Yve

Fig. 5.42 Large cell carcinoma. A Sheet-like growth pattern of large pleomorphic cells with abundant eosinophilic cytoplasm and prominent nucleoli. B Strong immunoreactivity for cytokeratin.

Fig. 5.43 Large cell carcinoma. A Organoid growth pattern. B Solid growth with peripheral palisading and rosette-like structures. Tumour cells have large and polygonal nuclei with vesicular chromatin and prominent nucleoli.

Fig. 5.43 Large cell carcinoma. A Organoid growth pattern. B Solid growth with peripheral palisading and rosette-like structures. Tumour cells have large and polygonal nuclei with vesicular chromatin and prominent nucleoli.

Electron microscopy

Ultrastructurally, tumour cells occasionally have a squamous or glandular differentiation not apparent on conventional light microscopic examination {1816, 2836}. Neuroendocrine differentiation is rare; neurosecretory granules have been described in 3 cases {1151,1432,1828}. Prominent desmosome-like junctions connect the tumour cells.

Genetics

Genetic studies of salivary gland large cell carcinoma are scant. TP53 mutation has been detected in two of three cases, and 1 case demonstrated loss of het-erozygosity (LOH) at chromosome 17p {1803,1828}. Two cases of large cell neuroendocrine carcinoma exhibited LOH at chromosome 9p21 {1828}.

Prognosis and predictive factors

Large cell carcinoma is an aggressive tumour with a propensity for local recurrence, cervical lymph node metastases, and distant spread. However, one study has shown that cell size (small vs large type of carcinoma) has no influence on prognosis {1151}. Tumour size has been found to be a prognostic indicator; all patients with tumours larger than 4 cm died of disease with distant metastases {1151}.

Definition

Lymphoepithelial carcinoma (LEC) is an undifferentiated carcinoma accompanied by a prominent non-neoplastic lym-phoplasmacytic infiltrate.

ICD-O code 8082/3

Synonyms

Lymphoepithelioma-like carcinoma (LEC) {1173,1387}; malignant lymphoepithelial lesion {236,2253}; undifferentiated carcinoma with lymphoid stroma {459,2304}; undifferentiated carcinoma {986,1359}; carcinoma ex lymphoepithelial lesion {152}.

Epidemiology

LEC of the salivary gland is rare, accounting for less than 1% of all salivary gland tumours. It shows a striking racial predilection for Inuits (Eskimo) in the Arctic regions (Greenland, Canada, Alaska), South-eastern Chinese, and Japanese {32,236,

986,1479,1821,2253,2326}. The Inuit populations have the highest worldwide incidence of malignant salivary gland tumours, with the majority represented by LEC {32,236,1708}. Slight female predominance, higher frequency of parotid gland involvement, more frequent high stage disease and apparently more aggressive clinical course have been reported in Inuits {236,1428,1479,1708, 2253,2326,2636}. Patients affected by LEC span a wide age range from the first to the ninth decades, with most cases occurring in the fifth decade. There is a slight male predominance {236}.

Etiology

The near 100% association of Epstein-Barr virus (EBV) with salivary gland LEC from the endemic areas, and the presence of the virus in a clonal episomal form suggest an important role of EBV in tumourigenesis {31,236,986,1143,1387, 1428,1479,1821,2636}. Serologic studies show elevated titres of anti-EBV viral capsid antigen IgA or anti-EBV nuclear antigen IgG, though non-specific, in more than 50% of patients with salivary gland LEC from the endemic areas {31,236,1479,2253}. In patients from non-endemic areas, EBV is usually absent, although rare cases may harbour the virus {209,857,1173,1359}. These findings indicate complex interactions of ethnic, geographic and viral factors in the pathogenesis of salivary gland LEC.

Localization

The parotid gland is affected in approxi mately 80% of the cases, followed by the submandibular gland {1479,2253,2326, 2636}. LEC can also rarely occur in the minor salivary glands of the oral cavity, oropharynx and hypopharynx.

Clinical features

LEC presents as a parotid or sub-mandibular swelling (which may be longstanding with recent rapid increase in size), with or without pain {236,857, 2253}. Advanced tumours may become fixed to the underlying tissues or the skin, although facial nerve palsy occurs in only about 20% of cases. Cervical lymph node involvement, which may be extensive, is seen in 10-40% of cases at presentation {236,1000,1387,1479,2253, 2636}. There is no clinical or serologic evidence of an underlying Sjögren syndrome {1373,1479,2253}. Since LEC of salivary gland is morphologically indistinguishable from nasopha-ryngeal carcinoma (which is much more common), it is important to examine and biopsy the nasopharynx thoroughly before accepting the salivary gland tumour as primary LEC {377,2252}.

