Definition/General
Introduction:
Metastatic disease to lymph nodes represents secondary malignant involvement from a distant primary tumor
It is the second most common cause of malignant lymphadenopathy after lymphomas
FNAC is highly effective in diagnosing metastatic carcinoma with sensitivity of 85-95%
Most common primary sites include breast, lung, gastrointestinal tract, and genitourinary organs.
Origin:
Results from hematogenous or lymphatic spread from primary tumor site
Tumor cells invade lymphatic channels and get arrested in regional lymph nodes
Initial involvement occurs in subcapsular sinuses
Progressive growth leads to architectural effacement
Sentinel lymph nodes are first to be involved in regional spread.
Classification:
Classified based on primary tumor type: Adenocarcinoma (most common, 60-70%)
Squamous cell carcinoma (20-25%)
Poorly differentiated carcinoma (10-15%)
Small cell carcinoma (5%)
Undifferentiated carcinoma (2-3%)
Melanoma and sarcoma are less common.
Epidemiology:
Accounts for 25-30% of all malignant lymphadenopathy
Most common in adults >40 years
Gender distribution depends on primary tumor type
Cervical nodes: head and neck primaries
Axillary nodes: breast primaries
Supraclavicular nodes: thoracic and abdominal primaries
Inguinal nodes: genitourinary and lower GI primaries.
Clinical Features
Presentation:
Progressive lymph node enlargement (rapid growth characteristic)
Hard, fixed lymph nodes
Matted lymph node masses
Skin infiltration and ulceration in advanced cases
Multiple node groups may be involved
Unilateral involvement more common than bilateral
Evidence of primary tumor may be present.
Symptoms:
Constitutional symptoms (weight loss, anorexia, fatigue) in 60-70%
Pain due to nerve involvement or rapid enlargement
Dysphagia or stridor if cervical/mediastinal nodes involved
Arm edema if axillary nodes involved
Leg edema if inguinal/iliac nodes involved
Superior vena cava syndrome if mediastinal involvement.
Risk Factors:
Known primary malignancy (major risk factor)
Advanced stage of primary tumor
Poor differentiation of primary tumor
Lymphovascular invasion in primary
Age >50 years
Male gender for certain primaries
Smoking history (lung, head and neck cancers)
Family history of cancer.
Screening:
Complete physical examination including all node groups
Imaging studies: CT scan of chest, abdomen, pelvis
PET-CT scan for staging and primary detection
Mammography if axillary nodes in females
Upper/lower GI endoscopy if supraclavicular nodes
Tumor markers (PSA, AFP, beta-HCG, CEA, CA 19-9).
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Gross Description
Appearance:
Enlarged, hard lymph nodes with loss of normal mobility
Irregular surface and fixed to underlying structures
Cut surface shows gray-white to tan-colored areas
Areas of necrosis and hemorrhage common
Complete architectural replacement in advanced cases
Capsular invasion and perinodal extension.
Characteristics:
FNAC aspirate shows variable cellularity depending on tumor type
Hemorrhagic aspirate common
Necrotic debris in background
Cohesive cell clusters characteristic of carcinoma
Three-dimensional clusters and papillary fragments in adenocarcinoma
Cellular pleomorphism and nuclear atypia.
Size Location:
Node size varies from 1-15 cm
Cervical nodes: primaries from head, neck, thyroid, upper GI
Supraclavicular nodes: lung, breast, GI, genitourinary primaries
Axillary nodes: breast, lung, upper extremity primaries
Inguinal nodes: genitourinary, lower GI, lower extremity primaries.
Multifocality:
Regional node involvement following lymphatic drainage patterns
Skip metastases possible
Bilateral involvement suggests advanced disease or multiple primaries
Distant nodal involvement indicates systemic spread
Multiple site involvement common in late stages
Extracapsular extension indicates poor prognosis.
Microscopic Description
Histological Features:
Malignant epithelial cells in cohesive clusters and sheets
Loss of normal nodal architecture
Subcapsular and sinusoidal involvement initially
Nuclear pleomorphism and prominent nucleoli
Increased nuclear-cytoplasmic ratio
Mitotic activity variable
Necrosis common in poorly differentiated tumors.
Cellular Characteristics:
Adenocarcinoma: Glandular/acinar arrangements, mucin production, moderate to abundant cytoplasm
Squamous cell carcinoma: Polygonal cells, keratinization, intercellular bridges
Small cell carcinoma: Small cells with scant cytoplasm, molding, salt-and-pepper chromatin
Poorly differentiated carcinoma: Sheets of pleomorphic cells, loss of differentiation features.
Architectural Patterns:
Glandular pattern: Adenocarcinoma from various sites
Solid sheets: Poorly differentiated carcinomas
Nested pattern: Neuroendocrine tumors, paraganglioma
Single cell infiltration: Lobular breast carcinoma, signet ring cell carcinoma
Papillary pattern: Thyroid, ovarian, renal primaries
Spindle cell pattern: Sarcomatoid carcinoma.
Grading Criteria:
Well-differentiated: Maintains differentiation features of primary site
Moderately differentiated: Partial loss of differentiation
Poorly differentiated: Minimal differentiation, high nuclear grade
Undifferentiated: No specific differentiation features
Grade correlates with prognosis and treatment response
Primary site identification crucial for grading.
