Warthin's Tumor (Papillary Cystadenoma Lymphomatosum)

Names / Synonyms

• Adenolymphoma
• Papillary cystadenoma lymphomatosum
• Branchial cyst of parotid

Basic Concept (as in the picture)

1. Papillary cystadenoma - the epithelial cystic element
2. Lymphomatosum - the lymphoid stromal element

Development / Pathogenesis

1. Heterotopic Salivary Rest Theory

2. Neoplastic Proliferation Theory

3. Hypersensitivity Theory (Allegra)

Clinical Features

Histopathological Features

Epithelial Component

• It is an adenoma exhibiting cyst formation, with papillary projections into the cystic spaces
• The lymphoid matrix forms the connective tissue core of the papillae
• Epithelial cells covering the papillary projections are columnar or cuboidal, arranged in two rows:
  • Outer (luminal) layer: Pseudociliated tall columnar cells with eosinophilic granular cytoplasm (oncocytes); nucleus polarized away from the basement membrane
  • Inner layer: Low cuboidal cells
• Basement membrane distinctly separates epithelium from lymphoid tissue
• The granular eosinophilia of oncocytes is due to abundant mitochondria in the cytoplasm - Cummings Otolaryngology, p. 1843

Lymphoid Component

• Abundant lymphoid stroma with germinal centers in the connective tissue core of the papillae
• No such extensive lymphoid component is found in oncocytoma (a key distinguishing feature)

Cyst Contents

• Frequently, an eosinophilic coagulum (chocolate-colored mucoid brown fluid) is present within the cystic spaces

Summary Diagram of Structure

Cystic space (with eosinophilic coagulum)
         ↑
Papillary projections of epithelium into cyst
         ↑
Two-layered epithelium:
  - Outer: Tall columnar oncocytes (eosinophilic granular cytoplasm)
  - Inner: Low cuboidal cells
         ↓
Basement membrane
         ↓
Lymphoid stroma (core of papillae, with germinal centers)

Treatment

Key Points to Remember

• Second most common benign parotid tumor (after pleomorphic adenoma)
• Always in the lower pole of the parotid
• Bilateral in 10% of cases
• Histology is pathognomonic: oncocytic bilayered epithelium + lymphoid stroma with papillary cysts
• Strong association with cigarette smoking
• The "lymphomatosum" in the name refers to the lymphoid stroma - NOT a lymphoma
• Clinically feels doughy/compressible - distinguishing quality among parotid masses

Warthin's Tumor - Histopathology (Figures 17.29 to 17.32)

Figure 17.29 - Low Power View

• This is a low-power H&E micrograph
• Large, branching papillary projections extend into an open cystic space (the background cavity)
• The core of each papillary projection is filled with dense, dark purple lymphoid tissue
• The projections are lined by a lighter-staining epithelial layer
• The overall pattern looks like fingers (papillae) of tissue dipping into a lake (the cyst)

Figure 17.30 - Medium Power View (Labeled)

Figure 17.31 - High Power View of Bilayered Epithelium

CYSTIC SPACE (CS)
      ↓
Outer layer: Tall columnar oncocytes (PC) — nuclei face the lumen
Inner layer: Low cuboidal cells (IC) — on the basement membrane
      ↓
Lymphoid Stroma (LS) with Germinal Centers (GC)

Figure 17.32 - High Power View of Papillary Projection

• A close-up view of the papillary projection
• Right side: Brightly eosinophilic (pink/red), granular cytoplasm of the bilayered oncocytic epithelium - this pink granularity is due to abundant mitochondria
• Left side: Dense, dark purple nuclei of the underlying lymphoid stroma
• The sharp contrast between the pink epithelium and purple lymphoid core is the characteristic microscopic signature of Warthin's tumor

Lymphoid Component - Significance

1. Normal lymphoid tissue of the lymph node within which the tumor developed (supporting the heterotopic salivary rest theory)
2. Reactive cellular infiltrate involving both humoral and cell-mediated mechanisms (supporting the hypersensitivity theory)

Management

• Superficial parotidectomy
• Seldom recurs after removal - prognosis is excellent

Points to Remember (from the box)

