Mucoceles result either from disruption of salivary ducts, often due to trauma, with salivary extravasation and reactive inflammation, or due to ductal obstruction and accumulation of saliva in dilated ducts. They commonly arise in minor salivary glands of the lip and oral cavity, and in the sublingual gland (ranula). When tense and deep seated, these may lead to clinical suspicion of neoplasia and are, therefore, not infrequently targets for FNA.

Cytological findings: mucocele

• Watery or viscous fluid

• Scanty cellularity

• Leucocytes and macrophages in variable numbers

• Few epithelial cells

• Many leucocytes and epithelial atypia if secondarily infected.

The fluid is watery or viscous depending upon whether the epithelium is predominantly serous or mucinous (Fig. 5.2). It is relatively hypocellular, containing only a few leucocytes and macrophages and perhaps occasional sheets of columnar cells. Occasionally, leucocytosis is pronounced and the epithelial cells display reactive and inflammatory atypia. Collagenous spherulosis within a mucocele has been described.⁷

Fig. 5.2 Mucocele. Fluid is relatively hypocellular, containing only a few leucocytes and macrophages (A) PAP, (B) MGG.

Diagnostic pitfalls: mucocele

Cystic change occurs in both benign (Warthin’s tumour, pleomorphic adenoma) and malignant (mucoepidermoid carcinoma, acinic cell carcinoma, high-grade carcinoma) salivary gland tumours.⁸ Low-grade mucoepidermoid carcinoma cannot be excluded in aspirates diagnosed as mucinous cystic lesions.⁶

Bilateral and multiple lymphoepithelial cysts (LECs) of major salivary glands, in particular of parotid glands, are uncommon but are reported in human immunodeficiency virus (HIV) infected patients with an incidence of about 3–6% (Fig. 5.3). They represent an early manifestation of HIV infection and are rarely found in patients with advanced disease. They are the most common presentation (58.9%) of HIV infection in children.⁹

Fig. 5.3 Lymphoepithelial cyst. (A) Bilateral and multiple lymphoepithelial cysts of major salivary glands, in particular of parotid glands, are quite rare and have been reported in HIV-infected patients. (B) The aspirates contain foamy macrophages, lymphoid cells, epithelial (squamous) cells and, occasionally, multinucleated giant cells (MGG).

Branchial cysts are usually asymptomatic but one-third present acutely due to inflammation (Fig. 5.4). Aspirates yield abundant or scanty viscous fluid, which contains mature squamous cells and keratinous debris. Although lymphoid tissue is present in its wall, aspirates are usually taken from the centre of the lesion and therefore almost never contain lymphoid cells. Macrophages, cholesterol crystals and acute inflammatory cells are found in cysts where the epithelial lining has been disrupted. With associated inflammation, the squamous epithelial cells often exhibit mild nuclear atypia. In such cases, differentiation of a branchial cyst from cystic metastasis of a squamous cell carcinoma from upper aerodigestive tract and occasionally lungs becomes important. Examination of alcohol-fixed smears with better presentation of keratin and nuclear detail, and careful scrutiny for immature cells, dyskaryotic nuclei, pleomorphism and necrosis, should clarify the distinction in most cases. Well-differentiated squamous cell carcinoma metastasis with only mild nuclear abnormalities can be difficult to exclude and in such a case, radiological imaging and panendoscopy with biopsies should be recommended. Branchial cysts usually present before the age of 40 but so can some squamous carcinoma; age alone is not a reliable discriminator.

Fig. 5.4 Branchial cleft cyst. (A) Cyst is usually lined by squamous and occasionally by columnar epithelium. It may contain variable numbers of inflammatory cells but usually does not contain necrotic background (PAP). (B) Aspirate from a squamous cell carcinoma shows marked degenerative changes, secondary inflammation and necrotic debris. The nuclei are irregular (PAP).

Acute sialadenitis is due to specific bacterial or viral infection such as mumps parotitis. It is usually clinically obvious and FNA is not indicated. CMV sialadenitis should be considered in the differential diagnosis of painless salivary gland enlargement in patients with AIDS.¹³ The presence of acute inflammatory cells in a salivary gland FNA does not always indicate acute sialadenitis; some salivary gland tumours may contain acute inflammation, either due to necrosis or as a result of a previous FNA. Such aspirates should be carefully assessed for other pathology that may be obscured by inflammation.

