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Salivary gland lesions: recent advances and evolving concepts Ruta Gupta, MD, FRCPA,a,b Deepak Balasubramanian, MS, DNB, MCh,c,d and Jonathan R. Clark, M.Biostat FRACSb,c,d Recently, there have been significant developments in our understanding of salivary gland pathology, and new entities, such as mammary analogue secretory carcinoma, have been described. Attempts are being made to identify effective therapeutic agents for salivary duct carcinomas by using molecular diagnostic techniques. Concepts such as high-grade transformation have been described, which not only influence macroscopic and microscopic evaluation of a specimen but, given the high incidence of metastases and morbidity, also carry significant treatment implications. Specific chromosomal translocations, which can be detected by fluorescent in situ hybridization, can augment diagnostic accuracy and carry prognostic implications. The landscape of benign salivary gland lesions is changing with better understanding of chronic sclerosing sialadenitis related to IgG4. This multiorgan inflammatory condition may primarily present as a salivary gland lesion and clinically and radiologically mimic a salivary gland malignancy. Histology and immunohistochemistry play a critical role in its accurate diagnosis. The purpose of this article is to review these changes, with an emphasis on their effect on patient management. Given their diagnostic, prognostic, and therapeutic implications, it is critical that surgeons, oncologists, pathologists, and those involved in caring for patients with salivary gland tumors are aware of these changes while considering management options. (Oral Surg Oral Med Oral Pathol Oral Radiol 2015;-:1-14)
The classification of salivary gland tumors is rapidly evolving with description of new entities, such as mammary analogue secretory carcinoma (MASC).1 Other entities, such as salivary duct carcinoma, are being increasingly recognized with improved understanding of their molecular characteristics.2,3 The concept of high-grade transformation has been described in adenoid cystic carcinoma, acinic cell carcinoma, and other salivary gland tumors.4,5 Furthermore, specific chromosomal translocations, which can be easily detected by fluorescent in situ hybridization (FISH), have been described in adenoid cystic carcinoma, mucoepidermoid carcinoma, MASC, and in the rare hyalinizing clear cell carcinoma.6-9 These chromosomal translocations may improve diagnostic accuracy and carry prognostic implications.6-10 Most of these changes are being fueled by increased use of ancillary diagnostic techniques and genetic sequencing. However, considering their diagnostic, prognostic, and therapeutic implications, it is critical that surgeons and
those involved in caring for patients with salivary gland tumors are aware of these changes while considering management options. Here, we review the changes in our understanding of salivary gland lesions, with an emphasis on their effect on patient management. We also look at the recently described disease in the salivary gland associated with immunoglobulin G4 (IgG4). Table I briefly summarizes both the conventionally recognized salivary gland tumors and the current evolution in salivary gland pathology.
NEW ENTITIES Mammary analogue secretory carcinoma MASC, a low-grade malignant neoplasm of the salivary gland, was described by Skalova et al. in 2010.1 Skalova et al. studied 16 examples of morphologically similar salivary gland tumors, which had been designated as zymogen granuleepoor acinic cell carcinomas in the past, and identified a specific, novel chromosomal translocation (ETV6-NRTK3 fusion gene; (12; 15) (p13; q25)).1 This rearrangement results
a
Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia. b Central Clinical School, University of Sydney, NSW 2006, Australia. c Sydney Head and Neck Cancer Institute, The Chris O’Brien Lifehouse, Missenden Road, Camperdown NSW 2050, Australia. d Department of Head and Neck Surgery, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia. Received for publication Jul 6, 2014; returned for revision Feb 7, 2015; accepted for publication Feb 20, 2015. Ó 2015 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2015.02.481
Statement of Clinical Relevance This article reviews the changes in salivary gland pathology, with an emphasis on their effect on diagnosis, prognosis, and patient management, and provides relevant information for surgeons, oncologists, and pathologists involved in caring for patients with salivary gland tumors. 1
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Table I. Current evolution in salivary gland pathology New entities a. Mammary analog secretory carcinoma b. Hyalinizing clear cell carcinoma c. IgG4-related chronic sclerosing sialadenitis
Old entities: new concepts a. Salivary duct carcinoma: Genetic alterations amenable to targeted therapy: -Her2 amplification in salivary duct carcinoma -BRAF mutations in salivary duct carcinoma b. Epithelialemyoepithelial carcinoma: improved recognition of a wide morphologic spectrum. c. High-grade transformation in: -Acinic cell carcinoma -Adenoid cystic carcinoma -Epithelialemyoepithelial carcinoma -Myoepithelial carcinoma -Mammary analog secretory carcinoma -Mucoepidermoid carcinoma
New ancillary diagnostic/prognostic/ predictive tests Chromosomal translocations of diagnostic or prognostic utility detectable by fluorescent in situ hybridization: -Mucoepidermoid carcinoma -Adenoid cystic carcinoma -Hyalinizing clear cell carcinoma -Mammary analog secretory carcinoma
IgG4, immunoglobulin G4.
in fusion of transcription regulator ETV6 with membrane receptor kinase NTRK3.1 MASCs show morphologic and molecular features similar to the secretory carcinomas of the breast, leading to the proposal of the nomenclature mammary analog secretory carcinoma.1,11,12 MASCs occur in men and women in both major and minor salivary glands. Previous diagnosis. These tumors were largely categorized as zymogen granuleepoor acinic cell carcinoma or rarely as mucoepidermoid carcinoma in the past.1,13 Histology, special stains, and immunohistochemistry. Macroscopically, MASCs are relatively well-defined, lobulated neoplasms with a cystic component (Figure 1A).1,14 These tumors show a solid, tubular or microcystic pattern (Figure 1B). The tubular and microcystic spaces contain thin eosinophilic, bubbly secretions. The lining polygonal cells show eosinophilic, granular, or vacuolated cytoplasm and a uniform central round nucleus with a single distinctive nucleolus1,4,14 (Figure 1C). Invasion into periglandular tissue has been described.1,14 Lymphovascular and perineural involvement, although rare, have been described.14 Special stains, such as periodic acid Schiff’s reagent following diastase digestion (DiPAS) (Figure 1D) and mucicarmine highlight the secretions. Immunohistochemically, the tumor cells show strong and diffuse positivity with S100 (Figure 1E), MUC4, and mammoglobin and lack immunoreactivity with squamous and myoepithelial markers, such as p63, calponin, and SMA.1 Diagnosis. PREOPERATIVE FINE-NEEDLE ASPIRATION. A definitive preoperative diagnosis is difficult, although there are case reports describing the cytologic features of MASC in fine-needle aspiration (FNA) specimens.