Immunohistochemistry
Positive Markers:
Cytokeratin (AE1/AE3, CAM 5.2): Universal epithelial marker
CK7: Lung, breast, ovarian, upper GI primaries
CK20: Lower GI, genitourinary primaries
TTF-1: Lung and thyroid primaries
Estrogen receptor: Breast and gynecological primaries
PSA: Prostate primaries
Thyroglobulin: Thyroid primaries.
Negative Markers:
CD45 (LCA): Negative (helps exclude lymphoma)
S-100: Negative except melanoma and nerve sheath tumors
CD68: Negative (excludes histiocytic proliferations)
Vimentin: Usually negative except renal cell carcinoma
CD3, CD20: Negative (excludes lymphoma)
Desmin: Negative (excludes muscle tumors).
Diagnostic Utility:
Essential for confirming epithelial nature of malignant cells
Crucial for primary site identification
Helps in differential diagnosis with lymphoma and sarcoma
Guides targeted therapy selection
Important for prognostication
Useful in detecting occult primaries
Critical for treatment planning.
Molecular Subtypes:
CK7+/CK20-: Lung, breast, ovarian, upper GI primaries
CK7-/CK20+: Colorectal, merkel cell carcinoma
CK7+/CK20+: Pancreas, biliary tract, urothelial
CK7-/CK20-: Prostate, squamous cell carcinoma, hepatocellular carcinoma
Neuroendocrine markers: Chromogranin, synaptophysin, CD56.
Molecular/Genetic
Genetic Mutations:
TP53 mutations common in metastatic disease
KRAS mutations in colorectal and pancreatic primaries
EGFR mutations in lung adenocarcinoma
HER2 amplification in breast and gastric primaries
BRAF mutations in melanoma and colorectal cancer
PIK3CA mutations in various carcinomas.
Molecular Markers:
Microsatellite instability (MSI) in colorectal primaries
PD-L1 expression important for immunotherapy
BRCA1/2 mutations in breast and ovarian primaries
ALK rearrangements in lung adenocarcinoma
ROS1 rearrangements in lung adenocarcinoma
MET amplification in various carcinomas.
Prognostic Significance:
Mutation status affects prognosis and treatment options
MSI-high tumors have better response to immunotherapy
BRCA-mutated tumors respond to PARP inhibitors
HER2-positive tumors benefit from targeted therapy
PD-L1 expression predicts immunotherapy response
Tumor mutational burden influences treatment decisions.
Therapeutic Targets:
HER2: Trastuzumab, pertuzumab for HER2-positive tumors
EGFR: Erlotinib, gefitinib for EGFR-mutated tumors
ALK: Crizotinib, alectinib for ALK-rearranged tumors
PD-1/PD-L1: Pembrolizumab, nivolumab for high PD-L1 expression
PARP: Olaparib for BRCA-mutated tumors
CDK4/6: Palbociclib for HR-positive breast cancer.
Differential Diagnosis
Similar Entities:
Primary lymphoma (especially large cell lymphomas)
Reactive lymphadenopathy
Granulomatous inflammation
Primary nodal carcinoma (rare)
Melanoma metastasis
Sarcoma metastasis
Germ cell tumor metastasis
Neuroendocrine tumor metastasis.
Distinguishing Features:
Lymphoma: CD45 positive, cytokeratin negative, lymphoid morphology
Reactive lymphadenopathy: Polymorphous population, tingible body macrophages
Melanoma: S-100, Melan-A positive, cytokeratin negative
Sarcoma: Vimentin positive, cytokeratin negative
Germ cell tumors: AFP, beta-HCG positive
Primary nodal carcinoma: Extremely rare, requires extensive workup.
Diagnostic Challenges:
Poorly differentiated carcinoma vs large cell lymphoma
Small cell carcinoma vs lymphoblastic lymphoma
Squamous cell carcinoma vs nasopharyngeal carcinoma
Adenocarcinoma vs reactive lymphoid follicles
Signet ring cell carcinoma vs histiocytes
Anaplastic carcinoma vs anaplastic large cell lymphoma.
Rare Variants:
Micrometastases (<2mm deposits)
Isolated tumor cells (single cells or small clusters <0.2mm)
Occult primaries (5-10% of cases)
Synchronous multiple primaries
Collision tumors (two different tumors in same node)
Pseudometastases (benign epithelial inclusions)
Metastatic carcinoma ex pleomorphic adenoma.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Fine needle aspiration cytology of [site] lymph node
Clinical History
Known primary: [present/absent, specify if known]. Duration of lymphadenopathy: [duration]. Associated symptoms: [symptoms]
Adequacy
Adequate for evaluation - cellular smears with adequate malignant cells
Morphological Features
Cellular smears showing malignant epithelial cells in [cohesive clusters/sheets]. Cell morphology: [glandular/squamous/poorly differentiated]. Nuclear features: [pleomorphism, nucleoli]. Cytoplasm: [amount, characteristics]. Background: [necrosis, inflammation]
Immunocytochemistry
Cytokeratin: Positive. CK7: [result]. CK20: [result]. TTF-1: [result]. Other specific markers: [as applicable]. CD45: Negative
Primary Site Assessment
Morphology and immunoprofile consistent with [primary site] primary. Differential diagnosis includes: [other possibilities]
Cytological Diagnosis
Metastatic [adenocarcinoma/squamous cell carcinoma/poorly differentiated carcinoma], consistent with [primary site] primary
Recommendations
Staging workup including imaging studies. Identification of primary if unknown. Molecular testing for targeted therapy. Oncology consultation for treatment planning
Comments
The cytological and immunophenotypic features are diagnostic of metastatic carcinoma. Further evaluation for primary site identification and staging is recommended