Chronic sclerosing sialadenitis of the submandibular gland: an entity of IgG4-related sclerosing disease

Chronic sclerosing sialadenitis typically involves the submandibular gland. It usually occurs in the middle-aged and elderly adults with a slight male predominance. Recent evidences have suggested that it is an entity of IgG4-related sclerosing disease and has distinct histopathological features, such as a dense lymphoplasmacytic infiltrate, sclerosis and obliterative phlebitis. It is important to discriminate this entity from other diseases, trying to give effective treatment to the patients. In this report, we described a patient having chronic sclerosing sialadenitis in the submandibular gland.     

Kuttner tumor of the submandibular gland: fine-needle aspiration cytologic findings of seven cases.

Kuttner tumor or chronic sclerosing sialadenitis is a benign inflammatory condition of the submandibular gland that mimics a malignant neoplasm clinically because of presentation as a hard mass. This is an underrecognized entity in the surgical pathology and cytology literature. We describe thefine-needle aspiration cytologic findings of 7 cases with histologic correlation. The 6 men and 1 woman (age, 47-72 years) had unilateral (4 cases) or bilateral (3 cases) submandibular masses known to be present for 1 month to 6 years (mean, 15 months). The aspirates were paucicellular to moderately cellular. They were characterized by scattered tubular ductal structures often enveloped by collagen bundles or lymphoplasmacytic infiltrate, isolated fragments of fibrous stroma, a background rich in lymphoid cells, and paucity or absence of acini. Histologic examination of the excised submandibular glands revealed preserved lobular architecture, thickening of interlobular septa by sclerotic tissue, dense lymphoplasmacytic infiltrate, preservation of ducts with periductal fibrosis, and variable loss of acini. In combination with the clinical findings, the fine-needle aspiration cytologic findings can strongly suggest the diagnosis of Kuttner tumor and may obviate the need of surgical intervention.     

Tumour-like lesions of the salivary glands. The new WHO classification.

Tumour-like lesions must be distinguished from true tumours of the salivary glands. In the new WHO classification of salivary gland tumours seven entities were considered: sialadenosis, oncocytosis (diffuse oncocytosis and focal adenomatous oncocytic hyperplasia), necrotizing sialometaplasia (salivary gland infarction), benign lymphoepithelial lesion (chronic myoepithelial sialadenitis), salivary duct cysts (mucoceles of the minor salivary glands of extravasation or retention type, cysts of the major salivary glands, ranula and dysgenetic polycystic disease of the parotid gland), chronic sclerosing sialadenitis of the submandibular gland (Küttner tumour), and cystic lymphoid hyperplasia in AIDS. The main topics of clinical data and pathohistology were described and documented by the results of the Salivary Gland Register in Hamburg (1965-1989).     

Chronic sclerosing sialadenitis of the submandibular gland is mainly due to a T lymphocyte immune reaction.

The aim of our study was to investigate the role of immunopathological processes in the pathogenesis of chronic sclerosing sialadenitis of submandibular glands (Küttner tumor). For this purpose, biopsy specimens from submandibular glands of 22 patients with the histological diagnosis of chronic sclerosing sialadenitis were analyzed. Paraffin-embedded tissues were immunostained for T-lymphocyte subsets (CD3, CD4, CD8), cytotoxic T cells (granzyme B), B cells (CD20, Ki-B3), and macrophages (Ki-M1P). Polymerase chain reaction and capillary electrophoresis were used to detect rearrangements of the T-cell receptor gamma chain and the CDRIII region of the immunoglobulin heavy chain. In all cases, abundant cytotoxic T cells were found, especially in close association with ducts and acini. T-cell receptor gamma chain rearrangements showed a monoclonal pattern in 6 cases (27.3%), an oligoclonal pattern in 8 (36.4%), and a polyclonal pattern in 8 (36.4%). The B-cell reaction was less pronounced and largely restricted to lymph follicles. Molecular analysis of immunoglobulin heavy chain revealed a polyclonal rearrangement in 17 cases (77.3%). In conclusion, there is an intimate relationship between the T-cell-dominated inflammatory infiltrate and acinar and duct cells. This, together with the frequent demonstration of monoclonal and oligoclonal populations of cytotoxic T cells and their histopathological behavior, suggests that chronic sclerosing sialadenitis may be the result of an immune process triggered by intraductal agents.     

Diagnostic approach to lymphoid lesions of major salivary glands

Among lesions of the major salivary glands (parotid, submandibular, and sublingual glands), those with a prominent lymphoid component are encountered frequently in the surgical pathology laboratory and range from reactive lesions to benign and malignant neoplasms. A majority of these lymphoid lesions have a co-mingled epithelial component, which also ranges from benign to malignant. As a result, many of these lesions have similar and overlapping histopathologic features, and attention to details, sometimes subtle, is required to accurately distinguish one from another. This review will discuss these lymphoid-epithelial lesions of major salivary glands, with emphasis on features that help in the differential diagnosis. Entities discussed include lymphoepithelial sialadenitis, HIV-associated salivary gland disease, extranodal marginal zone B-cell lymphoma, lymphoepithelial carcinoma, lymphadenoma, sebaceous lymphadenocarcinoma, chronic sclerosing sialadenitis, and Warthin tumour.     