MASCs show several overlapping cytologic features with other low-grade salivary gland neoplasms, such as acinic cell carcinoma, low-grade mucoepidermoid carcinoma, and myoepithelial neoplasms.15,16 A cellblock with high cellular yield may facilitate special stains and discriminatory immunohistochemical panel. POSTOPERATIVE FINAL HISTOLOGIC DIAGNOSIS. Histologic diagnosis is relatively easily made in a resection specimen based on the morphologic features in conjunction with special stains and immunoreactivity for S100, MUC4, and mammoglobin.1,13,14,17 FISH studies for (ETV6NRTK3 fusion gene; (12; 15) (p13; q25)) (Figure 1F) are also available, if needed. The main differential diagnosis is acinic cell carcinoma. Distinction of acinic cell carcinoma from MASC is based on recognizing the presence of intracytoplasmic zymogenic granules in acinic cell carcinoma and their absence in MASC.18 Acinic cell carcinomas also lack immunoreactivity with S100 and MUC4. Lack of stromal matrix, spindle-shaped or clear cells, targetoid perineural invasion at the periphery, and a discriminatory immunohistochemical panel, as described above, comprising of S100, MUC4, p63, CK5/6, and calponin can help in distinguishing this entity from other low-grade myoepithelial neoplasms, mucoepidermoid carcinoma, and polymorphous lowgrade carcinoma, respectively.1,13,14 Management and prognosis. Prognostic information for MASC is still evolving. Historically, MASC has largely been classified as acinic cell carcinomas and has been considered a low-grade malignant neoplasm.13,14 Complete local resection constitutes adequate treatment. Although most tumors in the published series have shown an indolent behavior, a few local
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Fig. 1. A, Macroscopic appearance of mammary analogue secretory carcinoma. The tumor is well circumscribed, lobulated with solid and cystic components. B, Tumor surrounded by fibrous capsule. Infiltration into the capsule is seen. The tumor is composed of nests of cells with microcysts. The microcysts show presence of eosinophilic bubbly material (H&E, original magnification 20). C, The cells show indistinct cell membranes, vacuolated eosinophilic cytoplasm and relatively uniform nuclei with distinctive nucleoli. A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00504. D, Special stains with periodic acid Schiff’s reagent following diastase digestion show staining of the secretions and occasional intracytoplasmic globules (DiPAS, original magnification 20). E, Immunostaining with S100 shows strong diffuse immunoreactivity in the tumor cells. F, Fluorescent in situ hybridization (FISH) studies demonstrate ETV6 translocation from chromosome 12. The green signal demonstrates the centromeric (3’) end of ETV6 on chromosome 12, and the red signal demonstrates telemeric (5’) end of ETV6 on chromosome 12. Under normal circumstances, the green and the red signals are closely placed and often overlap producing a yellow signal. A split in the red and the green signals (white arrows) demonstrates translocation of ETV6 region.
recurrences and lymph node metastases have been described, some after a period of 7 to 8 years.1 Chiosea et al. in their study of 60 conventional acinic cell carcinomas and 10 MASCs reported an increased incidence of lymph node metastases in the latter.13 Thus, long-term follow-up is useful. Also, the role of adjuvant radiotherapy in managing various adverse features, such as incomplete resection and lymphovascular or perineural invasion, has not been formally evaluated in MASC to date. Hyalinizing clear cell carcinoma of the salivary gland The specific terminology of hyalinizing clear cell carcinoma was first introduced by Milchgrub in 1994.19 However, many authors have recognized and described this entity in the past, most often as “clear cell carcinoma.”20 Although the World Health Organization 2005 classification system21 categorizes these tumors as clear cell carcinoma, not otherwise classified, the identification of a specific translocation (EWSR1-ATF1 fusion t(12; 22) (q13; q12)) indicates
that these rare tumors are a distinct entity.9 Hyalinizing clear cell carcinomas have an equal incidence in both genders and arise predominantly in minor salivary gland tissue of the palate, tongue base, and the oral cavity.19 Histology, special stains, and immunohistochemistry. Macroscopically, hyalinizing clear cell carcinomas are relatively well-circumscribed, lobulated neoplasms. Histologically, as the name suggests, this tumor is composed of nests, trabaculae, and cords of cells, with clear cytoplasm embedded in dense eosinophilic hyaline stroma (Figure 2A). The cells typically show clear cytoplasm with relatively small uniform nuclei. Mitoses, although present, are rare, and necrosis is unusual. Perineural invasion has been described.22 The cytoplasmic clearing results from the presence of glycogen. This can be confirmed with special stains for periodic acid Schiff’s reagent which shows intracytoplasmic intensely pink granular material (Figure 2B). This intracytoplasmic pink appearance is lost following digestion of glycogen with diastase (see Figure 2B, inset). Immunohistochemically,
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Fig. 2. A, Hyalinizing clear cell carcinoma of the salivary gland comprising nests and trabaculae of cells with clear cytoplasm embedded in hyaline stroma (H&E, original magnification 20). B, Special stains with periodic acid Schiff’s reagent highlight the intracytoplasmic glycogen (PAS, original magnification 10). The intracytoplasmic glycogen disappears following digestion with diastase (inset, DiPAS, original magnification 20). C, Fluorescent in situ hybridization (FISH) studies demonstrate EWSR1 translocation from chromosome 22. The green signal demonstrates the centromeric end of EWSR1 on chromosome 22, and the red signal demonstrates the telomeric end of EWSR1 on chromosome 22. Under normal circumstances, the green and the red signals are closely placed and often overlap producing a yellow signal. A split in the red and the green signals (white arrows) demonstrates translocation of EWSR1 region.
hyalinizing clear cell carcinomas of the salivary gland show strong immunoreactivity with pancytokeratin, high-molecular-weight cytokeratins, and p63. These tumors are negative for myoepithelial stains, such as calponin, S100, SMA, and so on.23 Differential diagnoses include a range of primary salivary gland and metastatic neoplasms showing a combination of cells with clear cytoplasm and hyalinized stroma. Thus, hyalinizing clear cell carcinoma needs to be distinguished from clear cell variants of oncocytoma, myoepithelioma, mucoepidermoid carcinoma, myoepithelial carcinoma, acinic cell carcinoma, and metastatic clear cell renal cell carcinoma. Of these, hyalinizing clear cell carcinoma shows similar immunohistochemical profile as mucoepidermoid carcinoma and squamous cell carcinoma.24 A consistent chromosomal translocation (EWSR1-ATF1 fusion t(12; 22) (q13; q12)) has been described in approximately 82% to 93% of hyalinizing clear cell carcinoma and is of great diagnostic utility in confirming the diagnosis and distinguishing these rare tumors from their more common mimics (Figure 2C).9 Clear cell odontogenic carcinomas arising in the jaw show similar morphologic and immunohistochemical profiles as that of hyalinizing clear cell carcinoma. These tumors also show (EWSR1-ATF1 fusion t(12; 22) (q13; q12)) and are now considered to represent the odontogenic analogs of hyalinizing clear cell carcinoma.25 Management and prognosis. Hyalinizing clear cell carcinomas are considered low-grade and most show an indolent course. However, perineural invasion and recurrence have been reported in approximately 12% to 17% cases with occasional neck metastases.9,23,26
Resection forms the mainstay of the treatment; however, radiotherapy has been used as the primary modality for patients with tongue base tumors. Standard management guidelines for these rare tumors are lacking; however, overall, they have a good prognosis.23 IgG4-related chronic sclerosing sialadenitis IgG4-related disease is a multiorgan inflammatory disease, in which diverse manifestations are linked by a common pathogenesis and similar histopathologic and immunohistochemical features.27-29 IgG4-related diseases encompass a systemic chronic relapsing disorder affecting men in their 60s to 70s.28 This condition may affect any organ in the body but most commonly involves the pancreaticobiliary tree, salivary glands, lacrimal glands, and periorbital tissues.29 Previous terminology. The manifestations were variously designated as autoimmune pancreatitis, Mikulicz disease, Kuttner tumor, multifocal fibrosclerosis, and eosinophilic angiocentric fibrosis before the pathologic mechanisms and evolution of the condition were understood.30 Diagnosis. In the context of salivary gland lesions, most patients present with a bilateral, nontender, firm enlargement of the salivary glands, particularly the submandibular gland.31 Although a history of obstructive jaundice or autoimmune pancreatitis is helpful for accurate diagnosis, the salivary gland disease may antedate the pancreatic involvement by an average of 2.5 years.31 Serologic investigations showing serum IgG4 elevation may be useful; however, approximately 50% of the patients show normal serum IgG4 levels.32
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Fig. 3. IgG4erelated chronic sclerosing sialadenitis involving the submandibular salivary gland. A, The lesion diffusely involves the salivary gland and has a gray white, fibrous appearance. B, Diffuse lymphoplasmacytic infiltrate. The lobular pattern of the salivary gland is retained (H&E, original magnification 10). C, Storiform, fibrocellular fibrosis with a whorled appearance (H&E, original magnification 10). D, Obliterative thrombophlebitis (H&E, original magnification 10), which is further highlighted by special stains for elastin (inset). The fibrosis and lymphoplasmacytic infiltrate may often encircle and entrap nerve bundles. E, The dense lymphoplasmacytic infiltrate predominantly comprises large numbers of plasma cells, mature T lymphocytes, eosinophils, and macrophages. A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00506. F, Immunostains for IgG. A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00507. IgG4 (inset) demonstrating and IgG4/IgG ratio of greater than 40%. A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00508.
