Clinical Signs of Inoperability in Gastric Carcinoma

Why These Signs = Inoperability

1. Ascites

2. Secondaries in the Liver (Hepatic Metastases)

• Hepatomegaly with a hard, irregular nodular surface
• Right upper quadrant pain
• Jaundice (from biliary compression or widespread parenchymal replacement)
• Elevated alkaline phosphatase and bilirubin on liver function tests
• Lesions visible on CT/ultrasound

3. Para-aortic Lymph Node Involvement

4. Krukenberg Tumor

• Transcoelomic route (most common): tumor cells shed into the peritoneal cavity and implant on the ovarian surface
• Lymphatic spread: retrograde lymphatic dissemination
• Hematogenous spread: less common

• Palpable pelvic/adnexal mass on bimanual examination
• May cause menstrual irregularities, virilization (rare, from stromal luteinization)
• Can be the presenting feature before gastric primary is identified

5. Sister Mary Joseph Nodule (Umbilical Nodule)

• Direct peritoneal spread along the falciform ligament
• Lymphatic spread via para-umbilical lymphatics
• Hematogenous spread via para-umbilical veins
• Direct extension via the obliterated umbilical vein or median umbilical ligament

• Hard, irregular, often painless nodule at the umbilicus
• May be ulcerated or crusted
• Skin color may be reddish or violaceous
• Also called "Sister Joseph's nodule" or periumbilical adenopathy

6. Blumer Shelf (Rectal Shelf Deposits)

• Felt as a firm, gritty, shelf-like projection on the anterior rectal wall
• Not to be confused with a primary rectal tumor (which arises from the rectal mucosa)
• Usually non-tender
• The term "shelf" refers to its characteristic feel - like a horizontal ledge

7. Irish Node (Left Axillary Node)

8. Troisier's Sign: Virchow's Node (Left Supraclavicular Node)

• Gastric cancer cells enter the lymphatic system and travel up through the cisterna chyli into the thoracic duct
• The thoracic duct drains into the left subclavian vein at the junction of the left internal jugular vein
• Just before this junction, the left supraclavicular nodes lie along the thoracic duct's terminal segment
• These nodes are the "sentinel nodes" of the thoracic duct, trapping tumor emboli ascending from intra-abdominal organs

• Palpable, hard, rubbery node in the left supraclavicular fossa (behind the clavicular head of the left sternocleidomastoid)
• Often called the "sentinel node" because it is frequently the first distant sign detected on examination
• Other abdominal cancers (pancreas, colon, esophagus) can also cause Virchow node

9. Paraneoplastic Effects: Trousseau's Syndrome and DVT

Trousseau's Syndrome (Migratory Thrombophlebitis)

• Migratory, recurrent superficial thrombophlebitis - veins become red, tender, cord-like, then resolve and reappear elsewhere
• May precede cancer diagnosis by months to years
• Can involve visceral veins (portal, mesenteric, splenic)
• Associated with non-bacterial thrombotic endocarditis (NBTE/marantic endocarditis) and arterial thromboembolism (cerebral infarcts, limb ischemia)

Deep Vein Thrombosis (DVT)

• DVT is the most common thrombotic event in cancer patients overall
• Gastric cancer, pancreatic cancer, and lung cancer are among the highest-risk cancers for VTE
• DVT may present as unilateral leg swelling, pain, and erythema
• Unprovoked DVT in an otherwise well patient should prompt evaluation for occult malignancy, including gastric cancer screening
• Pulmonary embolism (PE) is a major cause of death in advanced gastric cancer patients

• Trousseau's syndrome = migratory superficial thrombophlebitis
• DVT = deep venous thrombosis, usually lower limbs
• Both share the same underlying cancer-induced hypercoagulable mechanism
• Together they fall under the umbrella of cancer-associated thrombosis (CAT)

1. Aggressive, mucin-secreting tumor biology
2. Systemic pro-coagulant tumor burden
3. Significant perioperative thrombotic risk (DVT/PE is a major surgical complication in these patients)

• Goldman-Cecil Medicine, p. 2038; Sleisenger & Fordtran's, p. [paraneoplastic section]

Summary Table: Signs of Inoperability in Gastric Carcinoma

Memory Aids

• "VIrchow = VIsceral drainage - left supraclavicular" (thoracic duct → left subclavian)
• "Blumer = Bottom of the belly" (gravitational drop metastases to the pouch of Douglas, felt on DRE)
• "Krukenberg = Kitchen (cooking) pot sign" - signet ring cells look like "rings" in a pot - ovarian bilateral
• "Sister Mary Joseph = belly button nodule" (umbilicus = Mary Joseph's landmark)
• "Trousseau's = moving clots" (migratory, not fixed - the hallmark)

