Definition/General
Introduction:
Salivary gland adenocarcinoma NOS (not otherwise specified) represents a heterogeneous group of malignant epithelial tumors that do not fit into specific categories
Accounts for 10-15% of salivary gland malignancies
Shows glandular differentiation but lacks specific features of other carcinoma types
Often represents high-grade tumors with aggressive behavior.
Origin:
Arises from ductal epithelium of major or minor salivary glands
May originate from intercalated or striated ducts
Shows loss of specific differentiation markers
May represent de-differentiated forms of specific tumor types
Can arise from carcinoma ex pleomorphic adenoma.
Classification:
WHO Classification: Adenocarcinoma, NOS
Milan System: Category VI - Malignant
Grading: Usually high-grade tumors
Subtypes include ductal, papillary, cribiform variants
Many are poorly differentiated adenocarcinomas.
Epidemiology:
Represents 10-15% of salivary gland malignancies
Wide age range with peak in 6th-7th decades
Slight male predominance
Minor salivary glands commonly affected
Parotid and submandibular glands also involved
Indian population shows increasing incidence with environmental exposures.
Clinical Features
Presentation:
Rapidly growing, firm mass
Often painful (60-70% cases)
Fixed to underlying structures
May cause facial nerve paralysis
Skin involvement or ulceration
Regional lymphadenopathy common.
Symptoms:
Pain is prominent feature (distinguishes from benign tumors)
Neural symptoms: numbness, weakness
Dysphagia (pharyngeal/laryngeal involvement)
Trismus from muscle invasion
Bloody discharge from ducts
Weight loss in advanced cases.
Risk Factors:
Advanced age (>60 years)
Male gender (slight predominance)
Radiation exposure
Occupational exposures (rubber, asbestos)
Prior salivary tumors
Immunosuppression
Genetic syndromes (rare).
Screening:
Clinical examination for suspicious masses
Assessment of cranial nerve function
Imaging: CT/MRI for staging
PET-CT for metastatic workup
FNAC for rapid diagnosis
Biopsy may be needed for typing.
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Gross Description
Appearance:
FNAC aspirate typically moderately to highly cellular
Often blood-tinged due to vascularity
Turbid appearance
Volume usually 2-4 ml
May contain necrotic debris.
Characteristics:
Viscous consistency variable
May contain tissue fragments
Hemorrhagic background common
Necrotic material may be present
Inflammatory exudate possible.
Size Location:
Usually yields abundant cellular material
Heterogeneous sampling may occur
Necrotic areas may yield poor material
Multiple passes often needed for adequate representation
Core biopsy may complement FNAC.
Multifocality:
Usually unifocal tumor
May show satellite nodules
Lymph node metastases common (30-40%)
Perineural spread frequent
Distant metastases to lung, bone, liver.
Microscopic Description
Histological Features:
Malignant epithelial cells with glandular differentiation
Pleomorphic nuclei with prominent nucleoli
Increased nuclear:cytoplasmic ratio
Mitotic activity prominent
Necrosis may be present
Inflammatory background common.
Cellular Characteristics:
Large pleomorphic cells with eosinophilic cytoplasm
Irregular nuclear contours
Coarse chromatin pattern
Prominent nucleoli
Cytoplasmic vacuoles (glandular differentiation)
Atypical mitoses may be seen.
Architectural Patterns:
Glandular pattern: true lumina with mucin
Solid pattern: sheets of cells
Papillary pattern: papillary projections
Cribriform pattern: sieve-like spaces
Single cell dispersion
Mixed architectural patterns common.
Grading Criteria:
Usually high-grade tumors
Nuclear pleomorphism marked
High mitotic activity (>10/10 HPF)
Necrosis present
Poor glandular differentiation
Invasive features prominent.
Immunohistochemistry
Positive Markers:
CK7 positive (most cases)
CK8/18 positive
EMA positive
CEA positive (variable)
CK19 positive
GCDFP-15 positive (subset)
Mammaglobin positive (subset).
Negative Markers:
CK5/6 negative
p63 negative
S-100 negative
Chromogranin negative
Synaptophysin negative
TTF-1 negative
Thyroglobulin negative
PSA negative.
Diagnostic Utility:
Confirms epithelial origin
Excludes squamous differentiation
Helps distinguish from metastatic adenocarcinoma
Site-specific markers rule out metastases
Ki-67 index typically high (>30%)
p53 often overexpressed.
Molecular Subtypes:
No specific molecular subtypes for adenocarcinoma NOS
May represent various genetic backgrounds
TP53 mutations common
KRAS mutations in subset
PIK3CA alterations
EGFR overexpression.
Molecular/Genetic
Genetic Mutations:
TP53 mutations in 50-70% cases
KRAS mutations in 20-30%
PIK3CA mutations in 15-25%
PTEN loss in subset
CDKN2A deletions
MYC amplification
Complex karyotypes common.
Molecular Markers:
p53 overexpression (mutational)
EGFR overexpression
HER2 amplification (rare)
High proliferation indices
Aneuploidy common
Microsatellite instability rare.
Prognostic Significance:
Generally poor prognosis
5-year survival 40-60%
Stage at presentation critical
Grade affects outcome significantly
Lymph node involvement worsens prognosis
TP53 mutations associated with aggressive behavior.
Therapeutic Targets:
EGFR inhibitors (cetuximab, erlotinib)
PI3K/mTOR inhibitors
Immunotherapy (checkpoint inhibitors)
Chemotherapy for metastatic disease
Radiation sensitizers
Targeted therapy based on molecular profile.
Differential Diagnosis
Similar Entities:
Metastatic adenocarcinoma (breast, lung, GI)
Salivary duct carcinoma (androgen receptor positive)
Mucoepidermoid carcinoma (mixed cell types)
Acinic cell carcinoma (granular cytoplasm)
Polymorphous adenocarcinoma (minor gland specific).
Distinguishing Features:
Primary salivary: Site-specific markers negative
Clinical history important
Salivary duct: Androgen receptor positive
Apocrine features
Mucoepidermoid: Mixed cell population
Mucin cells present
Acinic cell: Amylase positive
Granular cytoplasm
Metastatic: Site-specific markers positive.
Diagnostic Challenges:
Distinction from metastatic disease
Site-specific marker panel essential
Clinical correlation crucial
High-grade features may obscure primary site
Poorly differentiated tumors difficult to classify
Molecular profiling may help.
Rare Variants:
Invasive cribriform carcinoma
Polymorphous adenocarcinoma (high-grade)
Epithelial-myoepithelial carcinoma (dedifferentiated)
Clear cell adenocarcinoma
Oncocytic adenocarcinoma
Adenocarcinoma 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 from [location] salivary gland mass
Specimen Adequacy
Adequate for evaluation - contains malignant cells
Cellular Composition
Malignant epithelial cells with glandular differentiation
Morphological Features
High-grade nuclear features with pleomorphism and prominent nucleoli
Architectural Pattern
Predominantly [glandular/solid/papillary] growth pattern
Background
Hemorrhagic background with inflammatory cells and debris
Milan System Category
Category VI - Malignant
Cytological Diagnosis
Adenocarcinoma, favor primary salivary gland origin
Recommendation
Urgent oncological consultation. Site-specific marker panel to exclude metastases. Staging studies recommended