• Adenolymphoma / heterotopic salivary rest / neoplastic proliferation / hypersensitivity theory
• Located in parotid gland
• Slow-growing tumor, spherical in shape
• Lined by columnar or cuboidal cells (pseudociliated)
• Cells show eosinophilic granular cytoplasm (oncocytes - mitochondria-rich)
• Cyst contains eosinophilic coagulum (chocolate-colored fluid)
• May show reactive cellular infiltrate
• Treatment: Parotidectomy

Summary of all 4 Figures Together

Malignant Salivary Gland Tumors - Mucoepidermoid Carcinoma (MEC)

Introduction

• The term Mucoepidermoid Carcinoma (MEC) was introduced in 1945 by Stewart, Foote and Becker
• It consists of both mucus-secreting cells AND epidermoid (squamous) cells - hence the name
• Developed from an excretory duct reserve cell (Dardick's theory of histogenesis)
• It is the most common primary malignant tumor of the salivary glands - Robbins Basic Pathology, p. 3516

Incidence / Prevalence

• About half the cases occur in the major salivary glands
• 8-13% occur in the submandibular gland
• 2-4% involve the sublingual gland
• In minor salivary glands: most commonly on the palate, retromolar area, floor of mouth, buccal mucosa, lip, and tongue

Histogenesis (Origin)

Etiology

• The most commonly implicated factor is radiation
• Up to 44% of patients with a history of radiation-associated salivary tumor developed MEC (Kaste et al., 1994)
• Latency period: 7 to 32 years after radiation exposure
• Rarely, MEC can arise as primary jaw or heterotopic intranodal tumors, or as laryngeal, lacrimal, nasal, paranasal, tracheal, or pulmonary tumors

Clinical and Radiological Features

Age and Sex

• Most frequent in 35-65 years but can occur at any age
• Slight predilection for women

Site

• ~60% occur in the parotid gland
• ~30% in minor salivary glands, especially the palate
• Other intraoral sites: buccal mucosa, tongue, retromolar area

Onset / Presentation

• Appears as a slowly enlarging painless mass - simulates pleomorphic adenoma
• Usually not completely encapsulated
• Often contains cysts filled with viscid mucoid material

Grading - Based on Clinical and Histological Features

Low-Grade Malignancy

• Slowly enlarging, painless mass
• Resembles pleomorphic adenoma clinically
• Seldom exceeds 5 cm in diameter
• Good prognosis: >90% five-year survival
• Local recurrence in ~15% of cases; metastasis is rare

High-Grade Malignancy

• Grows rapidly
• Pain is an early symptom
• Ulceration is seen in aggressive cases (as in Figures 17.40 and 17.41)
• Aggressive clinical course
• 5-year survival only ~50%; recurrence in 25-30%; metastasis in ~30%

Figures Explained

Figure 17.40 - Intraoral Ulceration (High-Grade MEC)

• Shows an intraoral ulcerative lesion on the left side of the mouth
• This is caused by a high-grade mucoepidermoid tumor
• High-grade MEC breaks through the mucosa causing painful, bleeding ulcers
• The aggressive behavior of the tumor causes tissue destruction and ulceration

Figure 17.41 - Extraoral Skin Ulceration (High-Grade MEC)

• Shows mucoepidermoid carcinoma of the left parotid gland with ulceration of the overlying skin
• The tumor has grown so large and aggressively that it has eroded through the skin of the face/cheek
• The ulcerated, fungating mass on the cheek near the ear is characteristic of a neglected/advanced high-grade MEC
• This represents a very aggressive clinical course - a hallmark of high-grade MEC

Histopathology (from Robbins)

1. Squamous (epidermoid) cells - flat, keratin-producing
2. Mucus-secreting cells - mucin-filled, glandular
3. Intermediate cells - hybrid cells with both squamous features AND mucin-filled vacuoles (detected by mucin stains)

• Up to 8 cm in diameter
• Pale gray to white cut surface
• Small mucinous cysts frequently seen
• Lacks a well-defined capsule; often infiltrative

Prognosis Summary

Key Points to Remember

• Most common malignant salivary gland tumor overall
• Most common malignant minor salivary gland tumor
• Radiation is the leading etiologic factor (latency 7-32 years)
• Develops from excretory duct reserve cells (Dardick's theory)
• Three cell types: squamous + mucous + intermediate
• Low grade = painless, slow; High grade = painful, ulcerated, aggressive
• Figures 17.40 and 17.41 both show ulceration - a feature of high-grade MEC
• Treatment: surgical excision; prognosis depends on grade

