Definition/General
Introduction:
Primary squamous cell carcinoma of salivary glands is a rare malignant tumor representing 1-2% of all salivary gland neoplasms
Must be distinguished from metastatic squamous cell carcinoma which is much more common
Characterized by squamous differentiation with keratinization
Shows aggressive behavior with poor prognosis.
Origin:
May arise from squamous metaplasia of ductal epithelium
Can develop from carcinoma ex pleomorphic adenoma
Occasionally arises from chronic sialadenitis with metaplasia
May represent dedifferentiation of other carcinoma types
HPV-associated cases rarely described.
Classification:
WHO Classification: Squamous cell carcinoma (primary)
Milan System: Category VI - Malignant
Grading: Well, moderately, poorly differentiated
Most are moderately to poorly differentiated
Keratinizing vs non-keratinizing variants.
Epidemiology:
Extremely rare: 1-2% of salivary gland tumors
Peak incidence in 6th-8th decades
Strong male predominance
Parotid gland most common site
History of radiation in some cases
Indian population: consider oral/oropharyngeal primary with salivary extension.
Clinical Features
Presentation:
Rapidly growing, painful mass
Often fixed and hard
Skin involvement common
Facial nerve paralysis frequent
Ulceration of overlying skin
Lymphadenopathy prominent.
Symptoms:
Severe pain (90% of cases)
Facial weakness/paralysis
Trismus from muscle invasion
Dysphagia (deep lobe involvement)
Bloody discharge
Weight loss and systemic symptoms.
Risk Factors:
Advanced age (>60 years)
Male gender (strong predominance)
Prior radiation therapy
Chronic sialadenitis
Smoking (weak association)
Immunosuppression
Previous head-neck cancer.
Screening:
Exclude metastatic disease first
Complete head-neck examination
Otolaryngology consultation
Imaging: CT/MRI for primary site
PET-CT for staging
FNAC for rapid diagnosis
HPV testing if indicated.
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Gross Description
Appearance:
FNAC aspirate often blood-tinged
Cellular to highly cellular
May be purulent if secondarily infected
Volume variable 1-4 ml
Contains necrotic debris.
Characteristics:
Hemorrhagic consistency
Contains inflammatory exudate
Necrotic material prominent
Keratin debris may be visible
Thick, turbid appearance.
Size Location:
Usually yields abundant material due to necrosis
Superficial ulcerated tumors easy to sample
Deep tumors may need imaging guidance
Multiple sampling sites may show different grades
Avoid necrotic areas for diagnosis.
Multifocality:
Usually unifocal primary tumor
Lymph node metastases very common (70%)
Skin involvement frequent
Perineural spread along facial nerve
Distant metastases to lung, bone.
Microscopic Description
Histological Features:
Malignant squamous epithelial cells
Intercellular bridges and keratinization
Nuclear pleomorphism prominent
Mitotic activity high
Keratin pearl formation
Necrosis and inflammation common.
Cellular Characteristics:
Large polygonal cells with eosinophilic cytoplasm
Pleomorphic nuclei with irregular contours
Prominent nucleoli
Intercellular bridges visible
Keratohyaline granules in cytoplasm
Atypical mitoses frequent.
Architectural Patterns:
Sheets and nests of squamous cells
Keratin pearl formation
Individual cell keratinization
Invasive pattern with stromal reaction
Ulceration with surface keratinization
Desmoplastic response.
Grading Criteria:
Well-differentiated: prominent keratinization, minimal pleomorphism
Moderately differentiated: moderate keratinization, moderate pleomorphism
Poorly differentiated: minimal keratinization, marked pleomorphism
Most salivary SCCs are moderately to poorly differentiated.
Immunohistochemistry
Positive Markers:
CK5/6 positive
p63 positive (nuclear)
p40 positive (more specific)
CK14 positive
34βE12 positive
EMA positive
CK19 positive (variable)
p16 positive (if HPV-related).
Negative Markers:
CK7 negative (mostly)
CK20 negative
TTF-1 negative
Thyroglobulin negative
PSA negative
S-100 negative
Chromogranin negative
Synaptophysin negative.
Diagnostic Utility:
p63/p40 confirms squamous differentiation
Helps distinguish from adenocarcinoma
Site-specific markers exclude metastases
p16/HPV testing for etiology
Ki-67 index typically high (>50%)
CK7 negativity supports primary salivary origin.
Molecular Subtypes:
HPV-associated (rare in salivary glands)
HPV-negative (majority)
TP53-mutated subtype
PIK3CA-mutated subtype
CDKN2A-deleted subtype
Molecular profiling for targeted therapy.
Molecular/Genetic
Genetic Mutations:
TP53 mutations in 60-80% cases
PIK3CA mutations in 30-40%
CDKN2A deletions common
NOTCH1 mutations in subset
HRAS mutations
FBXW7 mutations
Complex chromosomal aberrations.
Molecular Markers:
p53 overexpression (mutational)
EGFR overexpression common
Cyclin D1 amplification
High proliferation indices
Aneuploidy
Loss of tumor suppressors.
Prognostic Significance:
Generally very poor prognosis
5-year survival 20-40%
Stage at presentation crucial
Grade affects outcome
TP53 mutations worsen prognosis
HPV-positive may have better outcome (rare).
Therapeutic Targets:
EGFR inhibitors (cetuximab)
Immune checkpoint inhibitors (pembrolizumab)
PI3K/mTOR inhibitors
CDK4/6 inhibitors
Chemotherapy combinations
Radiation sensitizers.
Differential Diagnosis
Similar Entities:
Metastatic squamous cell carcinoma (head-neck, lung, skin)
Mucoepidermoid carcinoma (high-grade)
Salivary duct carcinoma (with squamous features)
Carcinoma ex pleomorphic adenoma
Necrotizing sialadenitis (reactive).
Distinguishing Features:
Primary salivary SCC: No other primary identified
Arises within gland parenchyma
Metastatic SCC: Primary site identified
Pattern of spread typical
Mucoepidermoid: Mixed cell population
Mucin cells present
Salivary duct: Apocrine features
Androgen receptor positive
Sialadenitis: Benign squamous metaplasia.
Diagnostic Challenges:
Distinction from metastatic disease critical
Clinical correlation essential
Complete head-neck examination
Imaging studies to identify primary
Poorly differentiated tumors difficult to classify
Secondary infection may obscure features.
Rare Variants:
HPV-related squamous cell carcinoma
Adenosquamous carcinoma
Basaloid squamous cell carcinoma
Spindle cell (sarcomatoid) carcinoma
Lymphoepithelial carcinoma with squamous features
Carcinoma ex pleomorphic adenoma with squamous differentiation.
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 squamous cells
Cellular Composition
Malignant squamous epithelial cells with keratinization
Morphological Features
High-grade nuclear pleomorphism with intercellular bridges and keratin formation
Keratinization
[Well/moderately/poorly] differentiated with [prominent/moderate/minimal] keratinization
Background
Hemorrhagic and necrotic background with inflammatory debris
Milan System Category
Category VI - Malignant
Cytological Diagnosis
Squamous cell carcinoma (primary vs metastatic to be determined)
Recommendation
Urgent ENT/oncological consultation. Complete head-neck examination to exclude primary source. Staging studies required