difficulty running/climbing stairs
• Proximal muscle weakness: iliopsoas, quadriceps, gluteals first → pretibial muscles (foot drop, toe-walking) → pectoral girdle (serrati, pectorals, latissimus, biceps, brachioradialis)
• Waddling gait, excessive lumbar lordosis, protuberant abdomen
• Gower's sign: To rise from the floor, the child assumes a four-point position and "walks" hands up the thighs to extend the trunk - classic sign of proximal lower limb weakness (first described by Gowers in 1879)
• Pseudohypertrophy of calves (also deltoids, lateral vasti) - firm, rubbery feel; represents fat and fibrous tissue replacing degenerated muscle fibres. In early stages there may be true hypertrophy, which gives way to pseudohypertrophy
• Progressively loses the ability to raise head fully off the bed (absent in DMD)
• Tendon reflexes diminish and disappear as muscle fibers are lost; ankle jerk is last to go
• Contractures: Heel-cord (Achilles tendon) contractures, then elbow and knee flexion contractures; scoliosis follows loss of ambulation

• Weakness and pseudohypertrophy in the same distribution as DMD
• Onset much later and course much slower
• Retains ability to raise head off the bed (distinguishes from DMD)
• May serve in the military with disease undetected
• If maternal uncles with the disease are still walking, diagnosis is relatively easy

Cognitive / Neuropsychiatric Features

Cardiac Involvement

Respiratory Involvement

Investigations

Treatment

Both conditions require multidisciplinary management:

• Largely supportive; corticosteroids rarely used
• Cardiac monitoring and management (heart transplantation in severe cardiomyopathy)
• Respiratory function monitoring

Prognosis

Quick Comparison Table