• Sabiston Textbook of Surgery, 21st ed. - Signs and Symptoms of Gastric Cancer
• Goldman-Cecil Medicine - Physical Examination and Paraneoplastic Syndromes in Gastric Cancer
• Sleisenger & Fordtran's Gastrointestinal and Liver Disease - Clinical Features
• Maingot's Abdominal Operations - Signs and Symptoms of Gastric Cancer

Paraneoplastic Effects in Advanced Gastric Carcinoma: Trousseau's Syndrome & DVT

What Are Paraneoplastic Syndromes?

1. They may be the earliest manifestation of an occult (hidden) neoplasm - appearing before the cancer is detectable
2. They can cause significant morbidity or even death independently of the tumor
3. They can mimic metastatic disease, confounding staging and treatment decisions

• Robbins & Cotran Pathologic Basis of Disease; Robbins & Kumar Basic Pathology

Trousseau's Syndrome (Migratory Thrombophlebitis)

Historical Background

Definition

• "Migratory" = thrombophlebitis appears at one site, then resolves and reappears at a different site
• "Superficial" = involves superficial veins (visible, palpable), distinct from deep vein thrombosis

Pathophysiology: Why Does Gastric Cancer Cause Clots?

1. Tissue Factor (TF) Expression

• Tumor cells overexpress Tissue Factor (TF / Factor III), the primary activator of the extrinsic coagulation pathway
• TF binds Factor VIIa → activates Factor X → activates thrombin (Factor IIa) → converts fibrinogen to fibrin
• This creates a continuous, systemic procoagulant drive

2. Tumor-Derived Mucin (Most Important in Gastric Ca)

• Mucin-secreting adenocarcinomas (gastric, pancreatic) release mucin glycoproteins (particularly MUC1, MUC5AC, MUC16) directly into the bloodstream
• These mucins can:
  • Directly activate platelets via selectin receptors (P-selectin and L-selectin)
  • Cross-link selectins on platelets and endothelial cells, forming platelet-rich thrombi
  • Activate coagulation independently of tissue factor - a unique mucin-driven pathway
• This is why gastric and pancreatic cancers (both heavy mucin producers) are the cancers most classically associated with Trousseau's syndrome

"Tumor-associated inflammation and release of coagulation factors (e.g., tissue factor) and procoagulants (e.g., mucin) from tumor cells all contribute to the increased risk of thromboembolism in disseminated cancers, so-called migratory thrombophlebitis or Trousseau syndrome." - Robbins, Cotran & Kumar Pathologic Basis of Disease

3. Tumor-Derived Microparticles (Cancer Procoagulant)

• Tumor cells shed small membrane vesicles called microparticles (MPs)
• These MPs carry TF and phosphatidylserine on their surface
• Phosphatidylserine provides a negatively charged phospholipid surface that dramatically accelerates the assembly and activity of the prothrombinase complex (Factor Xa + Va)
• MPs circulate freely and can activate coagulation at distant vascular sites - explaining the "migratory" nature of the thrombosis

4. Inflammatory Cytokine Environment

5. Suppressed Fibrinolysis

• Tumor cells produce PAI-1 (Plasminogen Activator Inhibitor-1), which blocks tissue-type plasminogen activator (t-PA)
• This prevents clot dissolution, allowing thrombi to persist and enlarge
• Advanced cancer is associated with low t-PA and high PAI-1 levels

6. Physical/Stasis Factors (Additional)

• Immobility, bed rest → reduced "milking action" of leg muscles → venous stasis
• Large tumors may directly compress veins → stasis
• Virchow's Triad is thus fulfilled: (i) hypercoagulable state, (ii) stasis, (iii) endothelial injury from tumor/treatment

Clinical Presentation of Trousseau's Syndrome

The Full Spectrum of Trousseau's/Cancer-Associated Thrombosis

A. Migratory Superficial Thrombophlebitis (Classic Trousseau)

B. Deep Vein Thrombosis (DVT)

• Most commonly in the popliteal, femoral, and iliac veins (lower limb)
• DVT is asymptomatic in ~50% of cases (detected incidentally or only after PE)
• When symptomatic: unilateral leg swelling, pain, warmth, erythema, Homans' sign (dorsiflexion pain - low sensitivity/specificity)
• Unprovoked DVT in a middle-aged or elderly patient is a red-flag for occult malignancy - mandates cancer workup including gastric evaluation (FOBT, endoscopy)

