Definition/General
Introduction:
Lymph node metastasis represents secondary malignant involvement of lymph nodes by tumor cells originating from distant primary sites
It is the most common malignant condition involving lymph nodes
Carcinomas are the most frequent metastatic tumors to lymph nodes
The pattern and extent of involvement has significant prognostic implications for staging and treatment planning.
Origin:
Results from hematogenous or lymphatic spread of malignant cells from primary tumor sites
Lymphatic route most common pathway for regional spread
Hematogenous spread for distant lymph node involvement
Direct extension from adjacent primary tumors
Retrograde spread when normal lymphatic drainage is obstructed
Skip metastases may occur bypassing regional nodes.
Classification:
Classified by primary tumor type: Carcinoma metastases (adenocarcinoma, squamous cell carcinoma, undifferentiated)
Sarcoma metastases (less common)
Melanoma metastases
Hematologic malignancies (primary vs secondary)
By extent: Micrometastases (<2mm)
Macrometastases (>2mm)
Isolated tumor cells (single cells or small clusters).
Epidemiology:
Most common malignant lymph node pathology in adults
Age distribution follows primary cancer patterns
Regional variation based on prevalent primary cancers
Common primaries in India: lung, breast, GI tract, head/neck
Gender distribution varies with primary site
Increasing incidence with aging population and improved diagnostic techniques.
Clinical Features
Presentation:
Progressive, painless lymphadenopathy (most common presentation)
Hard, fixed lymph nodes (distinguishes from reactive)
Regional lymph node involvement following drainage patterns
Unilateral involvement initially
Matted lymph node masses in advanced cases
Skin infiltration and ulceration possible
Associated primary tumor symptoms.
Symptoms:
Constitutional symptoms: weight loss, anorexia, fatigue
Pressure symptoms: dysphagia, dyspnea, voice changes
Vascular compromise: superior vena cava syndrome, limb edema
Neurological symptoms: nerve compression, Horner syndrome
Primary site symptoms: cough, dysphagia, bleeding
Pain (less common, indicates capsular distension or nerve involvement).
Risk Factors:
Advanced primary tumor stage (T3-T4)
High-grade histology of primary tumor
Lymphovascular invasion in primary tumor
Perineural invasion
Large primary tumor size
Poor differentiation of primary tumor
Molecular markers (high Ki-67, p53 mutations)
Delayed diagnosis of primary tumor.
Screening:
Imaging studies: CT, MRI, PET-CT for staging
Fine needle aspiration (FNA) for cytological diagnosis
Core needle biopsy when tissue architecture needed
Excisional biopsy for definitive diagnosis
Immunohistochemistry for primary site identification
Molecular studies when indicated
Staging workup for extent of disease.
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Gross Description
Appearance:
Enlarged, hard lymph nodes with loss of normal architecture
Cut surface shows white-gray tumor deposits replacing normal lymphoid tissue
Firm to hard consistency
Necrotic areas common in large metastases
Hemorrhagic areas may be present
Capsular invasion and extranodal extension
Matted lymph node masses in advanced cases.
Characteristics:
Complete or partial replacement of lymph node parenchyma
Multinodular appearance with tumor deposits
Central necrosis in large metastases
Capsular thickening and invasion
Adherence to surrounding structures
Variable pigmentation (melanoma metastases)
Mucinous appearance (mucinous adenocarcinoma).
Size Location:
Size varies from microscopic to >10 cm
Regional lymph nodes following drainage patterns most commonly involved
Cervical lymph nodes (head/neck primaries)
Axillary lymph nodes (breast, upper limb)
Mediastinal lymph nodes (lung primaries)
Retroperitoneal lymph nodes (GI, GU primaries)
Inguinal lymph nodes (lower GI, GU, lower limb).
Multifocality:
Multiple lymph nodes in same drainage region commonly involved
Progressive spread along lymphatic chains
Skip metastases bypassing proximal nodes
Contralateral spread in advanced cases
Distant lymph node involvement indicates systemic disease
Extranodal extension into surrounding tissues.
Microscopic Description
Histological Features:
Replacement of lymph node architecture by malignant cells
Tumor morphology usually resembles primary site
Subcapsular location typical for initial involvement
Progressive replacement of cortex and medulla
Desmoplastic reaction around tumor deposits
Necrosis common in large deposits
Vascular invasion within lymph node.
Cellular Characteristics:
Malignant cytological features: nuclear pleomorphism, increased nuclear-cytoplasmic ratio, prominent nucleoli
Increased mitotic activity with atypical forms
Variable differentiation depending on primary tumor
Adenocarcinoma pattern (glandular structures)
Squamous cell carcinoma (keratin formation, intercellular bridges)
Undifferentiated carcinoma (sheets of malignant cells).
Architectural Patterns:
Subcapsular growth pattern (early involvement)
Sinusoidal pattern (tumor cells in lymphatic sinuses)
Nodular pattern (discrete tumor nodules)
Diffuse pattern (complete architectural effacement)
Capsular invasion pattern with extranodal extension
Vascular invasion pattern
Mixed patterns common in large metastases.
Grading Criteria:
TNM staging system used for extent assessment
N0: no regional lymph node metastasis
N1-N3: increasing extent of regional involvement
Micrometastases (0.2-2mm) vs macrometastases (>2mm)
Isolated tumor cells (<0.2mm or <200 cells)
Extranodal extension (ENE) affects staging
Number of involved nodes prognostically significant.