Katsura et al. have described the radiologic findings of IgG4-related disease in the head and neck as having well-defined borders, T2 hypointensity on magnetic resonance imaging, a homogeneous and gradual enhancement pattern, and absence of vascular occlusion or compression.33 In addition, the lack of an obstructive sialolith or a discrete tumor mass may be helpful.31 Preoperative FNA. FNA is not useful and yields either lymphoplasmacytic population or an acellular aspirate, depending on the extent of sclerosis. Furthermore, there is insufficient evidence to support the use of FNA and cell block preparation in the diagnosis of IgG4-related disease.29 Histology and immunohistochemistry. Currently, histology is considered the gold standard for the diagnosis of IgG4-related disease. Macroscopically, the gland shows ill defined, diffuse firm white areas (Figure 3A). Histologic examination classically demonstrates (1) a dense lymphoplasmacytic infiltrate (Figure 3B), (2) storiform fibrosis (Figure 3C), and (3) obliterative phlebitis (Figure 3D).29,30,32 The dense lymphoplasmacytic infiltrate comprises predominantly of large numbers of polyclonal plasma
cells, mature T lymphocytes, eosinophils, and macrophages (Figure 3E).29 Neutrophils are sparse, and granulomata and necrosis are absent. An infective etiology should be considered if neutrophils, granulomata, and necrosis are present.29 Cellular storiform fibrosis is present, and obliterative phlebitis is seen with lymphocytes and plasma cells infiltrating the walls of a medium-sized vein.29 The fibrosis and lymphoplasmacytic infiltrate may often encircle and entrap nerve bundles (see Figure 3D). Immunohistochemistry for IgG4 provides confirmatory evidence in appropriate clinical and serologic contexts and becomes extremely critical at initial presentation and in cases with normal serum IgG4 levels. More than 100 IgG4 positive plasma cells per high-power field are required for a diagnosis of IgG4-related chronic sialadenitis in a salivary gland. Sections should be stained for both IgG and IgG4, as the ratio of IgG4/IgG (>40%) is more important than absolute numbers of IgG4-positive plasma cells (Figure 3F and inset).29 Although histopathology is the current gold standard for the diagnosis of IgG4-related disease, histopathologic features often develop to a variable extent, are
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Table II. Diagnostic terminology and categories for IgG4 related disease29 Histologically highly suggestive of IgG4-related disease: Presence of: e 2 of 3 histologic features, and e IgG4-positive plasma cell count >100/hpf e IgG4-positive plasma cells: IgG-positive plasma cells >40% Probable histologic features of IgG4-related disease: Presence of: e 1 of 3 histologic features e IgG4-positive plasma cell count >100/hpf e Needle biopsies e Additional clinical evidence required for confirmation: Serum IgG4 >135 mg/dl Other organ involvement Insufficient histologic evidence of IgG4-related disease: e Does not exclude the diagnosis of IgG4-related disease Sampling, treatment effects, late fibrotic stage IgG4, immunoglobulin G4; hpf, high-power field.
subject to sampling issues, particularly on needle biopsies, and may be altered by preceding treatment.29 Thus, often the diagnosis of IgG4-related disease requires clinical and serologic correlation. A three-tiered diagnostic terminology has been proposed to provide uniformity and guidelines to aid in optimal diagnosis and management of patients with IgG4-related disease (Table II).29 Differential diagnoses. The most important clinical differential diagnosis includes a malignancy, such as a carcinoma or lymphoma, particularly as these are more common than IgG4-related disease. Also, IgG4-related pathology is tumefactive and tends to cause firm, nontender, and sometimes unilateral enlargement of the salivary gland in an older patient.31 This may be further confounded by entrapment of nerve bundles within the fibroinflammatory process mimicking perineural invasion on imaging.33 Optimal sampling of the lesion is essential for histopathologic diagnosis as nonspecific fibroinflammatory changes and large numbers of IgG4-positive plasma cells may be seen at the periphery of a malignant neoplasm. Careful assessment of the IgG4/IgG ratio is essential, as increased numbers of IgG4 plasma cells may be seen in a variety of conditions, including rheumatoid arthritis, antineutrophil cytoplasmic antibodyeassociated vasculitis, and so on.29 Distinction from other autoimmune conditions, such as Sjogren syndrome, is relatively easy and is based on the relapsing nature of Sjogren syndrome, with waxing and waning of the salivary gland enlargement and appropriate serology.31 Chronic sialadenitis with scarring typically demonstrates lobular atrophy and acellular scar tissue, as opposed to storiform cellular fibrosis; also, obliterative phlebitis is absent following extensive sampling.31
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Management and prognosis. IgG4-related chronic sclerosing sialadenitis typically responds rapidly to glucocorticoids.34 Trials with rituximab are underway.35 The prognosis, however, is variable and largely depends on the extent of sclerosis and loss of functional units.29 Thus, timely and accurate early diagnosis of this multiorgan disorder is critical for systemic management and overall good prognosis.
OLD ENTITIES, NEW CONCEPTS Salivary duct carcinoma Salivary duct carcinoma accounts for approximately 2% of salivary gland neoplasms.21 First described by Kleinsasser et al. in 1968,18 this tumor has been slow in gaining recognition and has often been labeled as adenocarcinoma not otherwise specified or undifferentiated carcinoma.2,3 These tumors are predominantly seen in older men (male-to-female ratio 4:1).21,36 A significant number of patients present with facial nerve dysfunction, and more than a third have clinically detectable cervical lymph node involvement.2,36,37 With improved diagnostic techniques, the spotlight is now shifting to detection of HER2/neu amplifications and the potential benefits of trastuzumab therapy (Herceptin, Genentech, San Francisco, CA) in these high-grade tumors.38-40 Histology, special stains, and immunohistochemistry. Macroscopically, these tumors are gray to white, are firm, and have an infiltrative appearance with irregular edges (Figure 4A). Histologically, the tumors resemble high-grade in situ carcinoma and invasive ductal carcinoma of the breast and are characterized by infiltrative cords, nests, tubules, and cribriform structures. An intraductal cribriform pattern with formation of Roman bridges and comedo necrosis as seen in high-grade ductal carcinoma in situ of the breast are characteristic features. The epithelial cells show marked cytologic atypia with moderately abundant cytoplasm and enlarged hyperchromatic and pleomorphic nuclei (Figure 4B). Stromal desmoplasia is striking. Extensive lymphovascular emboli and perineural invasion are characteristically present. Several morphologic variants of salivary duct carcinoma, including mucin-rich, micropapillary, and sarcomatoid variants, have been described.3,41-43 The micropapillary and sarcomatoid variants have poorer prognosis compared with the conventional salivary duct carcinoma.41,42 Rare instances of pure in situ carcinoma with highgrade nuclear features are described.44 However, it is critical that the specimen is extensively examined for early invasive foci before this diagnosis is made. Histologic assessment of the entire specimen and immunohistochemistry on multiple blocks to
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Fig. 4. A, Macroscopic appearance of salivary duct carcinoma. Foci of necrosis are present. B, Widely infiltrative salivary duct carcinoma composed of nests of epithelial cells with hyperchromatic, pleomorphic nuclei. C, Uniform membranous immunoreactivity with Her2 (Immunohistochemistry, original magnification 100). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00505. D, Fluorescent in situ hybridization for Her2. This enumeration FISH probe quantifies HER-2/neu gene copy number using a orange probe and quantifies chromosome 17 copy number using a green alpha satellite DNA fragment. Normal cells show two green and two red signals each. Multiple red signals are seen in each nucleus, indicating amplification of the Her2 gene.