Chronic sclerosing sialadenitis of the submandibular gland associated with idiopathic retroperitoneal fibrosis

We report a case of a 57-year-old man who developed a fibrosclerosing lesion in the submandibular gland and idiopathic retroperitoneal fibrosis (IRF) involving the unilateral periureteral region within a year. Both lesions were resected surgically because of the suspicion of neoplasm. Pathologic examination revealed similar histologic and immunohistochemical features for both lesions, namely, fibrosclerosis with prominent hyalinizing collagen bundles and proliferation of myofibroblastic cells, and a non-neoplastic reactive nature. There was infiltration by lymphocytes with prominent lymph follicles, plasma cells and macrophages. The histologic and immunohistochemical findings suggest that the two lesions were of a similar pathogenesis, which was possibly mediated by macrophages. We think that the present case may be an unusual form of multifocal fibrosclerosis. Although sialolithiasis is thought to be a major pathogenic factor for chronic sclerosing sialadenitis of the submandibular gland, the present case suggests that certain cases might have an etiology similar to IRF.     

Oncocytic variant of mucoepidermoid carcinoma of submandibular gland: an unusual clinical and morphological entity

In this case report we describe a rare tumor--Oncocytic variant of Mucoepidermoid carcinoma of the submandibular salivary gland with a review of the literature. Oncocytic metaplasia in salivary glands is a benign change that is associated with increasing age and also seen in a few salivary gland neoplasms', which include oncocytoma, Warthin's tumor, and the rare, oncocytic carcinoma. Oncocytic differentiation in mucoepidermoid carcinoma (MEC) is uncommon. Only twelve well-documented cases of oncocytic MEC have been reported previously all of which occurred in the parotid gland. To the best of our knowledge this is the first case of oncocytic mucoepidermoid carcinoma involving the submandibular salivary gland. The recognition of this entity is important, since most of the other primary oncocytic lesions of the salivary gland are benign.     

Immunoprofile of kuttner tumor (chronic sclerosing sialadenitis)

In the present study, the immunoprofile of chronic sclerosing sialadenitis, also known as Kuttner tumor, was analyzed. Two cases that occurred in the submandibular gland of male patients were submitted to immunohistochemical reactions to different antibodies. Histological examinations showed a submandibular gland exhibiting various degrees of atrophy with destruction of acini, infiltration by inflammatory cells, and periductal fibrosis. Reactions to cytokeratins (CKs) showed acini and duct remnants positive to CKs 7, 8, 19, and 13. CK14 stained myoepithelial cells around preserved acini and intercalated duct, and also basal cell of excretory ducts, but was negative in proliferating and branching ducts. Smooth muscle actin (SMA) was expressed by myofibroblasts in periductal fibrosis, and an intense expression of extracellular components was also seen. Lymphocyte markers showed, besides mature follicles, a higher presence of CD45RO positive cells. Thus, the immunoprofile of Kuttner is much more in keeping with an inflammatory-induced degenerative disease than with a preneoplastic lesion.     

Chronic sialadenitis with psammoma bodies mimicking neoplasia in a fine-needle aspiration specimen from the submandibular gland

A 65-year-old woman with a submandibular gland nodule had a fine-needle aspiration specimen that contained groups of duct-type cells and a psammoma body, suggestive of adenocarcinoma. The resected gland showed chronic sialadenitis with sialolithiasis and psammoma bodies. In a series of 81 resected nonneoplastic submandibular glands from 72 patients, psammoma bodies, nonlaminated microcalcifications, or both were found in 46 (57%). They were located most commonly just outside of striated or intercalated ducts. When examining fine-needle aspiration specimens from the submandibular gland, it is important that one be aware that psammoma bodies may occur in normal, inflamed, irradiated, and neoplastic conditions.     

