# Head and Neck Pathology Essentials

## Overview

Head and neck pathology encompasses a wide range of neoplastic and non-neoplastic lesions arising from the salivary glands, upper aerodigestive tract mucosa, sinonasal region, and thyroid gland. Accurate classification demands integration of morphology, clinical context, and ancillary testing including p16 immunohistochemistry and molecular studies. The revolution in understanding HPV-related oropharyngeal carcinoma has fundamentally changed both classification and staging in this field.

## Salivary Gland Neoplasms

### General Principles

Salivary gland tumors are among the most histologically diverse neoplasms in the human body, with over 30 recognized types in the WHO 5th edition. The "rule of 80s" provides a useful framework: 80% of salivary gland tumors arise in the parotid, 80% of parotid tumors are benign, and 80% of benign parotid tumors are pleomorphic adenomas. Conversely, tumors of the sublingual and minor salivary glands are more likely malignant (greater than 50%). Fine needle aspiration is the standard first-line investigation for parotid masses, with core biopsy increasingly used as a complement.

### Benign Salivary Gland Tumors

Pleomorphic adenoma is the most common salivary gland neoplasm, composed of a mixture of epithelial and myoepithelial cells set within a characteristic chondromyxoid stroma. It can recur if incompletely excised, particularly when simple enucleation is performed rather than formal superficial parotidectomy, and recurrences are often multinodular. The risk of malignant transformation into carcinoma ex pleomorphic adenoma increases with tumor duration, reaching 10-15% over decades. PLAG1 and HMGA2 rearrangements are the characteristic molecular features.

Warthin tumor is the second most common parotid tumor. It features oncocytic epithelium with papillary and cystic architecture and a dense lymphoid stroma containing germinal centers. It occurs almost exclusively in the parotid gland, is bilateral or multifocal in 10-15% of cases, and has a strong association with smoking. It has no malignant potential.

### Malignant Salivary Gland Tumors

Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. It is composed of three cell types: mucous, intermediate, and epidermoid cells. Low-grade MEC is predominantly cystic with mucous cells predominating and carries an excellent prognosis. High-grade MEC is solid, predominantly composed of intermediate and epidermoid cells with necrosis, and behaves aggressively. The MAML2 rearrangement (CRTC1-MAML2 or CRTC3-MAML2) is present in most cases, especially low-grade tumors, and provides independent prognostic information: rearrangement-positive tumors have better outcomes regardless of histologic grade.

Adenoid cystic carcinoma (AdCC) displays three growth patterns: cribriform (the classic pattern with cylindrical pseudolumina), tubular (associated with best prognosis), and solid (worst prognosis). Perineural invasion is a hallmark of this tumor and can allow it to track far beyond the visible tumor margin along nerve sheaths. AdCC shows slow but relentless growth with late distant metastases, particularly to the lungs, sometimes appearing decades after initial treatment. MYB or MYBL1 rearrangements are the defining molecular features.

Secretory carcinoma (formerly mammary analogue secretory carcinoma) harbors the ETV6-NTRK3 fusion, making it targetable with TRK inhibitors such as larotrectinib and entrectinib. Morphologically, it shows microcystic, papillary-cystic, and tubular patterns with characteristic eosinophilic or bubbly secretions. It is positive for S100, mammaglobin, and GATA3.

Acinic cell carcinoma demonstrates serous acinar differentiation with basophilic zymogen-like granules. DOG1 immunohistochemistry is positive, and PAS staining is positive and diastase-resistant. It is generally low-grade but can undergo dedifferentiated or high-grade transformation.

Salivary duct carcinoma is a high-grade malignancy that morphologically resembles invasive breast ductal carcinoma. It is positive for androgen receptor (AR) and shows HER2 amplification in 25-30% of cases. It is aggressive, but androgen receptor represents a therapeutic target.