confirm the presence of myoepithelial cells may be required.44 Rare examples of intraductal cribriform proliferation of epithelial cells with relatively low-grade to bland cytologic features analogous to low-grade ductal carcinoma in situ have also been described. These tumors have been variously designated as low-grade cribriform cystadenocarcinoma or low-grade salivary duct carcinoma in the past, and there is some controversy in the literature regarding the relationship of these tumors to salivary duct carcinoma as well as the appropriate terminology.45 Brandwein-Gensler et al. propose that lowgrade salivary duct carcinoma should be the preferred term for these tumors with relatively good prognosis compared with conventional high-grade salivary duct carcinoma.46 Diagnosis. PREOPERATIVE FNA. Preoperative FNA yields pleomorphic malignant epithelioid cells with or without associated necrosis, stroma, or mucin.47 Solid, three-dimensional clusters with a cribriform, trabecular, tubular, or micropapillary pattern or discohesive malignant cells may be seen.47,48 Squamoid differentiation may be present.48 Given the highgrade, poorly differentiated nature of these neoplasms, a wide range of differential diagnoses may be considered, and immunoreactivity for pancytokeratin,
such as AE1/AE3, or CK7, on a cellblock is useful to establish a diagnosis of poorly differentiated carcinoma.3 Once a diagnosis of poorly differentiated carcinoma is made, the main differential diagnoses include highgrade primary salivary gland tumor, such as salivary duct carcinoma, and metastases; therefore, a comprehensive history, systemic examination, and radiologic correlation are important.47,49 POSTOPERATIVE FINAL HISTOLOGIC DIAGNOSIS. In a resected speci men, awareness of salivary duct carcinoma and its variants is essential for a confident histologic diagnosis based on morphologic features. Immunohistochemistry plays a supportive role and is a useful adjunct in excluding metastases. However, it is important to realize that the immunoprofile of salivary duct carcinoma significantly overlaps with those of prostate and breast cancers.21,50,51 In addition to pancytokeratin, such as AE1/AE3, or CK7, nearly 90% salivary duct carcinomas show immunoreactivity with androgen receptor, and approximately 60% demonstrate immunostaining with prostate-specific antigen.50 Approximately 30% to 100% of salivary duct carcinomas have been reported to show membranous immunoreactivity (3þ) with HER2/neu and demonstrate HER2 amplification on FISH studies in the literature (Figures 4C and 4D).52,53
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Fig. 5. A, Classic appearance of epithelialemyoepithelial carcinoma (EMC). A well-demarcated tumor comprises tubular and trabecular structures with a central lumen. The cuboidal luminal epithelial cells appear polygonal with moderate amounts of cytoplasm. The abluminal myoepithelial cells show moderate to abundant clear cytoplasm (H&E, original magnification 10). B, EMC showing a predominance of myoepithelial component with scanty epithelial elements. The myoepithelial cells show clear cytoplasm and appear spindle shaped (H&E, original magnification 10). C, EMC with epithelial elements showing cytoplasmic vacuolation and luminal granular secretions (H&E, original magnification 10). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00503.
Management and prognosis. Given the difficulties in obtaining a definitive preoperative diagnosis of salivary duct carcinoma on an FNA specimen, it is likely that a preoperative diagnosis of poorly differentiated carcinoma is all that can be obtained for a parotid or submandibular lesion. However, in the case of sublingual or minor salivary gland involvement, a biopsy with histologic assessment may be required for a definitive diagnosis so that a radical resection can be planned. Neck node metastases are seen in 65% of the cases; thus, elective neck dissection is recommended for all patients where a confident diagnosis can be made.2,37 Although the majority of long-term survivors have received adjuvant radiotherapy, its efficacy in these aggressive tumors has been evaluated in only a few studies.37 Recent therapeutic developments revolve around the use of chemotherapeutic agents exploiting their molecular biology. Androgen deprivation therapy has been reported to show clinical improvements and palliation in patients, including those with systemic metastases.54,55 Several case reports of patients with HER2/neu amplification treated with trastuzumab along with paclitaxel and carboplatin have described improved outcomes.38,56-58 Limaye et al. described response and long-term survival with trastuzumab in their study of 13 patients, including 5 with metastatic disease.58 At more than 2 years of follow-up, 5 of 8 patients showed no evidence of disease, and all 5 patients with metastatic disease responded to treatment (median duration 18 months), with 1 patient achieving a complete response at 52 months. Genotyping with detection of actionable genetic changes, such as BRAF and PIK3CA mutations, may direct selection of treatment in the
future.39,59 Thus, accurate diagnosis with appropriate predictive ancillary testing will play a crucial role in the management of these aggressive malignancies.
Epithelialemyoepithelial carcinoma (EMC): improved recognition of a wide morphologic spectrum EMCs are rare low-grade salivary gland neoplasms, which were first described by Donath et al. in 1972.60 As the name suggests, these are biphasic tumors comprising both epithelial and myoepithelial cells. EMCs have a vast morphologic spectrum, depending on the architecture, the proportion of both the epithelial and myoepithelial components, and their cytologic characteristics. Thus, these tumors have historically provided diagnostic challenges, which have been further confounded by their rarity and earlier restrictive definition requiring a tubular morphology with outer myoepithelial cell layer with clear cytoplasm.61 Improved understanding and recognition of their morphologic spectrum and availability of immunohistochemical stains has resulted in these tumors being recognized with increased frequency. It is possible that given their relatively rounded contours and bland cytologic features, the tumors were often placed in the category of adenomas previously.62 EMCs are considered to lie on a morphologic spectrum with pure myoepithelial carcinomas.63,64 This is further supported by the fact that both these low-grade salivary gland neoplasms show similar clinical features and outcomes, and it may be more useful to classify these low-grade myoepithelial-rich tumors together in the future.
