REVIEW
Advances in salivary gland pathology
W Cheuk & J K C Chan
Department of Pathology, Queen Elizabeth Hospital, Hong Kong
Cheuk W & Chan J K C
(2007) Histopathology 51, 1–20
Advances in salivary gland pathology
This review summarizes the new findings on salivary gland pathology under the following categories:
immunohistochemistry; molecular genetics; newly recognized tumour types; known tumour entities with new findings; and progression of salivary gland tumours. In the application of immunohistochemistry, CD117 can aid in highlighting the luminal cell component of various salivary gland tumours, whereas p63 or maspin can aid in highlighting the abluminal cell component. A high Ki67 index remains the most useful marker to predict adverse outcome in salivary gland carcinoma. Specific chromosomal translocations are recognized in pleomorphic adenoma (with trans- location involving PLGA1 or HMGA2 gene) and mucoepidermoid carcinoma (with MECT1–MAML2 gene fusion). Newly recognized entities include: sclero- sing polycystic adenosis (with recent molecular evidence supporting its neoplastic nature), sclerosing mucoepidermoid carcinoma with eosinophilia, kerato- cystoma, adenoma with additional stromal component
(lymphadenoma, lipoadenoma and adenofibroma), cri- briform adenocarcinoma of the tongue and signet ring adenocarcinoma of minor salivary gland. Known tumour entities with new findings include: salivary duct carcinoma (with newly recognized mucinous, micropapillary and sarcomatoid variants), intraductal carcinoma (with controversies in terminology), muco- epidermoid carcinoma (with newly proposed grading parameters and oncocytic variant), epithelial–myoepit- helial carcinoma (with newly recognized morphologi- cal variants), small cell carcinoma (with most cases being related to Merkel cell carcinoma), extranodal marginal zone B-cell lymphoma (with specific chromo- somal translocation) and chronic sclerosing sialadenitis (being a component of IgG4-related sclerosing disease).
Progression of salivary gland tumours can take the form of malignant transformation of a benign tumour, progression from low-grade to high-grade carcinoma, dedifferentiation, or stromal invasion of an in situ carcinoma.
Keywords: immunohistochemistry, molecular genetics, salivary gland neoplasm, tumour progression
Abbreviations: AFIP, Armed Forces Institute of Pathology; CK, cytokeratin; EMA, epithelial membrane antigen;
MALT, mucosa-associated lymphoid tissue; MAML, mastermind-like gene family; MECT1, mucoepidermoid carcinoma translocated-1; RT-PCR, reverse transcriptase-polymerase chain reaction; WHO, World Health Organization
Introduction
This review aims to take stock of the new information that has accumulated over the past decade on tumours and tumour-like lesions of the salivary gland. Emphasis
will be placed on findings of diagnostic importance and new concepts.
What is new in immunohistochemistry?
The entire glandular structure of the salivary gland exhibits a two-tiered organization comprising luminal (acinar and ductal cells) and abluminal cells (myo- epithelial and basal cells). The secretory acini and
Address for correspondence: Dr John K C Chan, Department of Pathology, Queen Elizabeth Hospital, Wylie Road, Kowloon, Hong Kong. e-mail: jkcchan@ha.org.hk
intercalated ducts are wrapped by myoepithelial cells, while the striated ducts and subsequent conducting portion are supported by basal cells. Use of immuno- histochemistry to differentiate between luminal and abluminal cells can help in understanding the complex architecture of salivary gland tumours and aid in diagnosis.
m a r k e r s f o r l u m i n a l c e l l s
Luminal cells are readily highlighted by immunohisto- chemistry for low-molecular-weight cytokeratin (CK) (such as CAM5.2), carcinoembryonic antigen or epithelial membrane antigen (EMA). Interestingly, although CD117⁄ c-kit is negative in normal salivary gland cells, it is often positive in luminal (glandular) cells of various types of salivary gland tumour, and thus can be utilized to highlight the rudimentary or abortive glands in tumours (Figure 1A). The prior
claim that CD117 is relatively specific for adenoid cystic carcinoma among salivary gland tumours cannot be confirmed.1,2 Although CD117 is expressed in ductal cells, clinical trials using a specific tyrosine kinase receptor inhibitor (imatinib) for adenoid cystic carcin- oma have shown no beneficial effects.3
m a r k e r s f o r a b l u m i n a l c e l l s
Traditionally, abluminal cells are highlighted by immunohistochemistry for high-molecular-weight CK (such as 34bE12 or CK14) and myoepithelial cells, in addition, are stained with antibodies against myoid proteins (such as muscle-specific actin, smooth muscle actin or calponin). p63 has recently become a popular marker for abluminal cells—both basal cells and myoepithelial cells, as well as their neoplastic counter- parts, show nuclear immunoreactivity (Figure 1B).4 However, p63 is not entirely specific for myoepithelial and basal cells. Squamous cells and their tumours are also positive. CD10 can also be used as a myoepithelial marker, but lacks specificity.
Another myoepithelial marker is maspin, a serine protease inhibitor that functions as a tumour sup- pressor.5 In the normal salivary gland, maspin is selectively expressed in the nuclei and cytoplasm of myoepithelial cells (Figure 2A).6 In salivary gland tumours with dual ductal cell–myoepithelial cell differentiation (such as pleomorphic adenoma, basal cell adenoma, adenoid cystic carcinoma and epithelial–
myoepithelial carcinoma), the myoepithelial or modi- fied myoepithelial cell component generally strongly expresses maspin, whereas the ductal cells are usually negative or show only weak focal immunoreactivity (Figure 2B). While immunohistochemistry for maspin can aid in highlighting the myoepithelial component of salivary gland tumours, it lacks specificity for support- ing the myoepithelial nature of myoepithelioma or myoepithelial carcinoma, because this marker is not uncommonly expressed in various types of neoplasm, such as colorectal cancer, lung cancer and oral cancer.7–9
m a r k e r s f o r p r o g n o s i s
The Ki67 proliferative index is the most widely used immunohistochemical marker for prognosis of salivary gland carcinomas. A high Ki67 index has been found to correlate with poor overall survival in mucoepider- moid carcinoma, acinic cell carcinoma and adenoid cystic carcinoma.10On the other hand, no statistically significant relationship has been found between p53 immunoreactivity and survival.
A
B
Figure 1. Immunohistochemistry of epithelial–myoepithelial carcinoma. A, The ductal component is clearly highlighted by CD117 antibody. B, The myoepithelial component, on the other hand, is highlighted by p63 antibody.
NM23 protein is a nucleoside-diphosphate kinase which plays a tissue-specific role in relation to tumour metastasis.11Both reduced expression and overexpres- sion of NM23 have been demonstrated to correlate with increased metastasis and poorer prognosis in cancers from different sites.12 Cytoplasmic NM23 staining can be demonstrated in the majority of pleomorphic aden- omas, adenoid cystic carcinomas and mucoepidermoid carcinomas, with no significant difference in the frequency of positive cells among these tumours.13 However, nuclear expression of NM23 is restricted to malignant salivary gland tumours with metastasis.13 Hence, nuclear NM23 staining may be used for predicting metastasis in salivary gland carcinomas.