Calculi (sialoliths) form in the salivary ducts as the result of mineralisation of debris. The submandibular gland is the most common site. Clinically, calculi are associated with pain and swelling and retrograde infection results in acute or chronic sialadenitis. Changes in the duct wall include squamous, oncocytic and mucous cell metaplasia, and if obstruction is longstanding, atrophy and fibrosis of acinar tissue will ensue. Cystic change with a variety of crystalloids may occasionally be encountered.

Chronic sclerosing sialadenitis (CSS), also known as Kuttner tumour, is a cryptogenic tumour-like condition of the salivary glands. Immune-mediated processes are suspected in its pathogenesis and CSS is occasionally reported to be associated with sclerosing pancreatitis.¹⁴

Cytological findings: chronic sialadenitis

• Scanty aspirate

• Ductal cells with possible metaplasia or atypia

• Paucity of acinar cells

• Inflammatory cells and background debris

• Possible cystic change and crystalloids.

Aspirates are generally hypocellular and epithelial cells, when present, are of ductal type. Acinar cells are unusual due to the atrophic changes (Fig. 5.5). Occasionally, large numbers of non-birefringent crystalloids (deep blue with May–Grünwald–Giemsa (MGG) or Diff-Quik and bright orange with Papanicolaou stain) of varying sizes and shapes are present. Lymphocytes, plasma cells, multinucleated histiocytes and neutrophils are also seen.^15,16

Fig. 5.5 Chronic sialadenitis. (A) Aspirates are generally hypocellular and acinar cells are unusual due to the atrophic changes. Clusters of tightly cohesive ductal epithelium are seen (MGG). (B) Ductal cells may show squamous metaplasia with possible atypia (MGG). (C) Occasionally, aspirates from chronic sialadenitis contain large numbers of non-birefringent crystalloids of varying sizes and shapes (MGG).

Diagnostic pitfalls: chronic sialadenitis

Severe inflammatory atypia of ductal cells with anisonucleosis and hyperchromasia may occur as does squamous metaplasia. With inflammatory cells and debris in the background, the appearance can be quite worrying and suggestive of a malignant neoplasm such as mucoepidermoid or squamous cell carcinoma.

Granulomatous involvement of salivary glands is present in about 6% of cases of sarcoidosis. Clusters of epithelioid cells, multinucleated histiocytes and lymphoid cells are seen in aspirates (Fig. 5.6). Duct obstruction with salivary leakage can incite a granulomatous reaction. Other causes include tuberculosis, fungal infection, cat scratch disease, brucellosis and toxoplas-mosis. Granulomatous reaction to non-tyrosine crystalloids can be associated with both neoplastic and non-neoplastic salivary gland disease, and they may be a product of oncocytic cell secretion.¹⁷

Fig. 5.6 Sarcoidosis. Multinucleated giant cells and clusters of epithelioid cells against a background of lymphocytes are seen in aspirates (MGG).

Myoepithelial sialadenitis (MESA) is commonest in middle-aged or elderly women and is usually bilateral and symmetrical, although sometimes initially unilateral. In cases of Sjögren’s syndrome, other manifestations such as dryness of eyes and mouth, rheumatoid arthritis and hypergammaglobulinaemia are present.

Lymphoid lesions are uncommon and thus cytological experience on FNA is limited. A spectrum of diseases, ranging from benign lymphoepithelial lesion (localised myoepithelial sialadenitis or MESA) to systemic Sjögren’s syndrome are included in this benign sialadenopathy, believed to be of autoimmune origin.

Cytological findings: MESA

• Reactive lymphoid cells, plasma cells and histiocytes

• Clusters of myoepithelial cells are sometimes present.