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Table III. High-grade transformation in salivary gland tumors Adenoid cystic67,68
Low grade High grade High-grade transformation
Acinic cell carcinoma5,13,73
Epithelialemyoepithelial carcinoma5,69
Lymph node metastases
Overall survival
Lymph node metastases
Overall survival
Lymph node metastases
Overall survival
5% 25% 57%
>5 years 3e4 years 1 year
3% NA 50%
28.5 years NA 4 years
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Salivary gland lesions: recent advances and evolving concepts Ruta Gupta, MD, FRCPA,a,b Deepak Balasubramanian, MS, DNB, MCh,c,d and Jonathan R. Clark, M.Biostat FRACSb,c,d Recently, there have been significant developments in our understanding of salivary gland pathology, and new entities, such as mammary analogue secretory carcinoma, have been described. Attempts are being made to identify effective therapeutic agents for salivary duct carcinomas by using molecular diagnostic techniques. Concepts such as high-grade transformation have been described, which not only influence macroscopic and microscopic evaluation of a specimen but, given the high incidence of metastases and morbidity, also carry significant treatment implications. Specific chromosomal translocations, which can be detected by fluorescent in situ hybridization, can augment diagnostic accuracy and carry prognostic implications. The landscape of benign salivary gland lesions is changing with better understanding of chronic sclerosing sialadenitis related to IgG4. This multiorgan inflammatory condition may primarily present as a salivary gland lesion and clinically and radiologically mimic a salivary gland malignancy. Histology and immunohistochemistry play a critical role in its accurate diagnosis. The purpose of this article is to review these changes, with an emphasis on their effect on patient management. Given their diagnostic, prognostic, and therapeutic implications, it is critical that surgeons, oncologists, pathologists, and those involved in caring for patients with salivary gland tumors are aware of these changes while considering management options. (Oral Surg Oral Med Oral Pathol Oral Radiol 2015;-:1-14)
The classification of salivary gland tumors is rapidly evolving with description of new entities, such as mammary analogue secretory carcinoma (MASC).1 Other entities, such as salivary duct carcinoma, are being increasingly recognized with improved understanding of their molecular characteristics.2,3 The concept of high-grade transformation has been described in adenoid cystic carcinoma, acinic cell carcinoma, and other salivary gland tumors.4,5 Furthermore, specific chromosomal translocations, which can be easily detected by fluorescent in situ hybridization (FISH), have been described in adenoid cystic carcinoma, mucoepidermoid carcinoma, MASC, and in the rare hyalinizing clear cell carcinoma.6-9 These chromosomal translocations may improve diagnostic accuracy and carry prognostic implications.6-10 Most of these changes are being fueled by increased use of ancillary diagnostic techniques and genetic sequencing. However, considering their diagnostic, prognostic, and therapeutic implications, it is critical that surgeons and
those involved in caring for patients with salivary gland tumors are aware of these changes while considering management options. Here, we review the changes in our understanding of salivary gland lesions, with an emphasis on their effect on patient management. We also look at the recently described disease in the salivary gland associated with immunoglobulin G4 (IgG4). Table I briefly summarizes both the conventionally recognized salivary gland tumors and the current evolution in salivary gland pathology.
NEW ENTITIES Mammary analogue secretory carcinoma MASC, a low-grade malignant neoplasm of the salivary gland, was described by Skalova et al. in 2010.1 Skalova et al. studied 16 examples of morphologically similar salivary gland tumors, which had been designated as zymogen granuleepoor acinic cell carcinomas in the past, and identified a specific, novel chromosomal translocation (ETV6-NRTK3 fusion gene; (12; 15) (p13; q25)).1 This rearrangement results
a
Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia. b Central Clinical School, University of Sydney, NSW 2006, Australia. c Sydney Head and Neck Cancer Institute, The Chris O’Brien Lifehouse, Missenden Road, Camperdown NSW 2050, Australia. d Department of Head and Neck Surgery, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia. Received for publication Jul 6, 2014; returned for revision Feb 7, 2015; accepted for publication Feb 20, 2015. Ó 2015 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2015.02.481
Statement of Clinical Relevance This article reviews the changes in salivary gland pathology, with an emphasis on their effect on diagnosis, prognosis, and patient management, and provides relevant information for surgeons, oncologists, and pathologists involved in caring for patients with salivary gland tumors. 1
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Table I. Current evolution in salivary gland pathology New entities a. Mammary analog secretory carcinoma b. Hyalinizing clear cell carcinoma c. IgG4-related chronic sclerosing sialadenitis
Old entities: new concepts a. Salivary duct carcinoma: Genetic alterations amenable to targeted therapy: -Her2 amplification in salivary duct carcinoma -BRAF mutations in salivary duct carcinoma b. Epithelialemyoepithelial carcinoma: improved recognition of a wide morphologic spectrum. c. High-grade transformation in: -Acinic cell carcinoma -Adenoid cystic carcinoma -Epithelialemyoepithelial carcinoma -Myoepithelial carcinoma -Mammary analog secretory carcinoma -Mucoepidermoid carcinoma
New ancillary diagnostic/prognostic/ predictive tests Chromosomal translocations of diagnostic or prognostic utility detectable by fluorescent in situ hybridization: -Mucoepidermoid carcinoma -Adenoid cystic carcinoma -Hyalinizing clear cell carcinoma -Mammary analog secretory carcinoma
IgG4, immunoglobulin G4.
in fusion of transcription regulator ETV6 with membrane receptor kinase NTRK3.1 MASCs show morphologic and molecular features similar to the secretory carcinomas of the breast, leading to the proposal of the nomenclature mammary analog secretory carcinoma.1,11,12 MASCs occur in men and women in both major and minor salivary glands. Previous diagnosis. These tumors were largely categorized as zymogen granuleepoor acinic cell carcinoma or rarely as mucoepidermoid carcinoma in the past.1,13 Histology, special stains, and immunohistochemistry. Macroscopically, MASCs are relatively well-defined, lobulated neoplasms with a cystic component (Figure 1A).1,14 These tumors show a solid, tubular or microcystic pattern (Figure 1B). The tubular and microcystic spaces contain thin eosinophilic, bubbly secretions. The lining polygonal cells show eosinophilic, granular, or vacuolated cytoplasm and a uniform central round nucleus with a single distinctive nucleolus1,4,14 (Figure 1C). Invasion into periglandular tissue has been described.1,14 Lymphovascular and perineural involvement, although rare, have been described.14 Special stains, such as periodic acid Schiff’s reagent following diastase digestion (DiPAS) (Figure 1D) and mucicarmine highlight the secretions. Immunohistochemically, the tumor cells show strong and diffuse positivity with S100 (Figure 1E), MUC4, and mammoglobin and lack immunoreactivity with squamous and myoepithelial markers, such as p63, calponin, and SMA.1 Diagnosis. PREOPERATIVE FINE-NEEDLE ASPIRATION. A definitive preoperative diagnosis is difficult, although there are case reports describing the cytologic features of MASC in fine-needle aspiration (FNA) specimens.