Mucoepidermoid carcinomas express, in varying proportions, a variety of membrane-bound mucins,
including MUC1, MUC4, MUC5AC and MUC5B. High MUC1 expression is associated with high histological grade, high rate of recurrence and metastasis and short disease-free interval. Conversely, expression of MUC4, a surrogate marker of tumour differentiation, is related to low histological grade, low recurrence rate and a long disease-free interval.14,15Positive staining for MUC5AC is also helpful in distinguishing high-grade mucoepi- dermoid carcinoma from squamous cell carcinoma.
u s e o f c d4 3 t o a i d i n d i a g n o s i s o f a d e n o i d c y s t i c c a r c i n o m a
CD43, a marker of T cells and histiocytes, has been reported to be preferentially expressed in adenoid cystic carcinomas. In one study, CD43 expression (using antibody L60) was found in 100% of cases of adenoid cystic carcinoma, 7% of polymorphous low-grade adenocarcinomas and 12% of monomorphic aden- omas.16 In another study, CD43 expression (using antibody MT1) was found in 48% of adenoid cystic carcinomas, but in none of the other types of salivary gland tumours.17 CD43 staining tends to be localized in abluminal cells, with a membranous pattern (Figure 3). CD43 immunohistochemistry may have some utility in supporting a diagnosis of adenoid cystic carcinoma in problematic cases.
What is new in molecular genetics?
In recent years, specific chromosomal translocations have been reported in pleomorphic adenomas and mucoepidermoid carcinomas. Further studies are A
B
Figure 2. Immunohistochemistry for maspin. A, In the normal salivary gland, the myoepithelial cells surrounding the acini, inter- calated ducts and parts of the striated ducts are immunoreactive.
Reactivity is in both the nuclei and cytoplasm. B, In a pleomorphic adenoma, both the myoepithelial cells around the tubular structures and the proliferated modified myoepithelial cells that radiate into the stroma show immunopositivity for maspin.
Figure 3. Immunohistochemistry for CD43 in adenoid cystic carcinoma. The myoepithelial⁄ basal cells in the cribriform and tubular structures show membranous positivity, whereas the luminal cells are typically negative.
required to explore the potential value of these trans- locations in the diagnosis of these two types of tumour.
p l e o m o r p h i c a d e n o m a
In approximately 70% of cases of pleomorphic aden- oma, cytogenetic aberrations can be demonstrated in one of the following three patterns:18 (1) rearrange- ment of 8q12 (39% of cases); (2) rearrangement of 12q13-15 (8% of cases); (3) sporadic, clonal changes not involving 8q21 or 12q13-15 (23% of cases).19
The target gene on chromosome 8q12 is PLAG1, which encodes a zinc finger transcription factor.
The partner genes include CTNNB1 (b-catenin) in t(3;8)(p21;112), LIFR (leukaemia inhibitory factor receptor) in t(5;8)(p13;q12) and SII (transcription elon- gation factor SII) in a cryptic translocation. The gene fusion results in dysregulated expression of PLAG1 due to swapping of the promoter region.20–23Overexpression of PLAG1 can also result from cryptic, intrachromosomal 8q rearrangements giving rise to novel fusion products CHCHD7–PLAG1 or TCEA1–PLAG1.24
The target gene on chromosome 12q13-15 is HMGA2 (previously known as HMGIC), which encodes one of the high mobility group proteins that are non-histone chromatin-associated. The partner genes are FHIT (fragile histidine triad gene) in t(3;12)(p14.2;q145) and NFIB (nuclear protein involved in transcriptional regulation) in ins(9;12)(p23;q12q15). The gene fusion results in separation of the DNA-binding domains from potential mRNA-destabilizing motifs, leading to deregu- lation of HMGA2 expression.25,26
Because the PLAG1 or HMGA2 gene translocations have so far been identified only in pleomorphic adenomas, their detection by reverse transcriptase- polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization may potentially aid in diagnosis.
m u c o e p i d e r m o i d c a r c i n o m a
A specific chromosomal translocation has been recog- nized in mucoepidermoid carcinoma. t(11;19)(q21;
p13), which fuses MECT1 (mucoepidermoid carcinoma translocated-1) at 19p13 with MAML2 (mastermind- like gene family) at 11q21, is found in up to 70% of cases.
The fusion protein is expressed in all different cell types that constitute mucoepidermoid carcinoma.27,28 This genetic alteration disrupts the Notch signalling path- way.29 MECT1–MAML2 fusion-positive patients have significantly less local recurrences, metastases and tumour-related deaths compared with fusion-negative patients. Median survival for fusion-positive patients exceeds 10 years, whereas that for fusion-negative
patients is only 1.6 years.30These findings suggest that MECT1–MAML2 fusion may be a useful prognostic marker for mucoepidermoid carcinoma. Although there were some prior reports on the presence of t(11;19) in Warthin’s tumour by conventional cytogenetic studies or molecular genetic studies,31–33a recent study using in situ hybridization and RT-PCR has failed to demon- strate the presence of MECT1–MAML2 fusion gene in seven cases of Warthin’s tumour.28
a d e n o i d c y s t i c c a r c i n o m a
The gene expression profile of adenoid cystic carcinoma has been studied by oligonucleotide array. The most overexpressed genes encode for basement membrane and extracellular matrix proteins of myoepithelial differentiation (e.g. laminin-b1, versican, biglycan and type IV collagen-a1). The most underexpressed genes are those encoding for proteins of acinar-type differentiation (e.g. amylase, carbonic anhydrase and salivary proline-rich proteins).34Loss of heterozygosity in chromosome 6q23-25 has been found in 76% of cases of adenoid cystic carcinoma.35
Newly recognized entities
s c l e r o s i n g p o l y c y s t i c a d e n o s i s
Clinical features and new evidence of its neoplastic nature Sclerosing polycystic adenosis was first characterized in 1996 as a rare lesion of uncertain nature with a striking morphological resemblance to fibrocystic chan- ges of the breast.36 Despite the presence of additional reports on this entity, it is still under-recognized and frequently misdiagnosed as various types of salivary gland carcinoma, such as acinic cell carcinoma.37–42
It occurs in patients from 9 to 80 years of age (mean 33–44.5 years) with a female:male ratio of 3 : 2.42Most cases arise in the major salivary glands, but rare cases can involve intraoral minor salivary glands.37,42,43The patients present with a slow-growing mass. Recurrence occurs in almost one-third of cases. So far there have been no reports on metastasis or mortality from this lesion.42
Sclerosing polycystic adenosis has been considered a pseudoneoplastic benign entity. A recent molecular study employing the human androgen receptor assay for clonality analysis has demonstrated that this lesion is clonal and, hence, probably neoplastic.44
Pathological features
The lesion is well circumscribed and partially encap- sulated. There is proliferation of microcysts, ducts and
acinar structures in a sclerotic stroma, which often shows focal lymphocytic infiltration. These glandular units can be widely spaced or crowded, but a lobular pattern is characteristic. There can be variable degrees of epithelial hyperplasia forming solid aggregates and cribriform structures. Strangulated tubules reminiscent of sclerosing adenosis of the breast are common (Figure 4).