### Key IHC in Salivary Gland Tumors

The most useful immunohistochemical markers in salivary gland pathology include p63/p40 as myoepithelial markers positive in most biphasic tumors, DOG1 for acinic cell carcinoma, AR and HER2 for salivary duct carcinoma, S100 and mammaglobin for secretory carcinoma, and SOX10 as a broad marker for salivary tumors with myoepithelial differentiation.

| Salivary Gland Tumor | Key IHC/Molecular | Characteristic Features |
|---|---|---|
| Pleomorphic adenoma | PLAG1/HMGA2 rearrangement | Biphasic; chondromyxoid stroma |
| Mucoepidermoid carcinoma | MAML2 rearrangement | Mucous, intermediate, epidermoid cells |
| Adenoid cystic carcinoma | MYB/MYBL1 rearrangement | Cribriform; perineural invasion |
| Secretory carcinoma | ETV6-NTRK3; S100+, mammaglobin+ | Microcystic; eosinophilic secretions |
| Acinic cell carcinoma | DOG1+; PAS+ diastase-resistant | Serous acinar differentiation |
| Salivary duct carcinoma | AR+, HER2 amplified (25–30%) | Resembles breast ductal carcinoma |

## Squamous Lesions of the Upper Aerodigestive Tract

### HPV-Related Oropharyngeal Squamous Cell Carcinoma

HPV-related oropharyngeal SCC has a rising incidence, particularly among young non-smoking males. The tonsil and base of tongue are the most common primary sites. Morphologically, these tumors are non-keratinizing with a basaloid appearance and syncytial growth pattern. They frequently present with cystic lymph node metastases that can mimic branchial cleft cysts. p16 immunohistochemistry serves as a surrogate for HPV status, with strong diffuse nuclear and cytoplasmic staining in more than 70% of tumor cells considered positive. Some guidelines recommend confirmatory HPV PCR or in situ hybridization. HPV-positive oropharyngeal SCC is staged separately from HPV-negative tumors in the AJCC 8th edition because of its significantly better prognosis, and T-category is based on size only rather than extension to adjacent structures.

### HPV-Negative (Conventional) SCC

HPV-negative squamous cell carcinoma is associated with tobacco and alcohol use. It shows keratinizing morphology with a desmoplastic stromal reaction and carries worse prognosis stage-for-stage compared to HPV-positive disease. Molecularly, it is characterized by TP53 mutations, CDKN2A loss, and EGFR overexpression.

### Laryngeal Squamous Lesions

Laryngeal squamous neoplasia spans a spectrum from squamous hyperplasia through dysplasia (mild, moderate, severe) to invasive squamous cell carcinoma. The WHO classification now uses a simplified two-tier system: low-grade and high-grade squamous intraepithelial lesion (SIL). Glottic carcinomas present early due to hoarseness and carry better prognosis than supraglottic or subglottic tumors, which tend to present at more advanced stages.

### Nasopharyngeal Carcinoma (NPC)

Nasopharyngeal carcinoma has a strong association with Epstein-Barr virus, especially the non-keratinizing subtypes. It is classified into keratinizing SCC, non-keratinizing differentiated, and non-keratinizing undifferentiated types. The undifferentiated type (previously termed "lymphoepithelioma") shows syncytial sheets of large epithelial cells with prominent nucleoli admixed with a dense lymphoid infiltrate. EBER in situ hybridization confirms EBV association, and plasma EBV DNA levels are used for monitoring treatment response and surveillance. NPC is endemic in Southeast Asia and southern China.

### Sinonasal Tumors

Sinonasal undifferentiated carcinoma (SNUC) is a high-grade tumor that lacks squamous or glandular differentiation. NUT carcinoma, defined by NUTM1 rearrangement, is very aggressive; NUT immunohistochemistry provides a rapid and specific diagnostic test. Olfactory neuroblastoma (esthesioneuroblastoma) is a neuroectodermal tumor of the olfactory region showing lobular growth with neurofibrillary matrix, graded using the Hyams system (I-IV). HPV-related multiphenotypic sinonasal carcinoma is a recently described entity showing surface dysplasia with ductal and myoepithelial differentiation; despite its complex morphology, it carries a favorable prognosis.

## Thyroid Pathology Fundamentals

### Nodular Thyroid Disease

Thyroid nodules are extremely common, identified in 50-65% of individuals on ultrasound, but fewer than 5% are malignant. Evaluation is driven by ultrasound risk stratification (TI-RADS) and FNA cytology classified by the Bethesda system.