Mucoepidermoid Carcinoma (MEC) - Continued (Page 441)

Advanced Clinical Features of High-Grade MEC

Spread / Metastasis (High-Grade)

• Infiltrates surrounding tissues in a high percentage of cases
• Regional lymph node metastasis is common
• Distant metastasis to: lungs, bones, brain, subcutaneous tissue

Radiological Features

• CT scan is the most useful imaging modality
• Helps in delineating the margins of the lesion

Figure 17.42 - CT Scan (Palatine MEC)

• Shows an axial CT scan image with a crosshair/measurement marker placed over a lesion of the palate
• The bright (white) area represents the tumor mass within the palatal region
• CT clearly shows the extent of the tumor and its relationship to surrounding structures
• This is a palatal mucoepidermoid carcinoma - the most common site for minor salivary gland MEC
• CT is essential for surgical planning to know how far the tumor has spread

Histopathological Features (Figs 17.43 to 17.51)

The Three Cell Types

1. Mucous Cells

• Cells with foamy cytoplasm filled with mucin
• Appear pale/clear on H&E staining
• Mucin can be confirmed with PAS or mucicarmine stain

2. Epidermoid Cells

• Large polygonal cells with:
  • Prominent nuclei
  • Distinct cell membranes
  • Intercellular bridges (desmosomes - like squamous cells)
  • Abundant eosinophilic cytoplasm
• Occasionally associated with keratin pearl formation
• These give the tumor its "epidermoid" component

3. Intermediate Cells

• Small, round basaloid cells
• Seldom the dominant cell type
• A hybrid cell - has both squamous features AND mucin-filled vacuoles
• Can undergo transformation into either mucous OR epidermoid cells
• Most easily detected with mucin stains

Additional Features

• Cellular pleomorphism and atypia - ranges from minimal (low grade) to severe (high grade)
• Great variability in the composition and proportion of cell types within any single tumor
• Ductal proliferation adjacent to the tumor is common
• Tumors show sheets or nests of epidermoid cells with similar nests of mucous cells, usually arranged in a glandular pattern showing microcyst formation

Histological Variants

1. Clear Cell Variant of MEC

• Sometimes, clusters of clear cells are present in abundance
• These cells generally contain mucinous material and glycogen
• When the clear cell population predominates, it is called the clear cell variant of MEC

2. Oncocytic Variant

• Occasional MECs are associated with a prominent oncocytic component
• These are referred to as the oncocytic variant of MEC

Figures Explained

Figure 17.43 - Clear Cells (CC) in MEC

• High-power H&E micrograph
• Shows pale, washed-out clear cells (CC) - cells with optically clear/empty-appearing cytoplasm
• These cells contain mucinous material and glycogen, which washes out during processing, leaving a "clear" appearance
• This is the clear cell variant of MEC
• The label CC (clear cells) is visible in two areas of the image
• Background shows the typical architecture of MEC with intermixed dark cells and clear cells

Figure 17.44 - Low Power View of MEC

• Low-power H&E micrograph showing the overall architecture of mucoepidermoid carcinoma
• Shows the mixed pattern of:
  • Cystic spaces (lighter areas - mucous-filled)
  • Solid nests of epidermoid/intermediate cells (darker pink areas)
  • Stroma surrounding the tumor nests
• The mixture of cystic and solid areas is characteristic of MEC
• This low-power "gestalt" appearance - cysts + solid epithelial nests - is used for initial diagnosis

Summary of All 3 Cell Types vs. Grade

LOW GRADE MEC:
  - Predominantly mucous cells
  - Many cystic spaces
  - Minimal atypia
  - Slow growing, good prognosis

HIGH GRADE MEC:
  - Predominantly epidermoid + intermediate cells
  - Solid sheets, minimal cysts
  - Marked cellular atypia
  - Aggressive, poor prognosis

Key Points from This Page

• High-grade MEC causes facial nerve paralysis, trismus, blood-tinged saliva - all signs of aggressive tumor behavior
• CT scan is the investigation of choice to delineate tumor margins
• Three cell types: mucous + epidermoid + intermediate (intermediate cells are the progenitors)
• Clear cell variant - when clear cells (mucin + glycogen-containing) predominate
• Oncocytic variant - when oncocytic cells predominate
• Microcyst formation and ductal proliferation are characteristic architectural features

Mucoepidermoid Carcinoma - Histological Grading (Figures 17.45 to 17.48)

Basis of Grading

1. Proportion of epidermoid cells vs. mucous cells
2. Degree of cystic transformation of the tumor
3. Degree of cellular atypia

Important note: Cysts may rupture, liberating mucus which pools in the connective tissue and evokes an inflammatory reaction - in such cases, lymphocytes are seen around the mucin pool (mucin extravasation reaction).