FNA preparations contain numerous lymphocytes mixed with follicle centre cells, plasma cells and histiocytes (Fig. 5.7). Clusters of myoepithelial cells, if present, are a helpful pointer to the disease but are not always evident in aspirates. Florid lymphocytosis is seen in other conditions, including chronic sialadenitis, Warthin’s tumour, mucoepidermoid carcinoma, acinic cell carcinoma and non-Hodgkin lymphoma.^18,19 Aspiration of perisalivary lymph nodes is another source of lymphoid tissue. Benign lymphoepithelial lesion can progress to malignant lymphoma; while high-grade lymphoma is easier to recognise, morphological differentiation from low-grade lymphoma can be difficult. Correlation with clinical findings and use of ancillary methods (flow cytometry, gene rearrangement studies) can help arrive at the diagnosis. FNA of lymphoid lesions with ancillary aids can make a definitive diagnosis.²⁰ The diagnosis of benign lymphoepithelial lesion is best established by correlating the clinical and cytopathological findings and using ancillary methods such as flow cytometry and gene rearrangement studies.^21,22

Fig. 5.7 Myoepithelial sialadenitis (MESA). FNA preparations contain numerous lymphocytes mixed with follicle centre cells, plasma cells and histiocytes. Acinar cells are seen trapped in the infiltrate (MGG).

Sclerosing polycystic adenosis is a recently described, rare lesion of the salivary gland. It can simulate a slow growing tumour. It is pseudoencapsulated and includes tubuloacinar adenosis with dilated ducts, apocrine metaplasia, epithelial hyperplasia and cystic changes associated with fibrosis, histologically resembling fibrocystic disease of the breast.²⁴ Recognition of this benign entity is important since the differential diagnosis includes other more common benign and malignant salivary gland neoplasms, particularly mucoepidermoid carcinoma and tumours with cystic and oncocytic features. The aspirates are characterised by flat cohesive sheets of epithelial cells with moderate amounts of finely granular oncocytic cytoplasm and enlarged round nuclei with indistinct nucleoli. Some epithelial groups form glandular structures with lumens, and the background contains small amounts of delicate mucoproteinaceous material. Occasional markedly vacuolated cells may be present, as well as many cells with apocrine change manifested by well-defined apical snouting.^25,26

Adenomatous ductal hyperplasia (ADH) of the salivary glands is rare, occurring almost exclusively in the palate. It is characterised histologically by the proliferating ducts which resemble intercalated duct epithelium. ADH is compared with adenomatoid acinar hyperplasia (AAH), a lesion found predominantly in intraoral salivary glands and histologically composed of hyperplastic acinar cells. The nature of these lesions is not clear. However, ADH may be a precursor lesion of salivary gland tumours (especially epithelial-myoepithelial carcinomas), whereas AAH may represent a reactive process of idiopathic nature. Clinically, it is generally misdiagnosed as a neoplasm.^27–29 It is a potential source of a false positive diagnosis of mucoepidermoid carcinoma.

The parotid and, to a lesser extent, the submandibular gland normally contain adipose tissue, which increases with advancing age. Lipomatosis is diffuse excess of interstitial fat, which may occur in obesity and diabetes and occasionally presents as a swelling. Fatty replacement of atrophic parenchyma, sialolipoma, periparotid lipomata and sialometaplasia in pleomorphic adenoma are other causes of fat cells in an aspirate.^30–35

Focal oncocytic change is common with increasing age. In diffuse hyperplastic oncocytosis of the parotid gland, extensive metaplasia of acinic and ductal cells leads to transformation of nearly all cells into oncocytes.³⁶ Cytologically, oncocytosis may be difficult to distinguish from oncocytoma or paucilymphocytic Warthin’s tumour. Areas of oncocytic differentiation can occur in pleomorphic adenoma.

Pleomorphic adenoma (mixed tumour) is the commonest salivary gland neoplasm, accounting for 60% of all tumours. Most (80%) occur in the parotid and besides salivary glands, it is occasionally encountered in the nasal cavity, paranasal sinuses, upper respiratory tract and gastrointestinal tract.³⁷ The tumour occurs most often in patients aged 30–50 years and is slightly more common in females. Bilateral synchronous pleomorphic adenomas occur infrequently.³⁸ Histologically, the typical tumour consists of glandular structures composed of a double layer of epithelial and myoepithelial cells embedded in myxoid stroma. Cytology demonstrates most of the histological features of pleomorphic adenoma of salivary gland and is a useful tool in initial assessment of the tumour.³⁹ Squamous metaplasia, oncocytosis, mucus production, sebaceous or adipocytic differentiation^30–35 may occur and the mesenchymal component can undergo chondroid metaplasia or even ossification. Collagenous crystalloids may be a clue to the diagnosis of pleomorphic adenoma.⁴⁰ Cystic change in some tumours presents a diagnostic pitfall both in imaging and cytology.⁴¹ Although a benign tumour, there are rare reports, in which these histologically benign tumours have inexplicably metastasised to distant sites.^42,43