The glandular epithelial cells exhibit a spectrum of nondescript, apocrine, foamy, vacuolated and mucin- ous appearance (Figure 5). Characteristically, some cells contain large, brightly eosinophilic granules (Figure 5B). Ductal epithelial atypia ranging from mild dysplasia to carcinoma in situ can be found in 40–75%
of cases.37,41
Immunohistochemically, luminal epithelial cells express EMA, BRST-2, oestrogen receptor (focal) and progesterone receptor (focal), but not c-erbB2.41,44 A continuous layer of myoepithelial cells can be demon- strated around the glandular units.
s c l e r o s i n g m u c o e p i d e r m o i d c a r c i n o m a w i t h e o s i n o p h i l i a
Clinical features
Sclerosing mucoepidermoid carcinoma with eosino- philia is an uncommon tumour of the thyroid gland that occurs in a setting of sclerosing Hashimoto thy- roiditis and is characterized by an indolent clinical course.45,46 Two morphologically similar cases have been reported to occur as primary tumour of the major salivary gland,47 and the tumours apparently behave like a low-grade malignant neoplasm based on the limited data. We have similarly encountered two cases in our consultation practice. Currently, it is unclear whe- ther this represents a distinctive tumour type or merely a variant of conventional mucoepidermoid carcinoma.
Pathological features
The tumour has infiltrative borders. In a sclerotic stroma heavily infiltrated by chronic inflammatory cells and eosinophils, there are islands and trabeculae of carcin- oma with low nuclear grade.47Most tumour cells have a squamoid appearance and focal keratinization can be present. There are admixed mucinous epithelial cells and glandular structures which merge with the squamoid islands or form discrete tubules (Figure 6).
k e r a t o c y s t o m a Clinical features
Keratocystoma is a very rare benign tumour, with only three cases having been reported.48,49 All cases have
involved the parotid glands of children or young adults (age 8–38 years). There is no recurrence after complete excision. This lesion can potentially be mistaken
A
B
C
Figure 4. Sclerosing polycystic adenosis. A, The lesion is typically well demarcated from the surrounding salivary gland parenchyma.
A lobular architecture is characteristic. B, The lobules comprise rounded glands, cysts and acini. In some glands or cysts, there is intraluminal epithelial proliferation, forming cribriform structures.
C, Narrow tubules, some with a ‘strangulated’ appearance, may be present, reminiscent of sclerosing adenosis of the breast. This pseudo- infiltrative appearance may lead to a misdiagnosis of carcinoma.
histologically for a well-differentiated squamous cell carcinoma.
Pathological features
Grossly, the tumour is a multilocular cystic lesion filled with creamy material. Histologically, there are mul- tiple, randomly disposed cystic structures and solid nests of squamous cells. The former are lined by bland- looking stratified squamous epithelium with ortho- or parakeratosis but lacking a granular layer. The lumens are filled with lamellated keratin. The epithelium is demarcated from the stroma by basement membrane.
The stroma is fibrotic and infiltrated by chronic inflammatory cells. There can be foreign-body reaction against keratin extruded from the ruptured cysts.
a d e n o m a w i t h a d d i t i o n a l s t r o m a l c o m p o n e n t In recent years, several types of salivary gland adenoma characterized by the presence of an additional stromal component, such as lymphoid cells, adipose cells or fibrocellular stroma, have been described. Within this group, the most important tumour to recognize is lymphadenoma, because it can potentially be misdiag- nosed as a malignant neoplasm and vice versa.
Lymphadenoma
Lymphadenoma is an adenoma accompanied by a dense lymphoid infiltrate. There is resemblance to sebaceous lymphadenoma except for the absence of a sebaceous component. Lymphadenoma is probably not A
B
Figure 5. Sclerosing polycystic adenosis, demonstrating the cyto- logical features. A, Many of the glands and cysts are lined by apocrine cells with variable degrees of foamy change in the cytoplasm. B, The gland in the left field is lined by nondescript columnar cells with lightly eosinophilic cytoplasm. Invariably, there are some acini or glands lined by cells with prominent eosinophilic globules in the cytoplasm. These cells may lead to a misdiagnosis of acinic cell carcinoma.
A
B
Figure 6. Sclerosing mucoepidermoid carcinoma with eosinophilia, involving the parotid gland. A, In a fibrotic stroma heavily infiltrated by lymphocytes and eosinophils, there are solid islands of tumour with interspersed glands or mucinous cells. The morphology is quite different from that of conventional mucoepidermoid carcinoma. B, In another case, islands and cords of tumour infiltrate a sclerotic stroma infiltrated by eosinophils and lymphocytes. The tumour islands comprise nondescript cells with mild nuclear atypia. Frank squamous features are absent.
a distinctive tumour type, but merely represents a basal cell adenoma or cystadenoma accompanied by a heavy lymphoid infiltrate.50–52 All cases have occurred in the parotid glands. Complete surgical excision is curative.
The tumour is well circumscribed and comprises intimately admixed adenomatous and lymphoid com- ponents present in variable proportions. The adeno- matous component takes the form of anastomosing trabeculae, islands, solid tubules, cystically dilated glands filled with proteinaceous materials, or papillary structures (Figure 7). The cyst or gland-lining cells are cuboidal to columnar without significant cytological atypia. The trabeculae and solid islands are composed of basaloid cells. The lymphoid component is made up of small lymphocytes and plasma cells, with or without
interspersed reactive lymphoid follicles. In some cases, the lymphoid component is so exuberant as to mask the epithelial component, resulting in morphological mim- icry of lymphoma. Examination of the lesion at medium magnification often reveals cohesive aggregates of larger cells (epithelial cells) among the lymphoid cells, and periodic acid–Schiff-diastase stain can aid in highlighting the adenomatous component by staining the basement membrane-like material around the epithelial islands.
Lymphadenoma should not be mistaken for lympho- epithelial carcinoma, and vice versa. The latter features invasive growth, definite nuclear atypia, significant mitotic activity and squamous or squamoid rather than glandular differentiation. Epstein–Barr virus can be demonstrated in the tumour cells of lymphoepithelial carcinomas occurring in Orientals and Eskimos. On the other hand, there is at least focal ductal differentiation in lymphadenoma.
Lymphadenoma can be distinguished from lympho- epithelial sialadenitis by the circumscribed borders and presence of a proliferated epithelial component. It can also potentially be mistaken for metastatic adeno- carcinoma in lymph node; the distinguishing features are lack of sinuses in the lymphoid tissue and lack of definite nuclear atypia.
Lipoadenoma (sialolipoma)
Lipoadenoma, also known as sialolipoma, is a benign tumour consisting of adipose tissue admixed with variable amounts of adenomatous glands. It affects patients of a wide age range, with male predilection.
The tumour presents as a slowly growing mass lesion in the major or minor salivary gland. Complete excision is curative.
Histologically, the tumour is thinly encapsulated or circumscribed. It comprises mature adipose cells and proliferated glandular tissue, with the former usually constituting > 90% of the tumour. The glandular component is sharply demarcated from the fat, and comprises duct-acinar units or proliferated glands, which may take the form of sertoliform tubules.
Oncocytic change, ductal dilation with fibrosis, seba- ceous differentiation or squamous metaplasia can occur in some cases.53–57 It is unclear whether the glandular component represents entrapped salivary tissue or an integral part of the tumour.
Adenofibroma
Adenofibroma is a very rare neoplasm characterized by an intimate admixture of adenomatous glands and a fibrocellular stroma. The adenomatous glands can show metaplastic changes (such as oncocytic meta- A
B
Figure 7. Lymphadenoma. A, The tumour is well circumscribed and clearly demarcated from the surrounding parotid gland (left field).