MASCs show several overlapping cytologic features with other low-grade salivary gland neoplasms, such as acinic cell carcinoma, low-grade mucoepidermoid carcinoma, and myoepithelial neoplasms.15,16 A cellblock with high cellular yield may facilitate special stains and discriminatory immunohistochemical panel. POSTOPERATIVE FINAL HISTOLOGIC DIAGNOSIS. Histologic diagnosis is relatively easily made in a resection specimen based on the morphologic features in conjunction with special stains and immunoreactivity for S100, MUC4, and mammoglobin.1,13,14,17 FISH studies for (ETV6NRTK3 fusion gene; (12; 15) (p13; q25)) (Figure 1F) are also available, if needed. The main differential diagnosis is acinic cell carcinoma. Distinction of acinic cell carcinoma from MASC is based on recognizing the presence of intracytoplasmic zymogenic granules in acinic cell carcinoma and their absence in MASC.18 Acinic cell carcinomas also lack immunoreactivity with S100 and MUC4. Lack of stromal matrix, spindle-shaped or clear cells, targetoid perineural invasion at the periphery, and a discriminatory immunohistochemical panel, as described above, comprising of S100, MUC4, p63, CK5/6, and calponin can help in distinguishing this entity from other low-grade myoepithelial neoplasms, mucoepidermoid carcinoma, and polymorphous lowgrade carcinoma, respectively.1,13,14 Management and prognosis. Prognostic information for MASC is still evolving. Historically, MASC has largely been classified as acinic cell carcinomas and has been considered a low-grade malignant neoplasm.13,14 Complete local resection constitutes adequate treatment. Although most tumors in the published series have shown an indolent behavior, a few local
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Fig. 1. A, Macroscopic appearance of mammary analogue secretory carcinoma. The tumor is well circumscribed, lobulated with solid and cystic components. B, Tumor surrounded by fibrous capsule. Infiltration into the capsule is seen. The tumor is composed of nests of cells with microcysts. The microcysts show presence of eosinophilic bubbly material (H&E, original magnification 20). C, The cells show indistinct cell membranes, vacuolated eosinophilic cytoplasm and relatively uniform nuclei with distinctive nucleoli. A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00504. D, Special stains with periodic acid Schiff’s reagent following diastase digestion show staining of the secretions and occasional intracytoplasmic globules (DiPAS, original magnification 20). E, Immunostaining with S100 shows strong diffuse immunoreactivity in the tumor cells. F, Fluorescent in situ hybridization (FISH) studies demonstrate ETV6 translocation from chromosome 12. The green signal demonstrates the centromeric (3’) end of ETV6 on chromosome 12, and the red signal demonstrates telemeric (5’) end of ETV6 on chromosome 12. Under normal circumstances, the green and the red signals are closely placed and often overlap producing a yellow signal. A split in the red and the green signals (white arrows) demonstrates translocation of ETV6 region.
recurrences and lymph node metastases have been described, some after a period of 7 to 8 years.1 Chiosea et al. in their study of 60 conventional acinic cell carcinomas and 10 MASCs reported an increased incidence of lymph node metastases in the latter.13 Thus, long-term follow-up is useful. Also, the role of adjuvant radiotherapy in managing various adverse features, such as incomplete resection and lymphovascular or perineural invasion, has not been formally evaluated in MASC to date. Hyalinizing clear cell carcinoma of the salivary gland The specific terminology of hyalinizing clear cell carcinoma was first introduced by Milchgrub in 1994.19 However, many authors have recognized and described this entity in the past, most often as “clear cell carcinoma.”20 Although the World Health Organization 2005 classification system21 categorizes these tumors as clear cell carcinoma, not otherwise classified, the identification of a specific translocation (EWSR1-ATF1 fusion t(12; 22) (q13; q12)) indicates
that these rare tumors are a distinct entity.9 Hyalinizing clear cell carcinomas have an equal incidence in both genders and arise predominantly in minor salivary gland tissue of the palate, tongue base, and the oral cavity.19 Histology, special stains, and immunohistochemistry. Macroscopically, hyalinizing clear cell carcinomas are relatively well-circumscribed, lobulated neoplasms. Histologically, as the name suggests, this tumor is composed of nests, trabaculae, and cords of cells, with clear cytoplasm embedded in dense eosinophilic hyaline stroma (Figure 2A). The cells typically show clear cytoplasm with relatively small uniform nuclei. Mitoses, although present, are rare, and necrosis is unusual. Perineural invasion has been described.22 The cytoplasmic clearing results from the presence of glycogen. This can be confirmed with special stains for periodic acid Schiff’s reagent which shows intracytoplasmic intensely pink granular material (Figure 2B). This intracytoplasmic pink appearance is lost following digestion of glycogen with diastase (see Figure 2B, inset). Immunohistochemically,
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Fig. 2. A, Hyalinizing clear cell carcinoma of the salivary gland comprising nests and trabaculae of cells with clear cytoplasm embedded in hyaline stroma (H&E, original magnification 20). B, Special stains with periodic acid Schiff’s reagent highlight the intracytoplasmic glycogen (PAS, original magnification 10). The intracytoplasmic glycogen disappears following digestion with diastase (inset, DiPAS, original magnification 20). C, Fluorescent in situ hybridization (FISH) studies demonstrate EWSR1 translocation from chromosome 22. The green signal demonstrates the centromeric end of EWSR1 on chromosome 22, and the red signal demonstrates the telomeric end of EWSR1 on chromosome 22. Under normal circumstances, the green and the red signals are closely placed and often overlap producing a yellow signal. A split in the red and the green signals (white arrows) demonstrates translocation of EWSR1 region.
hyalinizing clear cell carcinomas of the salivary gland show strong immunoreactivity with pancytokeratin, high-molecular-weight cytokeratins, and p63. These tumors are negative for myoepithelial stains, such as calponin, S100, SMA, and so on.23 Differential diagnoses include a range of primary salivary gland and metastatic neoplasms showing a combination of cells with clear cytoplasm and hyalinized stroma. Thus, hyalinizing clear cell carcinoma needs to be distinguished from clear cell variants of oncocytoma, myoepithelioma, mucoepidermoid carcinoma, myoepithelial carcinoma, acinic cell carcinoma, and metastatic clear cell renal cell carcinoma. Of these, hyalinizing clear cell carcinoma shows similar immunohistochemical profile as mucoepidermoid carcinoma and squamous cell carcinoma.24 A consistent chromosomal translocation (EWSR1-ATF1 fusion t(12; 22) (q13; q12)) has been described in approximately 82% to 93% of hyalinizing clear cell carcinoma and is of great diagnostic utility in confirming the diagnosis and distinguishing these rare tumors from their more common mimics (Figure 2C).9 Clear cell odontogenic carcinomas arising in the jaw show similar morphologic and immunohistochemical profiles as that of hyalinizing clear cell carcinoma. These tumors also show (EWSR1-ATF1 fusion t(12; 22) (q13; q12)) and are now considered to represent the odontogenic analogs of hyalinizing clear cell carcinoma.25 Management and prognosis. Hyalinizing clear cell carcinomas are considered low-grade and most show an indolent course. However, perineural invasion and recurrence have been reported in approximately 12% to 17% cases with occasional neck metastases.9,23,26
Resection forms the mainstay of the treatment; however, radiotherapy has been used as the primary modality for patients with tongue base tumors. Standard management guidelines for these rare tumors are lacking; however, overall, they have a good prognosis.23 IgG4-related chronic sclerosing sialadenitis IgG4-related disease is a multiorgan inflammatory disease, in which diverse manifestations are linked by a common pathogenesis and similar histopathologic and immunohistochemical features.27-29 IgG4-related diseases encompass a systemic chronic relapsing disorder affecting men in their 60s to 70s.28 This condition may affect any organ in the body but most commonly involves the pancreaticobiliary tree, salivary glands, lacrimal glands, and periorbital tissues.29 Previous terminology. The manifestations were variously designated as autoimmune pancreatitis, Mikulicz disease, Kuttner tumor, multifocal fibrosclerosis, and eosinophilic angiocentric fibrosis before the pathologic mechanisms and evolution of the condition were understood.30 Diagnosis. In the context of salivary gland lesions, most patients present with a bilateral, nontender, firm enlargement of the salivary glands, particularly the submandibular gland.31 Although a history of obstructive jaundice or autoimmune pancreatitis is helpful for accurate diagnosis, the salivary gland disease may antedate the pancreatic involvement by an average of 2.5 years.31 Serologic investigations showing serum IgG4 elevation may be useful; however, approximately 50% of the patients show normal serum IgG4 levels.32
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Fig. 3. IgG4erelated chronic sclerosing sialadenitis involving the submandibular salivary gland. A, The lesion diffusely involves the salivary gland and has a gray white, fibrous appearance. B, Diffuse lymphoplasmacytic infiltrate. The lobular pattern of the salivary gland is retained (H&E, original magnification 10). C, Storiform, fibrocellular fibrosis with a whorled appearance (H&E, original magnification 10). D, Obliterative thrombophlebitis (H&E, original magnification 10), which is further highlighted by special stains for elastin (inset). The fibrosis and lymphoplasmacytic infiltrate may often encircle and entrap nerve bundles. E, The dense lymphoplasmacytic infiltrate predominantly comprises large numbers of plasma cells, mature T lymphocytes, eosinophils, and macrophages. A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00506. F, Immunostains for IgG. A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00507. IgG4 (inset) demonstrating and IgG4/IgG ratio of greater than 40%. A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00508.
