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Fig. 5.26. Follicular variant of acinic cell carcinoma: the tumour is composed of follicle-like spaces of varying sizes lined with cu-boidal intercalated duct-type cells

Fig. 5.28. Acinic cell carcinoma. PAS-D emphasises coarse zymogen granules in the cytoplasm of the tumour cells

Fig. 5.27. Acinic cell carcinoma with lymphoid stroma: a characteristic microcystic appearance of this tumour subtype is seen

microscopy shows multiple, round, electron-dense cytoplasmic secretory granules [62]. The differential diagnosis depends on the subtype: serous cells resemble normal parotid acini, but with an abnormal architecture. The papillary-cystic type bears a close similarity to the controversial entity cystadenocarcinoma. A follicular pattern suggests metastatic thyroid carcinoma, but is thyroglobulin-negative. The clear cell variant must be differentiated from other neoplasms composed of clear cells, but there are always some cells with PASD-positive granules. AcCC is a genuine malignancy capable of killing, although this may take many years. Average figures for recurrence are 35% and death from disease 16% [62]. Several unsuccessful attempts have been made to predict the clinical outcome of AcCC from morphology, as even the blandest of tumours may cause death. Two studies have shown that Ki-67 (MIB1) is an independent prognostic indicator [94, 198]. Skalova et al. found that tumours with a proliferation index <5% were cured by complete excision, whereas more than half of AcCCs with indices above this either recurred or metastasised [198]. The most effective treatment is complete surgical excision of the primary. Radiation may have a role if this is not possible.

5.9.2 Mucoepidermoid Carcinoma

ICD-O:8430/3

Mucoepidermoid carcinoma (MEC) demonstrates a wide age distribution with a mean of 45 years. Patients with tumours in the palate tend to be younger than those with tongue lesions. It is also the commonest salivary malignancy in children, and can be seen in patients as young as 4 years old [35]. There is a slight 3:2 female predominance. It can occur in either major or minor glands. MEC is "a tumour characterised by the presence of mucus-producing cells, epidermoid cells and cells of intermediate type". The proportion of the different cell types and their architectural configuration (including cyst formation) vary between tumours and sometimes within any individual neoplasm. Mucous cells tend to be more numerous in MECs with cyst formation. Mucous cells are cuboidal, columnar or goblet-like and form solid masses or line cysts, where they may be single or multi-layered [173]. The mucin stains with PASD, Alcian blue and mucicarmine, and these are particularly useful in cases where mucus cells are few. Mucus-filled cysts may rupture and elicit an inflammatory response. Epidermoid cells usually have intercellular bridges, but it should be noted that the term epidermoid does not indicate squamous differentiation, but simply a squamous-Zifce appear-

Fig. 5.29. Mucoepidermoid carcinoma: clear, intermediate and Fig. 5.31. High-grade mucoepidermoid carcinoma: "epidermoid"

mucus-secreting cells cells arranged in a solid pattern also show nuclear pleomorphism. Mucus-secreting cells may be scarce

Fig. 5.29. Mucoepidermoid carcinoma: clear, intermediate and Fig. 5.31. High-grade mucoepidermoid carcinoma: "epidermoid"

mucus-secreting cells cells arranged in a solid pattern also show nuclear pleomorphism. Mucus-secreting cells may be scarce

