Definition

A tumour composed of glandular and often cystic structures, sometimes with a papillary cystic arrangement, lined by characteristic bilayered epithelium, comprising inner columnar eosinophilic or oncocytic cells surrounded by smaller basal cells. The stroma contains a variable amount of lymphoid tissue with germinal centres.

ICD-O code 8561/0

 Synonyms

Adenolymphoma, cystadenolymphoma, papillary cystadenoma lymphomatosum. Warthin tumour is preferred to avoid any possible confusion with a lymphoid malignancy, and with the separate entity, lymphadenoma {1591}.

Epidemiology

In most countries, Warthin tumour is the second commonest tumour of the salivary glands. In the United States (US) it comprised about 3.5% of all primary epithelial tumours (5.3% in the parotid) {668}. Other studies revealed higher percentages, such as 14.4% of primary epithelial tumours of the parotid gland in the United Kingdom (UK) {703}, 27% in Denmark {2075}, and 30% in Penn - sylvania, USA {1765}. Warthin tumour occurs in Caucasians and Asians {451}, but has a lower incidence in African- Americans {668} (although this may now be increasing {2856}) and in Black Africans {2590}. The mean age at diagnosis is 62 years, (range 12-92) {668}, and it is rare before 40. The relative sex incidence has changed during the last half-century: In 1953 the male to female ratio was 10:1 {786}, whereas in 1996 it was 1.2:1 {668}, and in 1992 it was equal {1765}. In the UK in 1986 the ratio was 1.6:1 {705}.

Localization

Warthin tumour is almost exclusively restricted to the parotid glands and the periparotid lymph nodes. Most cases involve the lower pole although 10% are in the deep lobe. Occasional tumours (2.7% in one series) arise within adjacent lymph nodes {664}. Very rare examples have been reported in other glands {2669}, but some tumours thought initially to be within the submandibular gland have usually arisen from the anterior tail of the parotid or from lymph nodes {668}. Warthin tumour is clinically multicentric in 12-20% of patients (either synchronous or metachronous), and is bilateral in 5- 14% {899,1610}. In addition, serial sectioning revealed additional sub-clinical lesions in 50% of cases {1417}.

Etiology

There is a strong link between Warthin tumour and cigarette smoking {633,2052} – the incidence is eight times that of non-smokers {1360}. In addition, the increased numbers of female smokers during the second half of the 20th century closely parallels the increase in Warthin tumour in women, and largely explains the change in sex incidence during this period {1421,2856}. The mechanisms are not clear but in has been speculated that irritants in tobacco smoke cause metaplasia in the parotid {2866}. Radiation exposure may be relevant as there is an increase in Warthin tumour among atomic bomb survivors {2229}. There is also said to be a higher frequency of autoimmune disorders in patients with Warthin tumour than in those with pleomorphic adenomas or healthy subjects {899}. At present, the balance of probabilities is that EBV does not play a significant role in the etiology of Warthin tumour {2733}. The metaplastic (infarcted) variant can follow trauma, particularly from FNA biopsy {596,706}.

Clinical features

 Most patients present with a painless mass, on average, 2-4 cm, although  occasional cases have reached 12 cm {2783}. The mean duration of symptoms is 21 months, but in 41% of patients it is less than six months {705 Many patients notice fluctuation in size of the tumour, especially when eating {1711}. Pain has been reported in 9% {705}, particularly those with the metaplastic variant {2866}. Facial paralysis is very rare, and is the result of secondary inflammation and fibrosis, and likewise can be seen in the metaplastic variant {706,1876}. Warthin tumour is able to concentrate Technetium (99mTc), appearing as a “hot” lesion. It is usually well-circumscribed, but secondary inflammation can cause the edges to become indistinct.

 Macroscopy

 Most Warthin tumours are well-circumscribed, spherical to ovoid masses, and partly cystic. The cysts vary from small slits to spaces up to several centimetres, and contain clear, mucoid, creamy white or brown fluid. Solid areas are tan to white, and often firm and fibrous in the metaplastic variant. In all cases of Warthin tumour, the parotidectomy specimen should be examined for other lesions.