It comprises anastomosing trabeculae of epithelial cells lying in a lymphoid cell-rich stroma. B, The tumour cells in the trabeculae show mildly atypical pale-staining nuclei. In between are numerous small lymphocytes and plasma cells.
plasia) or cystic dilation. The stroma comprises delicate spindly cells with uniform nuclei. These spindly cells are CD34+ and lack myoepithelial features (S100-, actin- and p63-negative).
c r i b r i f o r m a d e n o c a r c i n o m a o f t h e t o n g u e In 1999, Michal et al. described eight cases of an unusual carcinoma of the tongue designated ‘cribri- form adenocarcinoma’.58 Histologically, this is an infiltrative tumour exhibiting diverse growth patterns, including solid, microcystic, follicular, cribriform and papillary. The tumour cells are bland looking and possess uniform, often overlapping, nuclei with vesic- ular or ‘ground-glass’ chromatin (Figure 8). There is no significant mitotic activity, necrosis or haemor- rhage.
It is currently unclear whether this is a distinctive tumour type or merely a morphological variant of polymorphous low-grade adenocarcinoma.59However, in contrast to the latter, this tumour occurs exclusively in the base of tongue and the frequency of cervical lymph node metastasis at presentation is much higher (100%).
s i g n e t - r i n g c e l l ( m u c i n - p r o d u c i n g )
a d e n o c a r c i n o m a o f m i n o r s a l i v a r y g l a n d Clinical features
An uncommon signet ring cell adenocarcinoma of the minor salivary gland has recently been characterized.60 The mean age of patients is 56.4 years with a female predilection. All reported cases have occurred in the minor salivary glands of the oral cavity, in the form of
an exophytic mass that can be fixed to the underlying tissue. Surprisingly, this behaves as a low-grade malignant neoplasm, with no recurrence or metastasis after excision.
Pathological features
The tumour is infiltrative and comprises narrow parallel strands, randomly scattered small nests or isolated cells.
Signet ring cells predominate and possess single or several cytoplasmic mucin vacuoles and eccentric indented nuclei. There are admixed minor populations of tumour cells with eosinophilic or clear cytoplasm. The overall cytological atypia is very mild. Mitotic figures are rare or absent, and there is no necrosis. Extracellular mucin pools are seen in only one of seven reported cases.60Perineural invasion is not uncommon.
Known tumour entities with new findings
s a l i v a r y d u c t c a r c i n o m a
A number of morphological variants of salivary duct carcinoma have recently been described. These vari- ants will not usually pose problems in diagnosis because a component of classical salivary duct carcin- oma is always present at least focally.
Mucin-rich variant
The mucin-rich variant features areas of mucinous⁄ colloid carcinoma in which clusters of carcinoma cells, with or without cytoplasmic mucin, float in mucin pools.61
Invasive micropapillary variant
The micropapillary variant is characterized by morule- like tumour cell clusters without fibrovascular cores, surrounded by a clear space, morphologically similar to the micropapillary variant of breast or urothelial carcinoma (Figure 9A). This variant appears to pursue an even more aggressive course than conventional salivary duct carcinoma.62
Sarcomatoid variant
In addition to a component of typical salivary duct carcinoma, there is an admixed sarcomatoid compo- nent comprising anaplastic spindly cells, bizarre multi- nucleated giant cells, rhabdoid cells and, rarely, osteosarcomatous cells (Figure 9B).63,64 These ana- plastic cells frequently demonstrate focal immunohisto- chemical and ultrastructural evidence of epithelial differentiation.65,66 Conceptually, we consider this variant a form of dedifferentiation of salivary duct carcinoma.
Figure 8. Cribriform adenocarcinoma of the tongue. The tumour is characterized by invasive cribriform islands comprising cells with uniform pale-staining nuclei and low mitotic activity—cytologically very similar to polymorphous low-grade adenocarcinoma.
i n t r a d u c t a l c a r c i n o m a : t h e c o n t r o v e r s i e s i n t e r m i n o l o g y
Intraductal carcinoma, first described by Chen in 1983,67is not a recognized entity in the 2005 World Health Organization (WHO) classification.68It is char- acterized by pure intraductal proliferation of tumour cells, similar to intraductal carcinoma of the breast.
The concept of intraductal carcinoma has not gained wide acceptance, probably because some salivary duct carcinomas with apparently pure intraductal-like growth still pursue an aggressive course, and an intraductal-like component can sometimes be found in the metastases. However, these observations can be attributable to the indiscriminate use of the term
‘intraductal-like’—such foci usually represent invasive growth rather than genuine in situ growth.
Strictly defined by the presence of an intact myoepit- helial layer around all tumour islands, intraductal carcinoma of the salivary gland represents a tumour of low malignant potential, with behaviour similar to that of the mammary counterpart.69This tumour has often been reported in the literature under the designation
‘low-grade salivary duct carcinoma’.70,71In fact, most cases of ‘low-grade salivary duct carcinoma’ are either pure intraductal carcinoma or intraductal carcinoma with microinvasion. The term ‘intraductal carcinoma’ is more appropriate than ‘low-grade salivary duct carci- noma’, because it emphasizes the fundamental nature of the tumour and avoids potential confusion with the vastly more aggressive salivary duct carcinoma. The term ‘low-grade cribriform cystadenocarcinoma’ adop- ted in the new WHO classification introduces more confusion72and we do not recommend adoption of this terminology, a view also shared by Weinreb et al.52,73 Whether intraductal carcinoma represents the precur- sor of conventional salivary duct carcinoma or is biologically a separate entity remains to be clarified.
Clinical features
Similar to salivary duct carcinoma, intraductal carcin- oma most frequently affects the parotid gland of the elderly. The minor salivary glands can also be affec- ted.69The outcome is excellent after complete excision, with no metastasis or mortality on follow-up, irres- pective of nuclear grade. Recurrence can occur as a result of incomplete resection. Given time, an invasive component can supervene.70,73
Pathological features
The tumour is characterized by multiple smooth- contoured ducts expanded by epithelial proliferation forming cribriform, fenestrated, solid-comedo, micro- papillary or Roman-bridge patterns, similar to the architectural patterns observed in atypical ductal hyperplasia or intraductal carcinoma of the breast (Figure 10A). The constituent cells usually show low to intermediate grade, but sometimes high-grade, cytological atypia (Figure 10B). They can also show apocrine features.73 The attenuated layer of myo- epithelial cells around the cell islands may or may not be evident on light microscopy. The stroma is sclerotic and may exhibit secondary changes such as haemorr- hage, chronic inflammatory infiltrate and dystrophic calcification.
In occasional cases, a microscopic invasive compo- nent is present, either at presentation or in recur- rence.70,74 The clinical significance of microinvasion remains uncertain, but the prognosis appears favourable.
A
B
Figure 9. Variants of salivary duct carcinoma. A, Micropapillary variant. B, Sarcomatoid variant. The component of conventional salivary duct carcinoma is seen in the left field. The sarcomatoid component in the right field comprises plump spindly cells with highly pleomorphic nuclei and high mitotic activity.