Fig. 5.30. Low-grade mucoepidermoid carcinoma: typical cystic and solid pattern

ance (Figs. 5.29-5.31). In fact, keratinisation is very rare in MEC, and indeed is much commoner as part of squamous metaplasia in pleomorphic adenoma or malignant myoepithelioma, and in metastatic squa-mous carcinoma from the skin or upper aerodigestive tract. Epidermoid cells may be sparse in MECs, and high molecular weight cytokeratin stains (e.g. LP34) and p63 can help identify them. Intermediate cells are small with dark-staining nuclei and they often form the stratified lining of cysts beneath the mucous cells. Clear cell change may be seen in either the squamous or intermediate cells and MEC may take the form of a clear cell carcinoma [182]. Similarly, oncocytes can be plentiful [109]. All MECs are malignant with a meta-static potential, regardless of their microscopic appearance. Nevertheless, histological features can be used to predict outcome to some degree, and MECs should be given one of three microscopic grades, based on the extent of the cystic component, neural invasion, necrosis, cytological pleomorphism and mitotic activity. This assessment has considerable prognostic significance, with death rates due to disease of 3.3, 9.7 and 46.3% for grades 1, 2 and 3 respectively [62]. Recently, a new grading system has been proposed, but it is still under evaluation [22]. Assessment of the MIB1 proliferation index has also been shown to be of value [196].

5.9.3 Adenoid Cystic Carcinoma

ICD-O:8200/3

Adenoid cystic carcinoma (AdCC) is a malignant tumour with no particular age or sex predilection. It can occur in any gland, but most often in the submandibular or minor salivary glands, particularly the palate. However, in spite of often apparently slow growth, outcome over the long term is poor. AdCC is an extensively infil-trative tumour with characteristic perineural invasion, and this is partly responsible for the clinical presentation of late, but repeated local recurrences. Unlike other salivary gland malignancies, when AdCC metastasises, it tends to involve distant organs (lung, bone) rather than local lymph nodes [117].

Histologically, AdCC is a generally solid tumour in which the cribriform pattern is easily recognised on microscopy, but tubular and solid structures can also be present. The commonest growth patterns are:

Cribriform: this is the most characteristic microscopic feature, dominated by multiple cribriform structures, composed of epithelial and basal/myoepithelial cells. The nuclei are usually dark, hyperchromatic and angu-lated. Mitotic figures are easy to find and may be abun-

Fig. 5.32. Adenoid cystic carcinoma, cribriform variant: multiple cribriform spaces composed of basaloid cells, with hyalinised material surrounded by small hyperchromatic cells
Fig. 5.34. Adenoid cystic carcinoma, solid variant. This is composed of multiple solid nodules, some displaying central comedolike necrosis. The tumour can be seen to infiltrate bone

Fig. 5.35. Adenoid cystic carcinoma, solid variant. Tumour islands contain small ducts lined with a layer of epithelial cells. In the absence of characteristic cribriform structures, the latter feature is diagnostic

Fig. 5.33. Adenoid cystic carcinoma, cribriform variant. Diffuse hyalinisation with compression of tumour cells. Nuclear pleomor-phism may be difficult to appreciate, leading to a false diagnosis of pleomorphic adenoma

Fig. 5.35. Adenoid cystic carcinoma, solid variant. Tumour islands contain small ducts lined with a layer of epithelial cells. In the absence of characteristic cribriform structures, the latter feature is diagnostic dant; the MIB1 proliferation index exceeds 10% [201]. The contents of the spaces can be loose and basophil-ic or dense and eosinophilic. Hyalinisation is common in adenoid cystic carcinoma and may be extreme. In those cases with excessive deposition of hyalinised material, the spaces are distended with loss of the cribriform pattern. Tumour cells may be sparse and bland, and thus the lesions may mimic a pleomorphic adenoma (Figs. 5.32, 5.33).

Tubular: this is composed of small tubules lined with one or two cell types, luminal and abluminal without significant cytological atypia. Because of this bland cy-tological appearance it may be mistaken for basal cell adenoma, except for the presence of infiltration.

Solid (basaloid): this is dominated by large solid sheets of tumour cells, sometimes with comedo-like central necrosis. Within the solid masses of tumour cells, there are small duct-like spaces surrounded by a definite layer of epithelial cells (Figs. 5.34, 5.35). This latter finding distinguishes solid variant AdCC from (relatively low-grade) basal cell adenocarcinoma and the aggressive basaloid squamous cell carcinoma, which in addition often shows intraepithelial dysplastic changes.