Macroscopy

The tumours can be circumscribed or show frank invasion into the surrounding

Fig. 5.44 Lymphoepithelial carcinoma of parotid gland. In this example, irregular islands of carcinoma (purple-staining) are intermingled with abundant lymphoid tissues which include lymphoid follicles (blue-staining).
Carcinome Lympho Pith Lial Parotide
Fig. 5.45 Lymphoepithelial carcinoma of parotid gland. A Carcinoma cells are admixed with many small lymphocytes. Note indistinct cell borders, vesicular nuclei and prominent nucleoli. B Tumour islands are heavily infiltrated by lymphocytes. C Uncommon cystic change in the tumour islands.

gland and extraglandular soft tissues. They are fleshy and firm, and range from 1-10 cm in size (mean 2-3 cm) {2252}.

Tumour spread and staging

LEC has a propensity to spread to regional cervical lymph nodes {236, 1479,2636}. Distant metastasis, which can be found in up to 20% of cases at presentation, tends to occur in the lung, liver, bone and brain. In metastatic deposits, the prominent lymphoplasma-cytic infiltrate characteristic of the primary lesion may or may not be present.

Histopathology

The tumour grows in infiltrative sheets, islands and cords separated by a lym-phoid stroma. The tumour cells possess indistinct cell borders, lightly eosinophilic cytoplasm, oval vesicular nuclei with open chromatin, and conspicuous nucle-oli. The nuclei usually show moderate variation in size, although rare cases exhibit fairly uniform-appearing nuclei. Necrosis and mitotic figures are usually easily found. Sometimes the tumour cells can be plump and spindly, with formation of fascicles {445}. Focal squamous differentiation in the form of increased amount of eosinophilic cytoplasm and vague intracellular bridges is occasionally present.

The tumour is by definition richly infiltrated by lymphocytes and plasma cells, often accompanied by reactive lymphoid follicles. The lymphoid component can sometimes be so heavy that the epithelial nature of the tumour may not evident. Histiocytes are abundant in the tumour islands in some cases, imparting a "starry sky" appearance {2253}. Other inconsistent findings are non-caseating granulomas with or without multinucleated giant cells, amyloid deposition {1387}, cyst formation in some tumour islands, perineural and lymphovascular invasion. Tumour cells are immunoreactive for pan-cytokeratin and epithelial membrane antigen. The lymphoid cells include a mixture of B cells and T cells. Electron microscopy shows features of squamous differentiation, with desmosomes and tonofilaments.

In endemic cases, EBV-encoded RNA (EBER) and EBV-DNA can be detected in the tumour cells by in-situ hybridization. Immunohistochemical expression of EBV latent membrane protein 1 is more variable {377,857,986,1316,1479,2326}.

Differential diagnosis

Important differential diagnoses include metastatic undifferentiated carcinoma, malignant lymphoma, lymphoepithelial sialadenitis (no definite cytological atyp-ia, presence of basement membrane-like material, no desmoplastic stroma, no EBV association), lymphadenoma (definite or subtle gland formation, no definite cytological atypia, no desmoplastic stro-ma, and no EBV association), and large cell undifferentiated carcinoma.

Precursor lesions

Most LEC arise de novo but rarely they may develop within lymphoepithelial sialadenitis (formerly myoepithelial sialadenitis) {938}.

Genetic susceptibility

Clustering of salivary gland LEC in family members has been reported {31,91, 1708}. One such family also showed dominantly inherited trichoepitheliomas, suggesting hereditary predisposition related to tumour suppressor genes {1708}.

Prognosis and predictive factors

Five-year survival rate of 75-86% has been reported in patients treated by combined surgery (including neck dissection) and radiation therapy, although local recurrence can occur {236,1387, 1479,2252,2636}. The prognosis is significantly related to tumour stage. There have been attempts to grade LEC based on nuclear pleomorphism and mitotic activity {459,1373}, with suggestion that high-grade tumours are more aggressive, but there are currently no widely accepted or well-validated grading systems.

Fig. 5.46 Lymphoepithelial carcinoma of salivary gland. A Immunostaining for cytokeratin highlights the irregular tumour islands. B In-situ hybridization for EBV (EBER) selectively highlights the islands of carcinoma. The lymphoid cells in the background are negative.

Sialoblastoma

M.S. Brandwein-Gensler

Definition

This is a rare, potentially aggressive, parotid or submandibular tumour that is usually present at birth and recapitulates the primitive salivary anlage.