Katsura et al. have described the radiologic findings of IgG4-related disease in the head and neck as having well-defined borders, T2 hypointensity on magnetic resonance imaging, a homogeneous and gradual enhancement pattern, and absence of vascular occlusion or compression.33 In addition, the lack of an obstructive sialolith or a discrete tumor mass may be helpful.31 Preoperative FNA. FNA is not useful and yields either lymphoplasmacytic population or an acellular aspirate, depending on the extent of sclerosis. Furthermore, there is insufficient evidence to support the use of FNA and cell block preparation in the diagnosis of IgG4-related disease.29 Histology and immunohistochemistry. Currently, histology is considered the gold standard for the diagnosis of IgG4-related disease. Macroscopically, the gland shows ill defined, diffuse firm white areas (Figure 3A). Histologic examination classically demonstrates (1) a dense lymphoplasmacytic infiltrate (Figure 3B), (2) storiform fibrosis (Figure 3C), and (3) obliterative phlebitis (Figure 3D).29,30,32 The dense lymphoplasmacytic infiltrate comprises predominantly of large numbers of polyclonal plasma
cells, mature T lymphocytes, eosinophils, and macrophages (Figure 3E).29 Neutrophils are sparse, and granulomata and necrosis are absent. An infective etiology should be considered if neutrophils, granulomata, and necrosis are present.29 Cellular storiform fibrosis is present, and obliterative phlebitis is seen with lymphocytes and plasma cells infiltrating the walls of a medium-sized vein.29 The fibrosis and lymphoplasmacytic infiltrate may often encircle and entrap nerve bundles (see Figure 3D). Immunohistochemistry for IgG4 provides confirmatory evidence in appropriate clinical and serologic contexts and becomes extremely critical at initial presentation and in cases with normal serum IgG4 levels. More than 100 IgG4 positive plasma cells per high-power field are required for a diagnosis of IgG4-related chronic sialadenitis in a salivary gland. Sections should be stained for both IgG and IgG4, as the ratio of IgG4/IgG (>40%) is more important than absolute numbers of IgG4-positive plasma cells (Figure 3F and inset).29 Although histopathology is the current gold standard for the diagnosis of IgG4-related disease, histopathologic features often develop to a variable extent, are
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Table II. Diagnostic terminology and categories for IgG4 related disease29 Histologically highly suggestive of IgG4-related disease: Presence of: e 2 of 3 histologic features, and e IgG4-positive plasma cell count >100/hpf e IgG4-positive plasma cells: IgG-positive plasma cells >40% Probable histologic features of IgG4-related disease: Presence of: e 1 of 3 histologic features e IgG4-positive plasma cell count >100/hpf e Needle biopsies e Additional clinical evidence required for confirmation: Serum IgG4 >135 mg/dl Other organ involvement Insufficient histologic evidence of IgG4-related disease: e Does not exclude the diagnosis of IgG4-related disease Sampling, treatment effects, late fibrotic stage IgG4, immunoglobulin G4; hpf, high-power field.
subject to sampling issues, particularly on needle biopsies, and may be altered by preceding treatment.29 Thus, often the diagnosis of IgG4-related disease requires clinical and serologic correlation. A three-tiered diagnostic terminology has been proposed to provide uniformity and guidelines to aid in optimal diagnosis and management of patients with IgG4-related disease (Table II).29 Differential diagnoses. The most important clinical differential diagnosis includes a malignancy, such as a carcinoma or lymphoma, particularly as these are more common than IgG4-related disease. Also, IgG4-related pathology is tumefactive and tends to cause firm, nontender, and sometimes unilateral enlargement of the salivary gland in an older patient.31 This may be further confounded by entrapment of nerve bundles within the fibroinflammatory process mimicking perineural invasion on imaging.33 Optimal sampling of the lesion is essential for histopathologic diagnosis as nonspecific fibroinflammatory changes and large numbers of IgG4-positive plasma cells may be seen at the periphery of a malignant neoplasm. Careful assessment of the IgG4/IgG ratio is essential, as increased numbers of IgG4 plasma cells may be seen in a variety of conditions, including rheumatoid arthritis, antineutrophil cytoplasmic antibodyeassociated vasculitis, and so on.29 Distinction from other autoimmune conditions, such as Sjogren syndrome, is relatively easy and is based on the relapsing nature of Sjogren syndrome, with waxing and waning of the salivary gland enlargement and appropriate serology.31 Chronic sialadenitis with scarring typically demonstrates lobular atrophy and acellular scar tissue, as opposed to storiform cellular fibrosis; also, obliterative phlebitis is absent following extensive sampling.31
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Management and prognosis. IgG4-related chronic sclerosing sialadenitis typically responds rapidly to glucocorticoids.34 Trials with rituximab are underway.35 The prognosis, however, is variable and largely depends on the extent of sclerosis and loss of functional units.29 Thus, timely and accurate early diagnosis of this multiorgan disorder is critical for systemic management and overall good prognosis.
OLD ENTITIES, NEW CONCEPTS Salivary duct carcinoma Salivary duct carcinoma accounts for approximately 2% of salivary gland neoplasms.21 First described by Kleinsasser et al. in 1968,18 this tumor has been slow in gaining recognition and has often been labeled as adenocarcinoma not otherwise specified or undifferentiated carcinoma.2,3 These tumors are predominantly seen in older men (male-to-female ratio 4:1).21,36 A significant number of patients present with facial nerve dysfunction, and more than a third have clinically detectable cervical lymph node involvement.2,36,37 With improved diagnostic techniques, the spotlight is now shifting to detection of HER2/neu amplifications and the potential benefits of trastuzumab therapy (Herceptin, Genentech, San Francisco, CA) in these high-grade tumors.38-40 Histology, special stains, and immunohistochemistry. Macroscopically, these tumors are gray to white, are firm, and have an infiltrative appearance with irregular edges (Figure 4A). Histologically, the tumors resemble high-grade in situ carcinoma and invasive ductal carcinoma of the breast and are characterized by infiltrative cords, nests, tubules, and cribriform structures. An intraductal cribriform pattern with formation of Roman bridges and comedo necrosis as seen in high-grade ductal carcinoma in situ of the breast are characteristic features. The epithelial cells show marked cytologic atypia with moderately abundant cytoplasm and enlarged hyperchromatic and pleomorphic nuclei (Figure 4B). Stromal desmoplasia is striking. Extensive lymphovascular emboli and perineural invasion are characteristically present. Several morphologic variants of salivary duct carcinoma, including mucin-rich, micropapillary, and sarcomatoid variants, have been described.3,41-43 The micropapillary and sarcomatoid variants have poorer prognosis compared with the conventional salivary duct carcinoma.41,42 Rare instances of pure in situ carcinoma with highgrade nuclear features are described.44 However, it is critical that the specimen is extensively examined for early invasive foci before this diagnosis is made. Histologic assessment of the entire specimen and immunohistochemistry on multiple blocks to
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Fig. 4. A, Macroscopic appearance of salivary duct carcinoma. Foci of necrosis are present. B, Widely infiltrative salivary duct carcinoma composed of nests of epithelial cells with hyperchromatic, pleomorphic nuclei. C, Uniform membranous immunoreactivity with Her2 (Immunohistochemistry, original magnification 100). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00505. D, Fluorescent in situ hybridization for Her2. This enumeration FISH probe quantifies HER-2/neu gene copy number using a orange probe and quantifies chromosome 17 copy number using a green alpha satellite DNA fragment. Normal cells show two green and two red signals each. Multiple red signals are seen in each nucleus, indicating amplification of the Her2 gene.