A rare finding in all types of AdCC is squamous metaplasia, either as single cells or with keratin pearl formation [62].

A system of three grades based on the presence of tubular, cribriform and solid pattern [171] has shown that outcome is better in tubular ACC, while the worst prognosis is seen in solid AdCC. Nevertheless, clinical stage appears to be a better predictor than grade [210].

Another unfavourable feature of AdCC is the frequent involvement of resection margins in the surgical specimen, particularly as the result of extensive perineural infiltration. As complete excision of AdCC is difficult, patients often require postoperative radiotherapy.

A most important histological differential diagnosis is between AdCC and polymorphous low-grade adenocarcinoma (see Sect. 5.9.4).

5.9.4 Polymorphous

Low-Grade Adenocarcinoma

ICD-O:8525/3

Polymorphous low-grade adenocarcinoma (PLGA) is also known as terminal duct or lobular carcinoma. It is more frequent in women, and the average age at presentation is 59 years (range 21-94) [62]. Most cases arise in intra-oral minor salivary glands, particularly the palate, with only rare examples in the parotid, sometimes developing into a pleomorphic adenoma [223]. The characteristic histological picture of PLGA is an infiltrating tumour with cytological uniformity and morphological diversity [171]. The architecture comprises a variety of patterns, including ducts, streams, and micropapillary, cribriform and solid structures (Fig. 5.36). Diffuse infiltration of tumour cells with Indian filing and concentric growth around nerves is reminiscent of lobular carcinoma of the breast (Fig. 5.37).

The cells each have single regular round, ovoid or fusiform bland nuclei, sometimes with intra-nuclear vacuoles [187] and absent or small nucleoli. Variably present are oncocytic, clear or mucous cells. Mitotic figures are scanty, and never atypical. The stroma varies from fibromyxoid to densely hyaline, but the chondroid matrix of a pleomorphic adenoma is not seen. Immuno-histochemistry shows positivity with epithelial markers (cytokeratins, EMA), S-100, bcl-2 and sometimes CEA, aSMA and vimentin [26]; MIB1 proliferation is low -mean 2.4% (range 0.2-6.4) in one study [201]. PLGA behaves as a low-grade malignancy; a literature review found a recurrence rate of 21%, regional nodal metastasis in 6.5%, distant metastasis in 1.8%, and death due to cancer in 0.9% [116]. However, after 10 years late recurrences and metastases are perhaps more common than that [63], although in another study with a long follow-up, recurrence was in large part due to incompleteness of excision - none of the 22 excised tumours recurred or caused death [159]. In a larger series of 164 PLGA, more than 95% of the patients had no evidence of disease after a long-term follow-up [26]. The recommend-

Fig. 5.36. Polymorphous low-grade adenocarcinoma. Perineural infiltration. Tumour cells show bland cytonuclear abnormality
Fig. 5.37. Polymorphous low-grade adenocarcinoma. Indian filing appearance resembling lobular carcinoma of the breast

ed treatment of PLGA is wide, but conservative surgical excision, postoperative radiation and chemotherapy have little place.

The most important histopathological differential diagnosis is from the much more aggressive adenoid cystic carcinoma. Although both are diffusely infiltrating carcinomas that display morphological diversity, at a cy-tological level the nuclei in AdCC are seen to be hyper-chromatic, angulated, pleomorphic and densely packed with more frequent mitotic figures, in contrast to the nuclei in PLGA, which are uniform with finely speckled chromatin. In addition, staining with S-100 protein is usually more diffuse and stronger in PLGA than AdCC [201, 225]. Other markers such as c-kit (CD117) are of little use in practice, as staining can be seen in AdCC and most PLGAs [59]. Much more reliable marker is the MIB1 proliferation index, which is almost always significantly lower in PLGA [201, 225]. Other differential diagnoses include pleomorphic adenoma, which in minor salivary glands can be poorly circumscribed. The presence of chondroid matrix and any circumscription fa

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