Histopathology

The tumour is sharply demarcated with a thin capsule. There are cystic and solid areas, composed of epithelial and lymphoid components. The cysts and slitlike spaces vary in size and shape, and papillary structures project into the lumina. The papillae have fibrovascular cores often with lymphoid stroma. The epithelium comprises two layers of cells: the oncocytic luminal cells are tall and columnar, and show palisading of their bland single ovoid nuclei. The surface often shows apocrine blebbing and cilia are occasionally identified {705}. Deep to this layer lie smaller flattened or cuboidal basal cells. Their cytoplasm is similar, but less abundant. No significant nuclear atypia or mitotic activity is identified. Small foci of squamous metaplasia, scanty goblet cells and very occasional sebaceous cells are seen. The stroma comprises lymphoid tissue displaying varying degrees of reactivity, and germinal centres are usual. Increased numbers of mast cells and plasma cells may also be seen. The cystic spaces contain eosinophilic secretions with occasional crystal formation and laminated bodies resembling corpora amylacea. Some tumours, variously termed, infarcted, infected or metaplastic, account for 6-7% of Warthin tumours {706,2295}. They are likely to be encountered more frequently in the future with the increasing use of pre-operative FNA. There is extensive necrosis, in which a ghost architecture of papillary structures is often identified – this can be highlighted with a reticulin stain. Non-keratinizing squamous metaplasia is prominent, consisting of tongues and cords of often spongiotic squamous cells extending into surrounding tissues in a pseudo-infiltrative pattern. Cytological atypia can be prominent, and mitotic figures numerous, but none is abnormal. Goblet cells can also be seen, but should not be numerous. At the periphery of the lesions, there is extensive fibrosis, with dense hypocellular collagen and myofibroblastic spindle cell proliferation. There is a heavy mixed inflammatory infiltrate, comprising neutrophils, chronic inflammatory cells, as well as sheets of macrophages, some with foamy cytoplasm. Lipogranulomas, with or without cholesterol crystals, are not uncommon. Areas of residual undamaged Warthin tumour can be found, but not in every case, and there may thus be few clues to the nature of the original lesion {596,706}.

Immunoprofile

 Lymphoid marker studies have shown B (CD20), NK (CD56) and T (CD3) cells, including helper (CD4) and suppressor (CD8) subtypes. This profile of lymphocyte subsets is similar to that in normal or reactive lymph nodes {432}. Special stains and immunohistochemistry have little to offer in the diagnosis of Warthin tumour, although there may be a role in diagnosing the metaplastic variant with epithelial markers, particularly when no residual viable Warthin tumour can be identified {596,2279}. 

Cytopathology

The cytopathological findings reflect the histopathological appearance, except that mast cells are more noticeable. The other cellular elements are oncocytic epithelial cells and lymphocytes, with a background of cell debris and proteinaceous material {776}. Uncommon findings include ciliated cells {2899}, squamous cells, mucous cells, siderophages, giant cells, calcifications and crystalloids {776}. The diagnostic sensitivity of FNA cytology is moderately accurate {1984}, but the error rate is clinically significant, as for example, the findings in lymphocyte- rich acinic cell carcinoma are almost identical {2135}.

Differential diagnosis

Of all salivary gland tumours, the typical type of Warthin tumour is usually unmistakeable. Papillary cystadenoma is similar and possibly related, but any lymphoid tissue is scanty. There is some resemblance to other lymphoepithelial cystic lesions such as simple benign lymphoepithelial cyst (unrelated to AIDS), lymphoepithelial sialadenitis (LESA) with cystically dilated ducts, cystic lymphoid hyperplasia of AIDS and MALT lymphoma with cystically dilated ducts {2372}. An important differential is from cystic metastases in intra and periparotid lymph nodes – the malignant nature of most should be obvious, but a recently-reported variant of papillary thyroid carcinoma has been described as “Warthin-like” {113,1572}. It is characterised by a heavy lymphoid stroma and oncocytic metaplasia of the epithelium. The best guide to its true nature is that the nuclei display typical chromatin clearing, inclusions and groove-formation, and the epithelial cells show immunohistochemical expression of thyroglobulin. If there is marked cytological atypia and mitotic activity, the metaplastic variant can be mistaken for squamous or mucoepidermoid carcinoma, either primary or metastatic {596}. The resemblance is particularly close if there has been total infarction of the original Warthin tumour. Clues to the true nature of the lesion include any ghost papillary architecture in the necrotic zones. Also, the squamous metaplasia lacks keratinization (seen in most squamous carcinomas), and mucinous goblet cells are usually much less numerous than in lowgrade cystic mucoepidermoid carcinoma.