Prerequisites of diagnosis
To render a diagnosis of intraductal carcinoma, the presence of an invasive component must be meticu- lously ruled out by complete sampling and immuno- histochemistry to demonstrate an intact myoepithelial layer around every tumour island (Figure 11).69,73
m u c o e p i d e r m o i d c a r c i n o m a Grading
Many attempts have been made to grade mucoepi- dermoid carcinoma to stratify patients into groups with different prognoses. Traditionally, mucoepider- moid carcinoma is subdivided into low grade, inter- mediate grade and high grade based on several morphological parameters, including prominence of cysts, abundance of mucus cells, mitotic activity and cytological atypia.75,76 Evans has proposed a sim-
pler two-tier grading system, assigning a case to low grade or high grade based on the presence of
> 10% and < 10% intracystic spaces, respectively, excluding areas occupied by stroma and extravasated mucus.77
The Armed Forces Institute of Pathology (AFIP) scoring system assigns scores to five features: intra- cystic component < 20% (score 2), neural invasion (score 2), necrosis (score 3), mitoses ‡ 4 ⁄ 10 high- power fields (score 3) and anaplasia (score 4); and a case is categorized as low grade (score 0–4), inter- mediate grade (score 5–6) or high grade (score ‡ 7) based on the total score. This system shows good correlation with outcome for intraoral and parotid mucoepidermoid carcinomas, but does not predict outcome for submandibular mucoepidermoid carcin- omas, which have a significant metastatic potential irrespective of histological grade.78,79However, there is a tendency for the AFIP scoring system to ‘under- grade’ mucoepidermoid carcinomas. A modified grading system adding three parameters (lymphovas- cular invasion, bone invasion and invasion in the form of small nests and islands) improves the reproduci- bility and predictability, and furthermore stratifies patients into three fairly uniform groups with different prognoses.80
Oncocytic variant
The rare oncocytic variant of mucoepidermoid car- cinoma, characterized by the extensive presence of oncocytic cells, can potentially be misdiagnosed as oncocytoma (Figure 12).81–85 Oncocytoma is usually composed of a pure population of cells, although some cells may show cytoplasmic clearing. The presence of A
B
Figure 10. Intraductal carcinoma of salivary gland. A, In this parotid gland, there are focal collections of glands and cysts showing micropapillary or cribriform epithelial proliferation, reminiscent of intraductal carcinoma of breast. B, The proliferated epithelial cells show moderately pleomorphic nuclei and eosinophilic cytoplasm.
Figure 11. Intraductal carcinoma of salivary gland. On immuno- histochemistry, all tumour islands are surrounded by actin- positive myoepithelial cells, indicating that the neoplastic process is in situ.
cytoplasmic mucin and mucin-containing cystic spa- ces, or the presence of occasional non-oncocytic tumour islands, makes a diagnosis of oncocytoma most unlikely—the possibility of an oncocytic variant of mucoepidermoid carcinoma has to be seriously consid- ered in such circumstances.
e p i t h e l i a l m y o e p i t h e l i a l c a r c i n o m a
Recent studies have broadened the morphological spectrum of epithelial–myoepithelial carcinoma.86 Oncocytic variant
Rare cases can exhibit extensive oncocytic change in the luminal cells alone or in both the luminal and abluminal cells.86,87Some of these cases may show a prominent papillary growth pattern and there can be sebaceous cell differentiation.86
Double clear variant
The double-clear variant is characterized by clear cell change not only in the abluminal myoepithelial cells, but also in luminal cells.86 When the epithelial com- ponent shows proliferation to form solid or cribriform architecture, it can be difficult to distinguish on morphological grounds between epithelial and myo- epithelial cells.
Ancient change
The myoepithelial component in epithelial–myoepithel- ial carcinoma can exhibit ‘ancient change’—occasional nuclei have enlarged hyperchromatic nuclei.86In con-
trast to dedifferentiation or high-grade transformation, the chromatin is smudged, the cytological atypia is random (i.e. occurring in a background of non-bizarre nuclei) and there is no increase in mitotic activity.
Other morphological features
Although myoepithelial cells with clear cytoplasm have been emphasized as a hallmark of epithelial–myoepit- helial carcinoma, clear cell change may be completely lacking in about 20% of cases.86 Sebaceous differenti- ation is described in up to 13.1% of cases.86Although it is known that the myoepithelial component can occasionally form spindly cells, exceptionally the nuclei can be palisaded, resulting in resemblance to Verocay bodies.86
Progression of epithelial–myoepithelial carcinoma
There are two forms of progression of epithelial–
myoepithelial carcinoma. The first is progression to high-grade myoepithelial carcinoma, characterized by overgrowth of the myoepithelial component with nuclear anaplasia (Figure 13). This phenomenon has also been reported as ‘epithelial–myoepithelial car- cinoma with myoepithelial anaplasia’ or defined as nuclear atypia in > 20% of myoepithelial cells.86,88The prognosis is worsened.
The second is dedifferentiation to high-grade car- cinoma lacking evidence of myoepithelial differenti- ation.86,89The dedifferentiated component shows high mitotic activity, and necrosis is common. The prognosis is greatly worsened.90
s m a l l c e l l c a r c i n o m a
Small cell carcinoma of the major salivary glands is an aggressive malignancy, with more than half of patients developing local recurrence or distant metastasis.91 The overall survival rate is 40–50%,92–95comparable to that of cutaneous Merkel cell carcinoma, but much superior to that of conventional pulmonary or non- pulmonary small cell carcinoma. Indeed, 73% of salivary gland small cell carcinomas express CK20, suggesting that the majority of cases are biologically related to Merkel cell carcinoma rather than pulmon- ary-type small cell carcinoma.96,97The Merkel cell type of small cell carcinoma also demonstrates longer overall survival than the pulmonary type (CK20–).96
e x t r a n o d a l m a r g i n a l z o n e b - c e l l l y m p h o m a o f s a l i v a r y g l a n d
The commonest type of primary salivary gland lym- phoma is extranodal marginal zone B-cell lymphoma of
Figure 12. Mucoepidermoid carcinoma, oncocytic variant. The tumour resembles oncocytoma by virtue of the growth pattern in the form of trabeculae and packets, and the predominance of oncocytic cells. Focally, as shown in this field, the presence of interspersed cysts and mucinous cells renders a diagnosis of oncocytoma most unlikely, but should rather raise the possibility of mucoepidermoid carcinoma.
mucosa-associated lymphoid tissue (MALT) type. Four distinctive types of chromosomal translocation are now recognized in this type of lymphoma:
t(11;18)(q21;q21): API2⁄ MALT1 t(1;14)(p22;q32): BCL10⁄ IGH t(14;18)(q32;q21): IGH⁄ MALT1 t(3;14)(p14.1; q32): FOXP1⁄ IGH.
Although these appear to be diverse types of chromosomal translocation, the final common path- way involves activation of nuclear factor-jB. These chromosomal translocations display organ specificity.
For example, t(11;18) is seen predominantly in MALT lymphomas of the gastrointestinal tract and
lung, but is very rare in MALT lymphomas at other sites. Among salivary gland MALT lymphomas, 12–22% of cases exhibit t(14;18)(q32;q21), whereas the other three types of chromosomal translocation are practically never found.98,99Interestingly, a study from North America failed to detect t(14;18) in salivary gland MALT lymphomas; the only common abnormality found in that study was trisomy 18.100 On the other hand, t(14;18)(q32;q21) is not uncom- monly found in MALT lymphomas of the eye, skin and liver. The reason for this organ specificity remains elusive.
c h r o n i c s c l e r o s i n g s i a l a d e n i t i s ( k u t t n e r t u m o u r )
New concept of the nature of chronic sclerosing sialadenitis Chronic sclerosing sialadenitis affects almost exclu- sively the submandibular glands and is called Kuttner tumour in its advanced stage, as it presents clinically as a hard swelling indistinguishable from a tumour.101 The disease can be bilateral. Patients are usually middle-aged or elderly and there is slight male pre- dominance.102–104
For many years, chronic sclerosing sialadenitis has been considered a chronic inflammatory disease result- ing from inspissated secretion, stones or microliths, and perpetuated by ascending infection.102–104Recent studies, however, have raised a different pathogenic mechanism for this disease—chronic sclerosing sia- ladenitis belongs to the spectrum of IgG4-related sclerosing disease.105 IgG4-related sclerosing disease is a syndrome characterized by involvement of one or more tissues (most commonly exocrine organs) by a chronic inflammatory cell infiltrate which includes abundant IgG4+ plasma cells, accompanied by atrophy of the normal tissue and sclerosis.106 Some patients have associated autoimmune disease (such as rheuma- toid arthritis) or circulating autoantibodies. The serum IgG4, IgG and IgG4⁄ IgG ratio (normally 3–6%) are typically elevated and there is an excellent response to steroid therapy.