"Deep vein thrombosis (DVT) involving one of the large leg veins - at or above the knee (e.g., the popliteal, femoral, and iliac veins) - is considered serious because such thrombi more often embolize to the lungs and give rise to pulmonary infarction." - Robbins, Cotran & Kumar

C. Pulmonary Embolism (PE)

• DVT thrombi can break off and embolize to the pulmonary vasculature
• PE is a leading cause of death in hospitalized cancer patients
• Presents as: sudden dyspnea, pleuritic chest pain, haemoptysis, hypoxia, tachycardia, syncope
• Massive PE = cardiovascular collapse

D. Non-Bacterial Thrombotic Endocarditis (NBTE) / Marantic Endocarditis

• Small (1-5 mm), sterile, bland thrombi deposit on cardiac valve leaflets (especially left-sided: mitral and aortic valves)
• No inflammatory reaction in the valve itself (distinguishes from infective endocarditis)
• Loosely attached - act as sources of systemic arterial emboli → stroke, renal infarcts, limb ischemia, MI
• Strongly associated with mucinous adenocarcinomas (gastric, pancreatic) via mucin and TF-mediated hypercoagulability

"Hypercoagulable states are the usual precursor to NBTE... those associated with underlying malignancy, particularly mucinous adenocarcinoma. The latter association is likely related to the procoagulant effects of tumor-derived mucin or tissue factor that can also cause migratory thrombophlebitis (Trousseau syndrome)." - Robbins, Cotran & Kumar Pathologic Basis of Disease

E. Disseminated Intravascular Coagulation (DIC)

• Systemic activation of coagulation overwhelms natural anticoagulant mechanisms
• Paradoxically produces both microvascular thrombosis (organ failure) and bleeding (consumption of clotting factors and platelets)
• In gastric cancer, DIC is less common than in AML or prostate cancer but can occur with advanced/fulminant disease

Summary Diagram of Mechanism

GASTRIC CARCINOMA (mucin-secreting adenocarcinoma)
            │
            ├──► Mucin secretion ──────────────────────────────┐
            │                                                   │
            ├──► Tissue Factor (TF) expression                  │
            │           │                                       ▼
            │           ▼                          Platelet activation via
            │    Extrinsic coagulation:            P-selectin / L-selectin
            │    TF + VIIa → X → Thrombin                      │
            │                                                   │
            ├──► Microparticles (TF + phosphatidylserine)       │
            │           │                                       │
            ├──► IL-1β, TNF-α → Endothelial TF↑ / Thrombomodulin↓
            │                                                   │
            └──► PAI-1 → Fibrinolysis suppressed                │
                        │                                       │
                        ▼                                       ▼
               SUSTAINED HYPERCOAGULABLE STATE
                        │
            ┌───────────┼───────────┬─────────────┬─────────────┐
            ▼           ▼           ▼             ▼             ▼
     Migratory      DVT          NBTE           DIC         Portal vein
   thrombophlebitis (→ PE)   (→ Arterial     (bleeding +  thrombosis
   (Trousseau's)             emboli/stroke)   thrombosis)

Other Paraneoplastic Syndromes in Advanced Gastric Carcinoma

Clinical Relevance: Management of Cancer-Associated Thrombosis (CAT)

• Goldman-Cecil Medicine Grade A References

Key Examination Points

• Trousseau's syndrome = migratory superficial thrombophlebitis in cancer patients = due to mucin + TF-driven hypercoagulability
• Most classically associated with: gastric and pancreatic carcinoma (both are heavy mucin producers)
• Mechanism keyword: mucin activates platelets via selectins + TF activates extrinsic coagulation pathway
• Trousseau's is resistant to warfarin - requires heparin (LMWH)
• NBTE (marantic endocarditis) = same mechanism, causes valvular vegetations → arterial emboli → stroke
• Trousseau himself had gastric cancer - classic historical vignette

• Robbins, Cotran & Kumar Pathologic Basis of Disease - Paraneoplastic Syndromes; Thrombosis chapter; NBTE
• Robbins & Kumar Basic Pathology - Paraneoplastic Syndromes (Table 6.5)
• Goldman-Cecil Medicine - Physical Examination in Gastric Cancer; CAT Grade A references
• Sleisenger & Fordtran's Gastrointestinal and Liver Disease - Clinical Features of Gastric Cancer