### Key Thyroid Malignancies (Brief Overview)

Papillary thyroid carcinoma accounts for 80-85% of thyroid malignancies and is diagnosed by its nuclear features: optical clearing (Orphan Annie eyes), nuclear grooves, and intranuclear pseudoinclusions. Follicular carcinoma requires demonstration of capsular and/or vascular invasion for diagnosis, which cannot be achieved on FNA cytology. Medullary thyroid carcinoma arises from C-cells, shows characteristic amyloid stroma, is positive for calcitonin and CEA, and is associated with MEN2 syndromes through RET mutations. Anaplastic thyroid carcinoma is undifferentiated, rapidly lethal, and may arise from dedifferentiation of a pre-existing well-differentiated carcinoma.

<image>A medical illustration showing the histologic features of the three most common malignant salivary gland tumors. Panel A: Mucoepidermoid carcinoma, low grade, with cystic spaces lined by mucous cells (highlighted with mucicarmine stain in an inset) intermixed with intermediate and epidermoid cells. Panel B: Adenoid cystic carcinoma, cribriform pattern, showing nests of basaloid cells arranged around cylindrical pseudolumina filled with basophilic mucoid material, with an inset demonstrating perineural invasion with tumor cells surrounding and infiltrating a nerve bundle. Panel C: Secretory carcinoma with microcystic and papillary architecture containing eosinophilic colloid-like secretions, with an inset showing S100 immunohistochemistry with strong diffuse positivity.</image>

<image>A medical illustration comparing HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma. Left panel: HPV-positive SCC showing non-keratinizing basaloid morphology with syncytial growth pattern, pushing borders, and a cystic lymph node metastasis; inset shows strong diffuse p16 immunostaining (nuclear and cytoplasmic, block-positive pattern). Right panel: HPV-negative SCC showing keratinizing morphology with keratin pearl formation, desmoplastic stromal response, and individual cell keratinization; inset shows p16 negativity. A comparison table below lists epidemiology, risk factors, molecular features, staging differences, and prognosis for each type.</image>

<image>A medical illustration depicting the spectrum of nasopharyngeal carcinoma subtypes with EBV association. Panel A: Non-keratinizing undifferentiated type showing syncytial sheets of large epithelial cells with vesicular nuclei, prominent nucleoli, and a dense background of small lymphocytes. Panel B: EBER in situ hybridization showing strong dark nuclear signal in tumor cells with lymphocytes remaining negative. Panel C: A diagram showing the geographic distribution and EBV association rates for nasopharyngeal carcinoma worldwide.</image>

## Clinical Pearls

p16 positivity is only a valid surrogate for HPV in the oropharynx; p16-positive squamous cell carcinoma at other head and neck sites (oral cavity, larynx, hypopharynx) should not be assumed to be HPV-driven and requires confirmatory HPV testing. Cystic neck masses in adults should raise suspicion for metastatic HPV-positive SCC rather than branchial cleft cyst; p16 immunohistochemistry should always be performed on cystic neck lesion biopsies in adults. Adenoid cystic carcinoma characteristically shows perineural invasion and can track along nerves far beyond the visible tumor margin, making close margin assessment critical. MAML2 rearrangement status in mucoepidermoid carcinoma provides prognostic information independent of histologic grade and should be considered in intermediate-grade tumors. NUT carcinoma is rare but important to recognize because it is rapidly fatal; any poorly differentiated carcinoma in the sinonasal tract or midline should be tested with NUT immunohistochemistry. Secretory carcinoma harboring ETV6-NTRK3 fusion is targetable with TRK inhibitors, making molecular confirmation clinically actionable.

## References
- WHO Classification of Tumours Editorial Board. *Head and Neck Tumours*. WHO Classification of Tumours, 5th ed. IARC; 2022.
- El-Naggar AK, et al. *WHO Classification of Head and Neck Tumours*. 4th ed. IARC; 2017.
- Lewis JS Jr, et al. Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline from the College of American Pathologists. *Arch Pathol Lab Med*. 2018;142(5):559-597.
- Skalova A, et al. Mammary Analogue Secretory Carcinoma of Salivary Glands: Molecular Analysis of 25 Cases. *Am J Surg Pathol*. 2015;39(6):744-752.
- Amin MB, et al. *AJCC Cancer Staging Manual*. 8th ed. Springer; 2017.