Pathology
The histological features of chronic sclerosing sialade- nitis are very similar to those of autoimmune pancre- atitis, which is a common component of IgG4-related sclerosing disease.102,104 The lobular architecture is preserved and the degree of involvement varies from lobule to lobule. In the early stages, lymphoplasma- cytic infiltrate commences around the salivary ducts, followed by periductal fibrosis. The ducts may con- tain inspissated secretion. The lymphocytic infiltrate A
B
Figure 13. Epithelial–myoepithelial carcinoma with progression to myoepithelial carcinoma. A, Parts of the tumour show typical features of epithelial–myoepithelial carcinoma. B, Other parts of the tumour show large islands and sheets of cells with larger and more pleomorphic nuclei. There is only one cell population, and myoepit- helial differentiation can be demonstrated immunohistochemically.
and fibrosis intensify and gradually involve the whole lobule, associated with atrophy of the acini (Figure 14A). Reactive lymphoid follicles are frequently present.
On immunohistochemistry, T cells predominate and show an intimate relationship with ducts and acini. B cells are mostly restricted to the lymphoid follicles.107 Abundant IgG4+ plasma cells are present (Figure 14B).105
We have described a case of chronic sclerosing sialadenitis featuring a few abnormal lymphoid follicles packed with signet ring cells of the cytoplasmic globular type, suggestive of incipient follicular lymphoma.102A case of extranodal marginal zone B-cell lymphoma of MALT type complicating chronic sclerosing sialadenitis
has also been reported.108 Thus, it appears that lymphoma can rarely emerge in the setting of chronic inflammation in chronic sclerosing sialadenitis.
Progression in salivary gland tumours
Tumour development or progression is a multistep process, often involving sequential accumulation of genetic changes. Salivary gland tumours provide a great opportunity to elucidate the mechanisms of tumour progression because of: (i) the complexity of cytoarchitecture of salivary gland tumours; and (ii) the existence of many different types of indolent tumours, which provide the ‘soil’ for accumulation of new mutations and hence tumour progression (risk increas- ing with duration of harbouring the tumour). The various forms of progression of salivary gland tumours are depicted in Figures 15–18.
c a r c i n o m a e x p l e o m o r p h i c a d e n o m a : w h a t ’ s n e w ?
Evolution of carcinoma ex pleomorphic adenoma
Sequential evolution can sometimes be traced in the development of carcinoma ex pleomorphic adenoma, and these different phases have prognostic significance.
1 In the earliest phase, carcinoma cells with large atypical nuclei replace the neoplastic ductal luminal cells while retaining an intact layer of non-atypical myoepithelial cells of the pre-existing pleomorphic adenoma (Figure 19). This can be considered a form of
‘carcinoma in situ’, and there is no metastatic potential.
2 With time, the carcinoma cells break out from the confines of the neoplastic myoepithelial sheath and invade into the surrounding stroma. If this process is still A
B
Figure 14. Kuttner tumour (chronic sclerosing sialadenitis) of sub- mandibular gland. A, The gland is heavily infiltrated by lymphocytes and plasma cells, accompanied by loss of acini and periductal sclerosis. There is an increase of delicate collagen fibres in the lobules, in addition to sclerosis of the lobular septa (not shown). A reactive lymphoid follicle is seen in the left upper field. B, There is a marked increase of IgG4+ plasma cells on immunohistochemistry.
Malignant transformation
Benign Malignant
Pleomorphic adenoma Carcinoma ex pleomorphic adenoma Basal cell adenoma Carcinoma ex basal cell adenoma
(including basal cell adenocarcinoma) Myoepithelioma Myoepithelial carcinoma
Warthin tumour Various types of carcinoma Oncocytoma Oncocytic carcinoma
Figure 15. Progression of salivary gland tumours: malignant transformation.
confined within the parent pleomorphic adenoma, the carcinoma is considered ‘intracapsular’ (Figure 20).
The prognosis is excellent with complete excision. There has been no metastasis,109–111except for a single case report with cervical lymph node metastasis.112
3 If the invasion extends beyond the fibrous capsule of the parent pleomorphic adenoma, the carcinoma ex pleomorphic adenoma is considered ‘invasive’. How- ever, it should be further categorized as being ‘minimally invasive’ or ‘frankly invasive’, although the optimal cut-off point to define minimally invasive carcinoma (tumour with minimal metastatic potential) is currently unsettled. In several series, excellent prognosis has been found in tumours with extracapsular invasion measur- Progression to high grade
Low grade carcinoma
Higher grade carcinoma
Adenoid cystic carcinoma Mucoepidermoid carcinoma Epithelial–myoepithelial carcinoma (progressing to myoepithelial carcinoma)
Figure 16. Progression of salivary gland tumours: progression from low grade to high grade.
Dedifferentiation
Carcinoma
High grade carcinoma with loss of original line of differentiation
Acinic cell carcinoma Adenoid cystic carcinoma
Polymorphous low grade adenocarcinoma Mucoepidermoid carcinoma
Epithelial–myoepithelial carcinoma Myoepithelial carcinoma
Salivary duct carcinoma
Figure 17. Progression of salivary gland tumours: dedifferentiation.
Stromal invasion
In-situ carcinoma Invasive carcinoma
Intraductal carcinoma (low or high grade)
Salivary duct carcinoma Intraductal carcinoma with microinvasion Figure 18. Progression of salivary gland tumours: stromal invasion.
A
B
Figure 19. Carcinoma in situ ex pleomorphic adenoma. A, The pre- existing pleomorphic adenoma, with tubules merging into a myxoid stroma, is seen in the left upper field. In situ carcinomatous change is seen in the lower field. B, The malignant cells show significant nuclear pleomorphism and prominent nucleoli, replacing the original luminal cells of the pleomorphic adenoma. These cells are still enveloped by neoplastic myoepithelial cells of the pre-existing pleomorphic adenoma.
ing < 8 mm, 5 mm or 1.5 mm beyond the capsule, respectively.109,110,113In the current WHO classifica- tion, tumours with invasion of < 1.5 mm from the tumour capsule are considered minimally invasive.114 In practice, although it is easy to make the measure- ments in some cases, it can be extremely difficult to do so in others due to difficulties in defining the boundaries of the parent pleomorphic adenoma.