ICD-O code 8974/1

Synonyms

Congenital basal cell adenoma, basal cell adenoma, basaloid adenocarcino-ma, congenital hybrid basal cell adenoma-adenoid cystic carcinoma, embry-oma {2570,2685}.

Epidemiology

Most tumours are identified at birth or shortly thereafter; occasional children may be diagnosed after the age of two years. The male to female ratio is 2:1. Sialoblastomas are extremely rare; 23 such cases have been reported {48,156, 251,867,945,1016,1574,1688,1786, 1952,2353,2570,2685}.

Localization

The ratio of parotid to submandibular gland involvement is approximately 3:1.

Clinical features

Most babies present with a mass of the cheek or submandibular region. Occasional tumours may reach massive proportions and ulcerate skin. One baby presented with a concomitant hepatoblastoma {2353}, and two other children both had congenital nevi associated with their tumours {251,945}. Some babies have been diagnosed by prenatal sonography. Radiographically, these tumours appear as expansile, lobulated masses. True-cut preoperative biopsy can be diagnostic, and is useful in ruling out neoplasia that require neoadjuvant chemotherapy, such as rhabdomyosar-coma.

Histopathology

Sialoblastomas are composed of basa-loid epithelial cells, with scanty cytoplasm, round to oval nuclei, single or few nucleoli, and relatively fine chromatin pattern. More mature cuboidal epithelial cells with pink cytoplasm can also be seen. These cells form ductules, bud-like structures and solid organoid nests, and may demonstrate peripheral palisading. The intervening stroma may appear loose and immature. Myoepithelial cells can be identified, and have been confirmed by ultrastructural study. More familiar salivary patterns such as adenoid cystic-like cribriform areas can be seen. The mitotic rate within sialoblas-tomas is highly variable, and may increase with subsequent recurrences {251}, as may necrosis, nuclear pleomor-phism and MIB1 proliferative index.

It has been suggested that these tumours be separated into benign and malignant based on the absence or presence of invasion of nerves or vascular spaces, necrosis and cytologic anapla-sia {251,1574}.

Immunoprofile

These tumours express S-100 and vimentin diffusely. Cytokeratin accentuates the ductal structures.

Histogenesis

It has been suggested that these tumours originate from retained blaste-mous cells rather than basal reserve cells {2570}. Dysembryogenic parotid changes have been described adjacent to the tumour, with proliferation of the terminal ductal epithelial bulbs {1952}.

Prognosis and predictive factors

Sialoblastomas have the potential to recur (22%), and can occasionally metastasize regionally (9%), and one fatality has been reported {251,1688}. Most of these children are cured by primary surgical resection.

Fig. 5.47 Sialoblastoma. A Solid nests composed of basaloid cells. B Brisk mitotic rate within this sialoblastoma.

Pleomorphic adenoma

J.W. Eveson K. Kusafuka G. Stenman T. Nagao

Definition

Pleomorphic adenoma is a tumour of variable capsulation characterized microscopically by architectural rather than cellular pleomorphism. Epithelial and modified myoepithelial elements intermingle most commonly with tissue of mucoid, myxoid or chondroid appearance.

Synonym

Mixed tumour

ICD-O code

8940/0

Epidemiology

Pleomorphic adenoma is the most common salivary gland tumour and accounts for about 60% of all salivary neoplasms {2439}. The reported annual incidence is 2.4-3.05 per 100,000 population {244, 2053}. The mean age at presentation is 46 years but the age ranges from the first to the tenth decades {703}. There is a slight female predominance {703,2711}.

Localization

About 80% of pleomorphic adenomas arise in the parotid, 10% in the sub-mandibular gland and 10% in the minor salivary glands of the oral cavity, nasal cavity and paranasal sinuses and the upper respiratory and alimentary tracts {703}. The lower pole of the parotid gland is the most common location but deep lobe tumours can present as a parapha-ryngeal mass. The accessory parotid is occasionally involved.

Clinical features

Pleomorphic adenomas usually are slow growing painless masses. Small tumours typically form smooth, mobile, firm lumps but larger tumours tend to become bossellated and may attenuate the overlying skin or mucosa. Multifocal, recurrent tumours may form a fixed mass. Pleomorphic adenomas are usually solitary but they may show synchronous or metachronous association with other tumours, particularly Warthin tumour, in the same or other glands {2298}. Pain or facial palsy are uncommon but are occasionally seen, usually in relation to infarcted tumours. The size of most tumours varies from about 2-5 cm but some reported cases have been massive {388}. In the palate, tumours are usually seen at the junction of the hard and soft palate unilaterally. In the hard palate they feel fixed due to the proximity of the underlying mucoperiosteum.