Grading Table

Detailed Grading Descriptions

LOW GRADE MEC

• Predominantly shows mucous cells with abundant extracellular mucin
• Several large cystic areas lined by cells are seen in the tumor mass
• Few epithelial nests are seen
• Tumor is well-differentiated; cells look almost normal
• Closely resembles a benign cystic lesion at low power

INTERMEDIATE GRADE MEC

• Cystic transformation is less as compared to low grade
• Predominance of intermediate cells, although areas of mucous and epidermoid cells are still seen
• Cellular atypia is minimal
• Represents a transitional appearance between low and high grade

HIGH GRADE MEC

• Predominant cellularity is of epidermoid cells with varying dysplastic features
• These cells show considerable cellular atypia (large irregular nuclei, prominent nucleoli, abnormal mitoses)
• Very few mucous cells and very few/no cystic spaces
• Solid sheets of atypical cells - looks most like a squamous cell carcinoma
• Most aggressive, worst prognosis

Figures Explained in Detail

Figure 17.45 - Low Grade MEC (Labeled)

• Large dominant cystic spaces (CS) filled with mucin dominate the image
• A balanced/equal mix of EC and MC lining the cysts and forming nests
• Cells are well-differentiated with minimal atypia
• This is the classic LOW GRADE appearance: cysts + mucous cells = predominant

Figure 17.46 - Low Grade MEC (Large Cysts)

• Low-power view showing large, irregular branching cystic channels
• Filled with pale-pink homogeneous extracellular mucin
• Cyst walls lined by epithelial cells projecting into the lumen
• This confirms well-differentiated (low-grade) MEC - the tumor is mostly cystic with abundant mucin
• Low power "gestalt": if you see lots of mucin-filled cysts = think LOW GRADE MEC

Figure 17.47 - High Grade MEC (Labeled)

• Solid, densely cellular tumor with sheets of atypical epidermoid cells
• Pleomorphism and dysplasia clearly visible in the EC nuclei
• Mucous cells (MC) are scarce - only a few scattered
• Cystic spaces (CS) are very rare and tiny - solid tumor predominates
• This is the HIGH GRADE appearance: solid sheets + epidermoid cells + atypia = aggressive tumor
• Could be mistaken for squamous cell carcinoma if not for the few mucous cells

Figure 17.48 - Cystic Areas in MEC

• High-magnification view of a cystic space in MEC
• Upper portion: pale amorphous pool of mucin in the cyst lumen
• Lower portion: stratified epithelial lining of the cyst wall - showing intermediate cells with round-to-oval nuclei and abundant cytoplasm
• Demonstrates how intermediate cells line the cystic spaces
• The smooth dome-shaped profile of the epithelial lining projecting into the mucin pool is characteristic

Summary Comparison: Low vs. High Grade (Visual Key)

LOW GRADE (Fig 17.45 & 17.46):         HIGH GRADE (Fig 17.47):
─────────────────────────────           ─────────────────────────
- Large cysts = DOMINANT                - Solid sheets = DOMINANT
- Mucous cells = MANY                   - Epidermoid cells = MANY
- Epidermoid cells = EQUAL              - Mucous cells = FEW
- Mucin = ABUNDANT                      - Mucin = SCARCE
- Atypia = MINIMAL                      - Atypia = CONSIDERABLE
- Prognosis = GOOD                      - Prognosis = POOR

Notes from Student's Notebook (visible on left page)

• Origin: Excretory duct reserve cell
• Etiology: Radiation
• Clinical features: Women, 3.5-6th decade, slow enlarging
• Grade: Based on cell proportions
• Cell types: Mucous cell, Intermediate cell, Epidermoid cell - "Ruin cell" (intermediate/basal)