Cell types that undergo malignant change in pleomorphic adenoma
In most cases (75%), luminal epithelial cells undergo malignant change. In the other cases, the supervening carcinoma shows dual epithelial–myoepithelial differ- entiation (19% of cases) or pure myoepithelial differ- entiation (6% of cases).115
Genetic mechanisms mediating malignant transformation Alterations or rearrangements of chromosome 8q21 and 12q13-15 are frequent in carcinoma ex pleomor- phic adenoma, similar to its benign counterpart. Loss of heterozygosity at 12q loci may identify a subset of pleomorphic adenomas with a potential for malignant transformation.116 Amplification and overexpression of genes in chromosome 12q13-15, including CDK4, HMGA2 and MDM2, may represent important genetic events in the malignant transformation.117,118
Alterations of p53 gene are found in 29–67% and p53 protein overexpression in 41–75% of cases, suggesting that the gene may play a role in transfor- mation in at least some cases.110,119–123
c-erbB2 overexpression or gene amplification occurs in 21–82% of cases.110,124–127
It has been suggested that immunopositivity for c-erbB2 may aid in distin- guishing carcinoma ex pleomorphic adenoma from atypical pleomorphic adenoma (Figure 21).123,125,127
d e d i f f e r e n t i a t i o n o f s a l i v a r y g l a n d c a r c i n o m a s
‘Dedifferentiation’ refers to the transformation of a salivary gland carcinoma to a high-grade carcinoma in which the original line of differentiation is no longer evident. The first type of salivary gland carcinoma reported to undergo dedifferentiation is acinic cell carcinoma. The dedifferentiated component takes the form of a high-grade adenocarcinoma, poorly differen- tiated carcinoma or undifferentiated carcinoma.128–130 In recent years, a wide variety of other types of salivary gland carcinoma have been documented to A
B
Figure 20. Intracapsular carcinoma ex pleomorphic adenoma.
A, Cords and islands of malignant cells infiltrate the stroma of the pleomorphic adenoma. B, Since the carcinoma is still confined within the parent pleomorphic adenoma, without breaching the original tumour capsule, this is considered ‘intracapsular’ and there is practically no metastatic potential.
Figure 21. Carcinoma ex pleomorphic adenoma. Immunohisto- chemistry for c-erbB2 selectively highlights the malignant cells that are still enveloped by residual neoplastic myoepithelial cells.
show dedifferentiation, although this is still an uncom- mon event (Figure 17). Examples are: mucoepidermoid carcinoma,131 adenoid cystic carcinoma,130,132–134
myoepithelial carcinoma,135 polymorphous low-grade adenocarcinoma,136,137 epithelial–myoepithelial car- cinoma,86,90,138–140hyalinizing clear cell carcinoma141 and salivary duct carcinoma.63–66All of these tumour types, with the exception of salivary duct carcinoma, are generally indolent tumours to begin with. New genetic alterations probably gradually accumulate in these indolent tumours, eventuating in the emergence of a high-grade aneuploid carcinoma.
Clinical features
Dedifferentiation of salivary gland carcinoma can occur either at initial presentation or at relapse. Clinically, there is usually recent onset of rapid tumour growth in a long-standing tumour, often resulting in bulky disease. Some cases present with a rapidly growing mass on relapse of a low-grade carcinoma. Recurrence and metastasis are common. The prognosis is generally very poor, with an accelerated clinical course com- pared with the original carcinoma type.
Common pathological features
The dedifferentiated component, which can be in the form of high-grade adenocarcinoma, undifferentiated carcinoma or sarcomatoid carcinoma, usually shows more frankly invasive growth and prominent coagu- lative necrosis (Figure 22). The neoplastic cells exhibit significant nuclear atypia, pleomorphism and brisk
mitotic activity. Usually the original carcinoma and dedifferentiated components are juxtaposed to each other without a transitional zone.
Genetic changes that mediate dedifferentiation
Our knowledge of the molecular mechanisms respon- sible for dedifferentiation of salivary gland carcinoma is limited. In some cases, involvement of one or several genes has been documented. Examples include p53 mutation (accompanied by strong expression of p53 protein), increased cyclin D1 expression, c-erbB2 pro- tein overexpression or gene amplification, and loss of expression of Rb protein.132–135,140,142
References
1. Mino M, Pilch BZ, Faquin WC. Expression of KIT (CD117) in neoplasms of the head and neck: an ancillary marker for adenoid cystic carcinoma. Mod. Pathol. 2003; 16; 1224–
1231.
2. Edwards PC, Bhuiya T, Kelsch RD. C-kit expression in the salivary gland neoplasms adenoid cystic carcinoma, polymor- phous low-grade adenocarcinoma, and monomorphic adenoma.
Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2003; 95;
586–593.
3. Hotte SJ, Winquist EW, Lamont E et al. Imatinib mesylate in patients with adenoid cystic cancers of the salivary glands expressing c-kit: a Princess Margaret Hospital phase II consor- tium study. J. Clin. Oncol. 2005; 23; 585–590.
4. Edwards PC, Bhuiya T, Kelsch RD. Assessment of p63 expression in the salivary gland neoplasms adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, and basal cell and canalicular adenomas. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2004; 97; 613–619.
5. Bailey CM, Khalkhali-Ellis Z, Seftor EA, Hendrix MJ. Biological functions of maspin. J. Cell Physiol. 2006; 209; 617–624.
6. Navarro Rde L, Martins MT, de Araujo VC. Maspin expression in normal and neoplastic salivary gland. J. Oral Pathol. Med.
2004; 33; 435–440.
7. Nakagawa M, Katakura H, Adachi M et al. Maspin expression and its clinical significance in non-small cell lung cancer.
Ann. Surg. Oncol. 2006; 13; 1517–1523.
8. Umekita Y, Souda M, Yoshida H. Expression of maspin in colorectal cancer. In Vivo 2006; 20; 797–800.
9. Cho JH, Kim HS, Park CS et al. Maspin expression in early oral tongue cancer and its relation to expression of mutant-type p53 and vascular endothelial growth factor (VEGF). Oral Oncol.
2007; 43; 272–277.
10. Luukkaa H, Klemi P, Leivo I, Vahlberg T, Grenman R.
Prognostic significance of Ki-67 and p53 as tumor markers in salivary gland malignancies in Finland: an evaluation of 212 cases. Acta Oncol. 2006; 45; 669–675.
11. Steeg PS, Bevilacqua G, Kopper L et al. Evidence for a novel gene associated with low tumor metastatic potential. J. Natl Cancer Inst. 1988; 80; 200–204.
12. Tee YT, Chen GD, Lin LY, Ko JL, Wang PH. Nm23-H1: a metastasis-associated gene. Taiwan J. Obstet. Gynecol. 2006; 45;
107–113.
13. do Nascimento KC, de Faria PR, Dib LL et al. Immunohisto- chemical localization of the NM23 protein in salivary gland Figure 22. Dedifferentiated adenoid cystic carcinoma. The right field
shows typical adenoid cystic carcinoma growing in the form of tubules and cribriform structures comprising luminal and abluminal cells. The left field shows mitotically active, high-grade carcinoma comprising only a single cell type, and represents the dedifferentiated component.
neoplasms with distinct biological behavior. Virchows Arch.
2006; 449; 660–666.
14. Alos L, Lujan B, Castillo M et al. Expression of membrane- bound mucins (MUC1 and MUC4) and secreted mucins (MUC2, MUC5AC, MUC5B, MUC6 and MUC7) in mucoepidermoid carcinomas of salivary glands. Am. J. Surg. Pathol. 2005; 29;
806–813.
15. Handra-Luca A, Lamas G, Bertrand JC, Fouret P. MUC1, MUC2, MUC4, and MUC5AC expression in salivary gland mucoepi- dermoid carcinoma: diagnostic and prognostic implications.
Am. J. Surg. Pathol. 2005; 29; 881–889.