Immunohistochemistry
Positive Markers:
Cytokeratin (AE1/AE3, CAM5.2) positive in carcinoma metastases
CK7 and CK20 patterns help identify primary site
TTF-1 (lung, thyroid primaries)
CDX-2 (colorectal primaries)
Mammoglobin and GCDFP-15 (breast primaries)
PSA (prostate)
PAX-8 (renal, thyroid, Müllerian).
Negative Markers:
Lymphoid markers (CD45, CD20, CD3) negative in carcinoma
S-100 negative (except melanoma, nerve sheath tumors)
Vimentin usually negative in carcinomas
Muscle markers negative
Neuroendocrine markers negative (unless neuroendocrine carcinoma)
Melanoma markers negative (except melanoma metastases).
Diagnostic Utility:
Primary site identification using organ-specific markers
CK7/CK20 immunoprofile narrows differential diagnosis
Transcription factors (TTF-1, CDX-2, PAX-8) highly specific
Hormone receptors (ER, PR) for breast primaries
p16 and HPV testing for head/neck primaries
Melanoma markers (S-100, Melan-A, SOX-10) for melanoma
Neuroendocrine markers (chromogranin, synaptophysin) when indicated.
Molecular Subtypes:
Molecular profiling increasingly used for primary site identification
Gene expression profiling (cancer of unknown primary)
Mutation analysis (EGFR, KRAS, BRAF) for targeted therapy
Microsatellite instability testing
PD-L1 expression for immunotherapy eligibility
HER2 amplification in adenocarcinomas
HPV status in squamous cell carcinomas.
Molecular/Genetic
Genetic Mutations:
Mutations reflect primary tumor genetics
TP53 mutations common across cancer types
KRAS mutations (colorectal, pancreatic, lung)
EGFR mutations (lung adenocarcinoma)
BRAF mutations (melanoma, colorectal)
PIK3CA mutations (breast, colorectal)
BRCA1/2 mutations (breast, ovarian)
Clonal evolution may occur in metastases.
Molecular Markers:
Tumor-specific mutations for primary site identification
Microsatellite instability (Lynch syndrome-associated tumors)
Chromosomal alterations specific to tumor types
Gene fusion products (ALK, ROS1 in lung cancer)
Viral markers (HPV, EBV) when relevant
Circulating tumor DNA for monitoring
Liquid biopsy markers.
Prognostic Significance:
Regional lymph node involvement significantly worsens prognosis
Number of involved nodes correlates with survival
Extranodal extension indicates aggressive behavior
Micrometastases have better prognosis than macrometastases
Molecular subtype influences treatment response
Primary site affects overall survival
Response biomarkers guide therapy selection.
Therapeutic Targets:
Targeted therapy based on molecular alterations
EGFR inhibitors for EGFR-mutated tumors
Anti-HER2 therapy for HER2-positive tumors
BRAF inhibitors for BRAF-mutated melanoma
Immunotherapy (PD-1/PD-L1 inhibitors) for eligible tumors
Chemotherapy based on primary site
Radiation therapy for local control
Surgical resection in selected cases.
Differential Diagnosis
Similar Entities:
Primary lymph node malignancies (lymphoma, leukemia)
Reactive lymphadenopathy (infectious, autoimmune)
Castleman disease (angiofollicular hyperplasia)
Sarcoidosis (granulomatous inflammation)
Kikuchi disease (necrotizing lymphadenitis)
Rosai-Dorfman disease (sinus histiocytosis)
Langerhans cell histiocytosis.
Distinguishing Features:
Metastatic carcinoma: cytokeratin positive, architectural effacement, malignant cytology, subcapsular location
Lymphoma: CD45 positive, monomorphic population, specific immunophenotype
Reactive: preserved architecture, polyclonal population, inflammatory background
Sarcoidosis: non-caseating granulomas, negative malignant markers
Kikuchi: necrotizing inflammation, crescentic histiocytes, absence of malignant cells.
Diagnostic Challenges:
Poorly differentiated carcinomas may be difficult to distinguish from lymphoma
Carcinoma of unknown primary requires extensive immunohistochemical workup
Small metastatic deposits may be overlooked
Reactive changes around metastatic deposits can obscure diagnosis
Necrotic metastases may lack viable tumor for analysis
Micrometastases require careful examination.
Rare Variants:
Signet ring cell metastases (gastric, breast primaries)
Clear cell metastases (renal cell carcinoma)
Spindle cell metastases (sarcomatoid carcinomas)
Small cell carcinoma metastases
Neuroendocrine carcinoma metastases
Melanoma metastases (amelanotic variants)
Germ cell tumor metastases
Cystic metastases (papillary thyroid carcinoma).
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
[Lymph node dissection/biopsy] from [anatomical location], [number] lymph nodes, largest measuring [X.X] cm
Diagnosis
Metastatic [carcinoma/adenocarcinoma/squamous cell carcinoma] in [number] of [total] lymph nodes
Staging Classification
TNM staging: N[1/2/3], extent: [macrometastases/micrometastases], extranodal extension: [present/absent]
Histological Features
Shows [malignant epithelial cells] with [glandular/squamous/undifferentiated] morphology and [architectural effacement/subcapsular growth]
Size and Extent
Largest metastasis: [X.X] cm, involvement: [partial/complete nodal replacement], extranodal extension: [present/absent]
Primary Site Assessment
Immunoprofile consistent with [organ system] primary: [list positive markers]
Special Studies
IHC: CK [positive], [organ-specific markers], [transcription factors]
Molecular: [if performed] [mutation analysis/gene expression profiling]
Staging studies: [imaging findings/additional sites of disease]
Final Diagnosis
Metastatic [specific carcinoma type] in [number] lymph nodes, consistent with [primary site] origin