Warthin Tumor

 Warthin tumor

Definition

"Warthin tumor, also known as adenolymphoma or papillary cystadenoma lymphomatosum, is composed of bilayered oncocytic and basaloid epithelium forming cystic structures, papillae, and glands accompanied by a dense lymphoid stroma."

    -Fletcher

"Warthin's tumor is an adenoma in which bilayered columnar and basaloid oncocytic epithelia form multiple cysts that havenumerous papillations; it is accompanied by a proliferation of follicle-containing lymphoid tissue."

    -Ellis

Synonyms:Papillary cystadenoma lymphomatosum-describes the histological features

                   Adenolymphoma-misnomer as it could be confused with malignancy

History:

It was first reported by Hildebrad in 1895 as a form of lateral cervical cyst variant.

 Albrechet and Artz, in 1910, termed this tumour as papillary cystadenoma. 

In 1929, Aldred Scott Warthin’s published two additional cases and called it as Papillary cystadenoma lymphomatosum (PCL). 

The term ‘Warthin’s tumour’ was first applied in 1944 by Martin and Ehrlich in respect to Warthin’s and since then the term ‘Warthin’s tumour’ has been extensively used. 

Clinical Features

Second most common salivary gland tumor

Accounts for one-fourth of all primary parotid tumors.

Almost restricted occurrence to the superficial lobe of the parotid glands and the periparotid lymph nodes. 

Commonly presents in the sixth to seventh decade and is rare below the age of 40 years, with a definite male predominance . 

Interestingly, a decline of the incidence in men and concurrent increased incidence in women has been observed in recent years-probably due to a decline in the smoking habit

 Studies conducted among atomic bomb survivors suggest that radiation may also be implicated in the tumorigenesis.

 This tumor typically presents as a doughy to cystic mass in the inferior pole of the parotid gland.

The patients can be asymptomatic or have pain, facial weakness, or ipsilateral ear symptoms such as earache, tinnitus, and deafness. 

Sudden painful increase in size associated with acute pain (known as papillary cystadenoma lymphomatosum syndrome) has been postulated to be caused by leakage of fluid into the surrounding tissue and retrograde infection from the oral cavity via the Stensen duct.

 Rarely, facial nerve palsy is seen in tumors complicated by inflammation and fibrosis, which may be mistaken clinically or intraoperatively for carcinoma.

 Warthin tumor is multicentric in 12% to 20% of patients (either synchronous or metachronous), and bilateral in 5% to 14%.

In addition, serial sectioning may reveal additional subclinical lesions in 50% of cases

This tumor is sometimes seen in association with other benign salivary gland tumors, especially pleomorphic adenoma.

Pathogenesis:

Initially Hildebrand proposed that the lesion may be a variant of lateral cervical cyst and remnants of the branchial pouches. 

Later Albrech and Artz proposed its hetertropic origin from neoplastic proliferation of salivary gland ducts present within intra-/para-parotid nodes . This theory is widely accepted and was supported by immunohistochemistry (IHC) finding which showed that luminal and basal epithelial cells of Warthin’s tumour posses characteristics similar to those of the striated duct cells and basal cells of the excretory duct of salivary gland

Warthin  in 1929 had suggested that PCL arose from heterotrophic pharyngeal endoderm when he introduced the lesion in American literature. He was supported by Hevenor and Clark who specified ectopic Eustachian tube endoderm to be the tissue of origin. Orbital inclusions, heterotopic oncocytes, sebaceous glands, hypertrophic lymph node endothelium, and thymic anlage have been included in other theories of histogenesis .

Allegra proposed hypersensitivity as the main cause of Warthin’s tumour histogenesis. The cascade of the event as suggested by him was: oxyphilic metaplasia of striated ducts followed by papillary formations with secretion leading to cyst formation. Then basophils and histocytes infiltrate the basement membrane and eventuate in a complete delayed hypersensitivity reaction and formation of a lymphoid stroma .

 Folusham et al., supported this concept by IHC investigation which showed distribution of immunoglobulin-A (IgA) and IgG similar that seen in autoimmune thyroiditis and also the presence of Langerhans cells. However, the highly organized structure of the lymphoid component, predominantly of IgA producing cells and lack of circulating auto-antibodies were factors against this theory .