 Histogenesis

 There are two principal theories of the histogenesis {668}: one is an origin from intercalated and basal cells of heterotopic salivary ductal inclusions in intra- or peri-parotid lymph nodes. In particular, this explains the distribution of Warthin tumour and its absence from other salivary tissue lacking incorporated lymph nodes. The alternative theory is that Warthin tumour is a benign epithelial neoplasm or proliferation that attracts a heavy lymphoid reaction, similar to that seen in certain other salivary neoplasms {83,1717,2372}. More recently, it has been suggested that Warthin tumour initially develops in a parotid lymph node as an adenomatous epithelial proliferation responding to as yet unidentified stimuli (probably including tobacco either as a direct stimulus or a promoter), followed by lymphocytic infiltration. The stage of this process seen at the time of surgery determines the proportions of epithelial and lymphoid elements {20}.

Genetics

Cytogenetic studies have shown Warthin tumour to have three main stemline groups, one with a normal karyotype, a second with numerical changes only (loss of Y chromosome or trisomy or monosomy 5) and a third group involving structural changes with one or two reciprocal translocations {1711}. Damage to the mitochondrial DNA may account for the ultrastructural changes seen in the mitochondria, as well as the oncocytic change seen morphologically {1494}. Analysis of the X chromosome-linked human androgen receptor gene showed that Warthin tumour is non-clonal, and thus likely to be non-neoplastic {1118}. This finding supports morphological observations that suggested Warthin tumour (as well as various thymic and head and neck cysts) resulted from the induction of cystic changes in branchial cleft epithelium by an inflammatory infiltrate, accompanied by oncocytic change in the epithelium {2199,2509}. A study of 13 cystadenolymphomas (Warthin tumours) showed minimal chromosomal alterations in these tumours {1905}. Interestingly, at least two tumours with cytogenetic analysis have been reported to have t(11;19) (q21;p13) translocation, suggesting a link to mucoepidermoid carcinoma {305,1638}. It is interesting, that the rearrangements on 8q and 12q have, so far, been found to be mutually exclusive {306,2239}.

Prognosis and predictive factors

 Primary treatment is surgical, either superficial parotidectomy or enucleation. After this, most studies show low recurrence rates of about 2-5.5% {668,705}, presumably the result of multifocality. Malignant change is rare, at about 1% {669,2295}, and may involve the epithelial or lymphoid components. Some patients give a history of radiation {1984,2229,2295}. Several types of carcinoma have been described, including squamous {2390}, adenocarcinoma {2295}, mucoepidermoid {1826,2294}, oncocytic {2585}, Merkel cell {788} and undifferentiated. The differential diagnosis includes squamous or mucous metaplasia, and metastases of extra-salivary malignancies to a pre-existing Warthin tumour. Lymphomas include nodal types {115,1694,2338}, and one report of lymphoepithelial lesions suggesting a MALTtype neoplasm {113}. Warthin tumour is sometimes seen in association with other benign salivary tumours, particularly pleomorphic adenoma {664,905,1458,2338,2395}, although it is not clear if this is greater than would be expected by chance with what is after all not an uncommon tumour. Another study found an increased incidence of extra-salivary neoplasms. A common etiology of cigarette smoking explains the carcinomas of the lung, larynx and possibly the bladder, whilst the others (lymphoma, kidney and breast cancers) could just be a coincidence {1610}.