Cytological findings: pleomorphic adenoma

• Cellular aspirates with large amount of myxoid background matrix

• Myoepithelial cells singly or in sheets

• Epithelial cells in form of tubules or as squamous or oncocytic cells

• Cell nuclei vary in size but have uniform chromatin

• Spindle-shaped mesenchymal cells

• Chondroid or other metaplastic changes are sometimes seen.

The cytological diagnosis of the great majority of pleomorphic adenomas is quite straightforward (Fig. 5.8). Aspirates contain plentiful myoepithelial cells, which are closely intermingled with fibrillary myxoid background substance. They lie singly or in sheets and have round to oval nuclei of uniform chromasia, although they may vary a little in size. A characteristic feature is the well-defined cytoplasmic membrane in the majority of these cells and bare nuclei are sparse. The background stromal substance is closely tangled with cells and stains pinkish-grey with Papanicolaou and bright magenta with MGG due to metachromasia. Chondroid change is indicated by a blue reaction with the latter technique. The presence of abundant fibrillary matrix material with single myoepithelial cells in the background is highly diagnostic of pleomorphic adenoma. Published studies based on these criteria confirm a high level of accuracy for FNA diagnosis of pleomorphic adenoma.

Fig. 5.8 Pleomorphic adenoma. (A–D) Aspirates contain epithelial cells, which are closely intermingled with loose clusters of mesenchymal cells and fibrillary mucomyxomatous background substance. The epithelial cells lie singly or in sheets and have nuclei of uniform chromasia, although they may vary a little in size. The mesenchymal cells are rounded or spindly with elongated nuclei. The background substance is closely tangled with cells and stains pinkish-grey with Papanicolaou and bright magenta with MGG. (A) MGG. (B) MGG. (C) PAP, LP. (D) PAP.

Diagnostic pitfalls: pleomorphic adenoma

• Dominance of one cell type

• Cytological atypia

• Globules of basement membrane material

• Cystic change

• Mucin production

• Squamous, mucinous, sebaceous metaplasia.

The histological heterogeneity of pleomorphic adenoma is reflected in its cytology. Problems in interpretation occur for two reasons: the predominance of one element over other components, or the presence of atypical cytomorphological features. If myoepithelial cells are numerous and mesenchymal material not readily apparent, the tumour may be classified as myoepithelioma. Clinically, this is of little significance. If the myxoid component is abundant, it may overwhelm the few epithelial cells present and the lesion may be mistaken for a retention cyst, nodular fasciitis,⁴⁴ schwannoma or intravenous pyogenic granuloma.⁴⁶ This is more likely to happen if only MGG-stained slides are examined, as strong metachromasia may mask other cellular components.

More serious is false suspicion of malignancy.⁴⁷ Some examples of pleomorphic adenoma are highly cellular and display marked cytological atypia. This is reflected in FNA specimens in which the myoepithelial cells can show loss of cohesion, nuclear enlargement and hyperchromasia to a worrying degree. It is important not to overdiagnose these changes. On histological examination, most such ‘atypical’ lesions are pleomorphic adenomas with mild cytological atypia within myoepithelial cells, which is acceptable in the spectrum of benign pleomorphic adenoma. If unequivocal cytological features of malignancy are present, the diagnosis of carcinoma ex-pleomorphic adenoma should be considered (see Carcinoma ex-pleomorphic adenoma, p. 245).