Earlier authors suggested that Epstein Barr Virus (EBV) may play an important role in the pathogenesis of Warthin’s tumour, especially in multiple and bilateral cases. This virus might infect ductal epithelial cells and the release of EBV gene products/ cytokine by infected cells might activate lymphoid tissue which will result in a polyclonal B-cell response . However, some studies have not substantially found any association of the EBV-DNA in tumour cells .

The association between smoking and Warthin’s tumour has been reported since 1980’s . Numerous studies have compared and reported that smoking habit has four- to-eight fold greater risk of Warthin’s tumour than do non-smokers .  The pathogenesis may relate to the fact that numerous chemical irritants of tobacco such as benzopyrene, arsenic, N-nitrosoguandine etc affect the aberrant salivary gland tissue in the lymph node . This result in metaplasia of the glandular tissue and secondary tumour changes occurs which is a lengthy phenomenon which would explain why tumours occur later in life .

Macroscopic Appearances

Well-circumscribed spherical to ovoid lesion. 

The cut surfaces often reveal solid tumor interspersed with cystic spaces containing clear, mucoid, brown or caseous semisolid debris; and the latter may sometimes give a false impression of tuberculous lymphadenitis on gross examination. 

There are usually fine papillary projections protruding into the cystic spaces.

 Prior fine-needle aspiration commonly results in areas of hemorrhage, necrosis, or fibrosis

Microscopic Appearances

 Irregular cystic structures with the lining epithelium thrown into papillary folds . 

The epithelium can also show downward extension to form loosely arranged or closely packed tubular glands. 

The epithelium consists of two layers—a luminal layer of oncocytic columnar cells supported by a discontinuous layer of oncocytic basal cells .

 The nuclei of the luminal cells appear uniform and display palisading toward the free surface. Their brightly eosinophilic granular cytoplasm is due to accumulation of mitochondria.

 The basal cells possess round to oval nuclei and small but conspicuous nucleoli. 

The lumens of the cysts contain thick proteinaceous secretions, cellular debris,cholesterol crystals, and sometimes laminated bodies that resemble corpora amylacea.

A distinct layer of basement membrane separates the cystic lining from the lymphoid stroma, which consists of small lymphocytes mixed with some plasma cells, histiocytes, and mast cells.

 Germinal centers and sinusoids can be seen in some cases. Sometimes there may be a granulomatous reaction with Langhans-type giant cells. 

The intimate relationship between glandular structures and lymphoid stroma earned the designation of adenolymphoma for this tumor.

 The origin of the lymphoid cells is still controversial: residual normal nodal lymphoid tissue versus tumor-associated reactive lymphoid proliferation.

 Tumors developing in extraparotid (such as cervical) lymph node can potentially be misinterpreted as metastatic Warthin tumor.

The epithelial component can undergo metaplastic change to squamous, mucous cells or even ciliated cells, especially in response to inflammation or infarction tumors with florid metaplastic changes are often called metaplastic Warthin tumor.

 Sometimes the tumor undergoes infarction, either spontaneous or following fine-needle aspiration, resulting in tumor necrosis, granulation tissue formation, inflammatory reaction, and fibrosis. 

Worse still, cellular atypia and a pseudoinfiltrative appearance of the metaplastic squamous epithelium in the residual tumor may invite an erroneous diagnosis of squamous cell or mucoepidermoid carcinoma.

 Lack of true infiltrative growth into the surrounding parenchyma and merging of the atypical squamous islands with oncocytic epithelium should point to the correct diagnosis 

The relative proportions of epithelial and lymphoid components in Warthin tumors vary. 

Cases with scanty lymphoid component may overlap morphologically with oncocytoma, such that some authors suggest that Warthin tumor and oncocytoma constitute the two extremes of a spectrum of lesions

Histologic subtypes as proposed by Steiphert Heterotropic Theory:

Classic

Stroma poor

Stroma rich

Metaplastic

Malignant change:

Less than 1 %

 In order of frequency, the commonest carcinomas are squamous cell carcinoma, oncocytic carcinoma, adenocarcinoma, undifferentiated carcinoma, mucoepidermoid carcinoma, and Merkel cell carcinoma

Lymphoma arising from the lymphoid stroma is characterized by a relatively monomorphic infiltrate with distortion of the epithelial and lymphoid architecture. Various types of non-Hodgkin lymphoma and Hodgkin lymphoma have been reported.

Differential Diagnosis:

Most of the times,the diagnosis is straight forward.When oncocytic changes predominate,oncocytoma can be considered as a differential diagnosis

Treatment:

Superficial parotidectomy