confirm the presence of myoepithelial cells may be required.44 Rare examples of intraductal cribriform proliferation of epithelial cells with relatively low-grade to bland cytologic features analogous to low-grade ductal carcinoma in situ have also been described. These tumors have been variously designated as low-grade cribriform cystadenocarcinoma or low-grade salivary duct carcinoma in the past, and there is some controversy in the literature regarding the relationship of these tumors to salivary duct carcinoma as well as the appropriate terminology.45 Brandwein-Gensler et al. propose that lowgrade salivary duct carcinoma should be the preferred term for these tumors with relatively good prognosis compared with conventional high-grade salivary duct carcinoma.46 Diagnosis. PREOPERATIVE FNA. Preoperative FNA yields pleomorphic malignant epithelioid cells with or without associated necrosis, stroma, or mucin.47 Solid, three-dimensional clusters with a cribriform, trabecular, tubular, or micropapillary pattern or discohesive malignant cells may be seen.47,48 Squamoid differentiation may be present.48 Given the highgrade, poorly differentiated nature of these neoplasms, a wide range of differential diagnoses may be considered, and immunoreactivity for pancytokeratin,
such as AE1/AE3, or CK7, on a cellblock is useful to establish a diagnosis of poorly differentiated carcinoma.3 Once a diagnosis of poorly differentiated carcinoma is made, the main differential diagnoses include highgrade primary salivary gland tumor, such as salivary duct carcinoma, and metastases; therefore, a comprehensive history, systemic examination, and radiologic correlation are important.47,49 POSTOPERATIVE FINAL HISTOLOGIC DIAGNOSIS. In a resected speci men, awareness of salivary duct carcinoma and its variants is essential for a confident histologic diagnosis based on morphologic features. Immunohistochemistry plays a supportive role and is a useful adjunct in excluding metastases. However, it is important to realize that the immunoprofile of salivary duct carcinoma significantly overlaps with those of prostate and breast cancers.21,50,51 In addition to pancytokeratin, such as AE1/AE3, or CK7, nearly 90% salivary duct carcinomas show immunoreactivity with androgen receptor, and approximately 60% demonstrate immunostaining with prostate-specific antigen.50 Approximately 30% to 100% of salivary duct carcinomas have been reported to show membranous immunoreactivity (3þ) with HER2/neu and demonstrate HER2 amplification on FISH studies in the literature (Figures 4C and 4D).52,53
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Fig. 5. A, Classic appearance of epithelialemyoepithelial carcinoma (EMC). A well-demarcated tumor comprises tubular and trabecular structures with a central lumen. The cuboidal luminal epithelial cells appear polygonal with moderate amounts of cytoplasm. The abluminal myoepithelial cells show moderate to abundant clear cytoplasm (H&E, original magnification 10). B, EMC showing a predominance of myoepithelial component with scanty epithelial elements. The myoepithelial cells show clear cytoplasm and appear spindle shaped (H&E, original magnification 10). C, EMC with epithelial elements showing cytoplasmic vacuolation and luminal granular secretions (H&E, original magnification 10). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM00503.
Management and prognosis. Given the difficulties in obtaining a definitive preoperative diagnosis of salivary duct carcinoma on an FNA specimen, it is likely that a preoperative diagnosis of poorly differentiated carcinoma is all that can be obtained for a parotid or submandibular lesion. However, in the case of sublingual or minor salivary gland involvement, a biopsy with histologic assessment may be required for a definitive diagnosis so that a radical resection can be planned. Neck node metastases are seen in 65% of the cases; thus, elective neck dissection is recommended for all patients where a confident diagnosis can be made.2,37 Although the majority of long-term survivors have received adjuvant radiotherapy, its efficacy in these aggressive tumors has been evaluated in only a few studies.37 Recent therapeutic developments revolve around the use of chemotherapeutic agents exploiting their molecular biology. Androgen deprivation therapy has been reported to show clinical improvements and palliation in patients, including those with systemic metastases.54,55 Several case reports of patients with HER2/neu amplification treated with trastuzumab along with paclitaxel and carboplatin have described improved outcomes.38,56-58 Limaye et al. described response and long-term survival with trastuzumab in their study of 13 patients, including 5 with metastatic disease.58 At more than 2 years of follow-up, 5 of 8 patients showed no evidence of disease, and all 5 patients with metastatic disease responded to treatment (median duration 18 months), with 1 patient achieving a complete response at 52 months. Genotyping with detection of actionable genetic changes, such as BRAF and PIK3CA mutations, may direct selection of treatment in the
future.39,59 Thus, accurate diagnosis with appropriate predictive ancillary testing will play a crucial role in the management of these aggressive malignancies.
Epithelialemyoepithelial carcinoma (EMC): improved recognition of a wide morphologic spectrum EMCs are rare low-grade salivary gland neoplasms, which were first described by Donath et al. in 1972.60 As the name suggests, these are biphasic tumors comprising both epithelial and myoepithelial cells. EMCs have a vast morphologic spectrum, depending on the architecture, the proportion of both the epithelial and myoepithelial components, and their cytologic characteristics. Thus, these tumors have historically provided diagnostic challenges, which have been further confounded by their rarity and earlier restrictive definition requiring a tubular morphology with outer myoepithelial cell layer with clear cytoplasm.61 Improved understanding and recognition of their morphologic spectrum and availability of immunohistochemical stains has resulted in these tumors being recognized with increased frequency. It is possible that given their relatively rounded contours and bland cytologic features, the tumors were often placed in the category of adenomas previously.62 EMCs are considered to lie on a morphologic spectrum with pure myoepithelial carcinomas.63,64 This is further supported by the fact that both these low-grade salivary gland neoplasms show similar clinical features and outcomes, and it may be more useful to classify these low-grade myoepithelial-rich tumors together in the future.
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Table III. High-grade transformation in salivary gland tumors Adenoid cystic67,68
Low grade High grade High-grade transformation
Acinic cell carcinoma5,13,73
Epithelialemyoepithelial carcinoma5,69
Lymph node metastases
Overall survival
Lymph node metastases
Overall survival
Lymph node metastases
Overall survival
5% 25% 57%
>5 years 3e4 years 1 year
3% NA 50%
28.5 years NA 4 years