Some pleomorphic adenomas contain adenoid cystic-like areas.⁴⁸ Globules of basement membrane material may be seen in pleomorphic adenoma and basal cell adenoma, risking a misdiagnosis of adenoid cystic carcinoma, which could result in radical surgery.⁴⁹ Great caution must be exercised not to confuse the globules in pleomorphic adenoma with true adenoid cystic carcinoma. If the globules are few and other cellular features of pleomorphic adenoma are present, false suspicion of malignancy should not be raised. The seemingly naked nuclei of neoplastic cells in adenoid cystic carcinoma with their coarse nuclear chromatin and irregular nucleoli can reliably distinguish adenoid cystic carcinoma from cylindromatous adenomas⁵⁰ (see Adenoid cystic carcinoma, p. 243). Occasionally, pleomorphic adenoma may exhibit marked cystic change.^36,41,51

Mucin production by pleomorphic adenomas is another difficulty and the differential diagnosis then includes Warthin’s tumour and low-grade mucoepidermoid carcinoma. Pleomorphic adenoma occasionally reveals focal squamous metaplasia. When extensive, it may be misdiagnosed as metastatic well-differentiated squamous cell carcinoma or mucoepidermoid carcinoma in FNA.⁵² Squamous cells can occur in other non-neoplastic and neoplastic lesions of the salivary such as chronic sialadenitis, lymphoepithelial cyst, Warthin’s tumour, and squamous cell carcinoma.⁵³ The presence of squamous, mucinous, and/or sebaceous metaplasia, especially in the absence of chondromyxoid stroma, presents the potential for misinterpretation of the FNA as indicative of malignancy.^34,54

Familiarity with the variable aspirate appearance of PA in addition to well-defined cytological and architectural criteria can help establish the proper diagnosis in the majority of cases.⁵⁵ There remain, however, few cases in which a definitive diagnosis is not possible.⁵⁶ Small tissue biopsies will not resolve these problems.⁵⁵

Myoepithelioma (myoepithelial adenoma) is defined as a benign tumour composed almost exclusively of cells showing myoepithelial differentiation. They can be spindle celled, plasmacytoid, epithelioid or clear cell in morphology (Fig. 5.9).³⁷ Many authorities would accept a minor epithelial subpopulation, usually less than 5% tumour volume, within this definition.⁵⁷ The surrounding stroma can be collagenous or mucoid. About 40% occur in the parotid followed by the minor salivary glands, especially the palate.³⁷

Fig. 5.9 Myoepithelioma. Myoepithelioma (myoepithelial adenoma) in its pure form is a rare, benign tumour composed exclusively of myoepithelial cells, devoid of any stromal component (PAP).

Basal cell adenoma (BCA) is a rare benign epithelial tumour of the salivary gland. BCA is seen most frequently in the parotid gland and less commonly in the submandibular gland and minor glands of the upper lips, oral cavity and hard palate.⁶⁴

Cytological findings: basal cell adenoma

• Well-polarised basaloid cells, often with peripheral palisading

• Accompanying hyaline stroma (Fig. 5.10).

Fig. 5.10 Basal cell adenoma. Aspirates contain well-polarised basaloid cells, often with peripheral palisading and accompanying hyaline stroma (MGG).

A variety of histological growth patterns such as solid, tubular, trabecular and membranous occurs and this diversity is recapitulated in FNA material. The membranous variant (‘dermal analogue tumour’) resembles an eccrine cylindroma of the skin and may occur either in isolation or in association with a variety of cutaneous adnexal neoplasms. The cells have uniform, round to oval nuclei with uniform chromasia. Scanty cytoplasm is often present as are bare nuclei in the background. Hyaline stroma is often in the form of small globules or finger-like fragments, to which cells adhere.

Diagnostic pitfalls: basal cell adenoma

The potential of mistaking basal cell adenoma for adenoid cystic carcinoma is evident from the above description and must be kept in mind. Hyaline globules are smaller and fewer than those seen in adenoid cystic carcinoma and critical examination of the shape and intensity of staining of the stroma, the cytonuclear morphology and any background content of a smear may facilitate a correct diagnosis. The differences are at best subtle and, on occasion, definitive interpretation may not be feasible (see Adenoid cystic carcinoma, p. 243).^50,65,66

The malignant counterpart of basal cell adenoma is basal cell adenocarcinoma.

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