Macroscopy

Pleomorphic adenomas tend to form well-defined, ovoid or round tumours. They are often encapsulated but the capsule varies in thickness and may be partially or completely absent, particularly in predominantly mucoid tumours. Those developing in the minor glands usually have a poorly developed or absent capsule. In major gland pleomorphic adenomas there is a distinct tendency for the tumour to separate from the capsule when handling the specimen. The outer surface of larger tumours is frequently bossellated. The cut surface is typically homogeneous and white or tan. It may have a glistening appearance where there are cartilaginous or myxo-chondroid areas. There may be areas of haemorrhage or necrosis. Recurrent tumours are usually multifocal and may be widely dispersed.

Histopathology

Pleomorphic adenoma shows a remark-

Fig. 5.48 Pleomorphic adenoma. Cut surface of the tumour showing a glistening appearance.

able degree of morphological diversity. The essential components are the capsule, epithelial and myoepithelial cells, and mesenchymal or stromal elements. The capsule varies in thickness and presence. A quantitative study showed the thickness ranged from 15-1750 mm {2732}. When tumours were serially sectioned areas of capsular deficiency were seen in all cases {1418}. In predominantly mucoid pleomorphic adenomas, the capsule may be virtually absent and the tumour abuts onto the adjacent salivary gland. Most tumours show areas where finger-like processes extend into the capsule. In addition, the tumour sometimes bulges through the capsule and forms what appear to be separate satellite nodules. These satellites are invariably attached to the main tumour by an isthmus {1418,1986}. There is a tenden

Fig. 5.49 Pleomorphic adenoma. Low-power view showing encapsulated tumour.
Fig. 5.50 Pleomorphic adenoma. A Epithelial component with ductal structures (left) and a mesenchymal myxoid component (right). B Ducts showing luminal cells and several layers of abluminal cells, the latter being merged into myxoid stroma. C Cellular type. D Plasmacytoid cells.

cy for clefts to form close to and parallel with the capsule. These clefts are within the tumour itself and leave tumour cells attached to the capsular wall. The epithelial component shows a wide variety of cell types including cuboidal, basaloid, squamous, spindle cell, plasmacytoid and clear cells. Rarely, mucous, sebaceous and serous acinar cells are seen. These cells are cytologi-cally bland and typically have vacuolat-ed nuclei, without prominent nucleoli, and a low mitotic frequency. The epithelium usually forms sheets or duct-like structures. There is a wide range of epithelial cellularity; sometimes, the epithelial component forms the bulk of the tumour (cellular pleomorphic adenoma). This phenomenon has no prognostic significance. The ducts show cuboidal luminal cells and there may be an abluminal layer of myoepithelial cells. These may be morphologically similar to the luminal cells or have clear cytoplasm and hyperchromatic and somewhat angulated nuclei. In limited material tumours showing these features could easily be confused with adenoid cystic carcinoma and epithelial-myoepithelial carcinoma. The ducts often contain eosinophilic secretory material and are usually small but may be distended to form microcysts. Squamous metaplasia, sometimes with the formation of keratin pearls, can be seen in both ducts and sheets and occasionally there is mucous metaplasia or conspicuous clear cell change. These appearances can be confused with mucoepidermoid carcinoma. More rarely, sebaceous cells or serous cells with zymogen granules are seen. Another rare feature is the presence of multinucleated epithelial cells. Myoepithelial cells may form a fine reticular pattern or sheets of spindle-shaped cells. These may be palisaded forming a Schwannoma-like appearance. A very distinctive appearance is seen when the myoepithelial cells are plasmacytoid or hyaline {1552}. Focal oncocytic change is not uncommon but occasionally the entire tumour is affected and may be mis-diagnosed as an oncocytoma {1973}. Crystalloid material in the form of collagenous crystalloids, tyrosine and oxalate crystals are occasionally present {324}.

The mesenchymal-like component is mucoid/myxoid, cartilaginous or hyalinised and sometimes this tissue forms the bulk of the tumour. Cells within the mucoid material are myoepithelial in origin and their cellular periphery tends to blend into the surrounding stroma. The cartilage-like material appears to be true cartilage and is positive for type II collagen and keratan sulphate. Occasionally it is the major component of the tumour. Bone may form within this cartilage or form directly by osseous metaplasia of the stroma. Deposition of homogeneous, eosinophilic, hyaline material between tumour cells and within the stroma can be a striking feature of some tumours. It forms globular masses or sheets and

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