16. Woo VL, Bhuiya T, Kelsch R. Assessment of CD43 expression in adenoid cystic carcinomas, polymorphous low-grade adeno- carcinomas, and monomorphic adenomas. Oral Surg. Oral Med.
Oral Pathol. Oral Radiol. Endod. 2006; 102; 495–500.
17. Seethala RR, LiVolsi VA, Pasha TL, Zhang PJ. CD43 expression in adenoid cystic carcinomas. Mod. Pathol. 2004; 17 (Suppl. 1);
232A (Abstract).
18. Eveson JW, Kusafuka K, Stenman G, Nagao T. Pleomorphic adenoma. In Barnes L, Eveson JW, Reichart P, Sidransky D eds. World Health Organization classification of tumours.
Pathology and genetics of head and neck tumours. Lyon: IARC 2005; 254–258.
19. Bullerdiek J, Wobst G, Meyer-Bolte K et al. Cytogenetic subtyping of 220 salivary gland pleomorphic adenomas:
correlation to occurrence, histological subtype, and in vitro cellular behavior. Cancer Genet. Cytogenet. 1993; 65; 27–31.
20. Kas K, Voz ML, Roijer E et al. Promoter swapping between the genes for a novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations.
Nat. Genet. 1997; 15; 170–174.
21. Voz ML, Agten NS, Van de Ven WJ, Kas K. PLAG1, the main translocation target in pleomorphic adenoma of the salivary glands, is a positive regulator of IGF-II. Cancer Res. 2000; 60;
106–113.
22. Voz ML, Astrom AK, Kas K, Mark J, Stenman G, Van de Ven WJ. The recurrent translocation t(5;8)(p13;q12) in pleomor- phic adenomas results in upregulation of PLAG1 gene expres- sion under control of the LIFR promoter. Oncogene 1998; 16;
1409–1416.
23. Astrom AK, Voz ML, Kas K et al. Conserved mechanism of PLAG1 activation in salivary gland tumors with and without chromosome 8q12 abnormalities: identification of SII as a new fusion partner gene. Cancer Res. 1999; 59; 918–923.
24. Asp J, Persson F, Kost-Alimova M, Stenman G. CHCHD7–PLAG1 and TCEA1–PLAG1 gene fusions resulting from cryptic, intra- chromosomal 8q rearrangements in pleomorphic salivary gland adenomas. Genes Chromosomes Cancer 2006; 45; 820–828.
25. Geurts JM, Schoenmakers EF, Roijer E, Astrom AK, Stenman G, van de Ven WJ. Identification of NFIB as recurrent transloca- tion partner gene of HMGIC in pleomorphic adenomas.
Oncogene 1998; 16; 865–872.
26. Geurts JM, Schoenmakers EF, Roijer E, Stenman G, Van de Ven WJ. Expression of reciprocal hybrid transcripts of HMGIC and FHIT in a pleomorphic adenoma of the parotid gland.
Cancer Res. 1997; 57; 13–17.
27. Nordkvist A, Gustafsson H, Juberg-Ode M, Stenman G.
Recurrent rearrangements of 11q14-22 in mucoepidermoid carcinoma. Cancer Genet. Cytogenet. 1994; 74; 77–83.
28. Martins C, Cavaco B, Tonon G, Kaye FJ, Soares J, Fonseca I.
A study of MECT1-MAML2 in mucoepidermoid carcinoma and Warthin’s tumor of salivary glands. J. Mol. Diagn. 2004; 6;
205–210.
29. Tonon G, Modi S, Wu L et al. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat. Genet. 2003; 33;
208–213.
30. Behboudi A, Enlund F, Winnes M et al. Molecular classification of mucoepidermoid carcinomas—prognostic significance of the MECT1–MAML2 fusion oncogene. Genes Chromosomes Cancer 2006; 45; 470–481.
31. Bullerdiek J, Haubrich J, Meyer K, Bartnitzke S. Translocation t(11;19)(q21;p13.1) as the sole chromosome abnormality in a cystadenolymphoma (Warthin’s tumor) of the parotid gland.
Cancer Genet. Cytogenet. 1988; 35; 129–132.
32. Mark J, Dahlenfors R, Stenman G, Nordquist A. A human adenolymphoma showing the chromosomal aberrations del (7)(p12p14-15) and t(11;19)(q21;p12-13). Anticancer Res.
1989; 9; 1565–1566.
33. Enlund F, Behboudi A, Andren Y et al. Altered Notch signaling resulting from expression of a WAMTP1–MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin’s tumors.
Exp. Cell Res. 2004; 292; 21–28.
34. Frierson HF Jr, El-Naggar AK, Welsh JB et al. Large scale molecular analysis identifies genes with altered expression in salivary adenoid cystic carcinoma. Am. J. Pathol. 2002; 161;
1315–1323.
35. Stallmach I, Zenklusen P, Komminoth P et al. Loss of hetero- zygosity at chromosome 6q23-25 correlates with clinical and histologic parameters in salivary gland adenoid cystic carci- noma. Virchows Arch. 2002; 440; 77–84.
36. Smith BC, Ellis GL, Slater LJ, Foss RD. Sclerosing polycystic adenosis of major salivary glands. A clinicopathologic analysis of nine cases. Am. J. Surg. Pathol. 1996; 20; 161–170.
37. Gnepp DR. Sclerosing polycystic adenosis of the salivary gland:
a lesion that may be associated with dysplasia and carcinoma in situ. Adv. Anat. Pathol. 2003; 10; 218–222.
38. Batsakis JG. Sclerosing polycystic adenosis: newly recognized salivary gland lesion—a form of chronic sialadenitis. Adv. Anat.
Pathol. 1996; 3; 298–304.
39. Donath K, Seifert G. [Sclerosing polycystic sialadenopathy. A rare non-tumorous disease]. Pathologe 1997; 18; 368–373.
40. Kabani S, Gallagher G. Sclerosing polycystic adenosis (SPCA) of minor salivary glands. Oral Surg. Oral Med. Oral Pathol. Radiol.
Endod. 2002; 94; 187.
41. Skalova A, Michal M, Simpson RHW, Starek I, Pradna J, Pfaltz M. Sclerosing polycystic adenosis of parotid gland with dysplasia and ductal carcinoma in situ. Report of three cases with immunohistochemical and ultrastructural examination.
Virchows Arch. 2002; 440; 29–35.
42. Gnepp DR, Wang LJ, Brandwein-Gensler M, Slootweg P, Gill M, Hille J. Sclerosing polycystic adenosis of the salivary gland: a report of 16 cases. Am. J. Surg. Pathol. 2006; 30; 154–164.
43. Noonan VL, Kalmar JR, Allen CM, Gallagher GT, Kabani S.
Sclerosing polycystic adenosis of minor salivary glands: report of three cases and review of the literature. Oral Surg. Oral Med.
Oral Pathol. Oral Radiol. Endod. 2007; Epub ahead of print.
44. Skalova A, Gnepp DR, Simpson RH et al. Clonal nature of sclerosing polycystic adenosis of salivary glands demonstrated by using the polymorphism of the human androgen receptor (HUMARA) locus as a marker. Am. J. Surg. Pathol. 2006; 30; 939–944.
45. Chan JK, Albores-Saavedra J, Battifora H, Carcangiu ML, Rosai J. Sclerosing mucoepidermoid thyroid carcinoma with eosino- philia. A distinctive low-grade malignancy arising from the metaplastic follicles of Hashimoto’s thyroiditis. Am. J. Surg.
Pathol. 1991; 15; 438–448.