In situ detection of hepatitis C virus RNA in salivary glands

Chronic hepatitis C virus (HCV) infection has been associated with several extrahepatic manifestations, among these, to diseases with oral manifestations such as Sj?gren's syndrome or sialadenitis. HCV-RNA has been detected in saliva and in salivary glands from patients with sialadenitis by polymerase chain reaction. However, morphological evidence of HCV replication in salivary gland cells is needed to support a role for HCV in causing sialadenitis or Sj?gren's syndrome. We have used in situ hybridization and immunohistochemistry to analyze the presence of HCV-RNA of sense and antisense polarity and HCV core antigen, respectively, in salivary gland biopsies from 19 patients with chronic sialadenitis or Sj?gren's syndrome (eight anti-HCV-positive; 11 anti-HCV-negative). HCV-RNA of both positive and negative polarity as well as HCV core antigen were detected in the epithelial cells of the salivary gland biopsies from all of the anti-HCV-positive patients but in none of the anti-HCV-negative cases. The percentage of HCV-infected cells ranged from 25 to 48.8% in the patients studied. In conclusion, we have shown that HCV infects and replicates in the epithelial cells from salivary glands of patients with Sj?gren's syndrome or chronic sialadenitis. However, its implication in the pathogenesis of these diseases deserves future research.     

Clear-cell myoepithelial carcinoma of the salivary glands: a clinicopathologic, immunohistochemical, and ultrastructural study of two cases involving the submandibular gland with review of the literature

Myoepithelial carcinoma (MC) is an uncommon neoplasm of the salivary glands, and cases of the clear-cell (CC) variant are extremely rare. Two cases of MC of the CC variant arising in the left submandibular gland are described herein. Both cases, which involved elderly women, almost exclusively consisted of large glycogen-rich CCs. Both cases were immunopositive for several epithelial and myoepithelial markers, and electron microscopy (EM) demonstrated hybrid epithelial and myoid differentiation in both. Case 1 arose in a pre-existing pleomorphic adenoma ("ex mixed tumor MC"), while Case 2 was a "de novo MC". CC-MC is an aggressive tumor with frequent recurrence, lymph node, and systemic metastases. A total of 14 cases of this type of neoplasm have been reported so far in the salivary glands, two arising from the submandibular gland. To date, only four cases have been studied using EM. The cases of CC-MC presented here are the third and fourth ones, respectively, originating from the submandibular glands, and the first two cases arising from this location, in which EM investigation succeeded in demonstrating myoepithelial differentiation. CC-MC needs to be distinguished from diverse primary and secondary CC neoplasms.     

Lymphocyte subsets in irradiation-induced sialadenitis of the submandibular gland

AIMS: Irradiation-induced sialadenitis is a significant cause of morbidity in head and neck cancer patients receiving radiotherapy. Neither the exact aetiopathology of chronic irradiation-induced sialadenitis nor the mechanisms leading to atrophy of the glandular cells associated with an increase in extracellular matrix are understood. The aim of our study was to determine the phenotype of the inflammatory infiltrate and to study its distribution in the affected submandibular glands. METHODS AND RESULTS: Paraffin-embedded submandibular glands from a homogeneous group of 19 patients with advanced oropharyngeal cancer who received conventional radiotherapy to the primary site and upper neck were analysed. In all patients the radiation dose and field were approximately equal. The submandibular glands were obtained during neck dissection. To characterize the lymphoid infiltrate, all tissue sections were immunostained for T cells (CD3, CD4, CD8), cytotoxic T cells (granzyme B), B cells (CD20), and macrophages (Ki-M1p). A histopathological classification into four grades was established based on the degree of glandular atrophy, fibrosis and lymphocytic infiltration. Phenotypic analysis of submandibular gland sections revealed that the great majority of lymphocytic infiltrates were cytotoxic T cells associated with acinar cell destruction. CONCLUSIONS: The significantly elevated frequencies of cytotoxic cells in the submandibular glands of patients with irradiation-induced sialadenitis suggest that cell-mediated immune mechanisms may play a part in the pathogenesis of this disease.     

Salivary gland pathology in HIV patients

HIV-associated salivary gland disease (HIV-SGD) typically presents with xerostomia and/or swelling of the major salivary glands. It encompasses multitude of conditions like lymphoepithelial lesions, cysts involving the salivary gland tissue and/or intraglandular lymph nodes, Sjögren's syndrome-like conditions, diffuse infiltrative lymphocytosis syndrome (DILS), and other reported lesions of the major salivary glands. HIV-related changes of the salivary glands are mostly identified based on the clinical findings and usually do not produce highly specific histomorphologic alterations. The histologic features associated with HIV-SGD are non-specific and similar to other inflammatory conditions of the salivary glands such as chronic sclerosing sialadenitis. Though this article is not all inclusive our aim is to highlight SG lesions or conditions that are directly related to or are caused by HIV infection and correlate both the clinical and salient histologic features. This chapter reviews the terminology, prevalence, symptoms, clinical features, diagnostic procedures, histopathology and the etiopathogenesis of HIV-SGD. We hope to provide ample insight into HIV-related salivary gland disease for physicians, dentists and clinicians in medical, dental and specifically otolaryngologic practice.     

A case of granulomatous sialadenitis of the submandibular gland

Granulomatous inflammation of the major salivary glands is very rare and may be due to obstruction. Little attention has been paid to this condition. The reaction is caused by extravasation of mucus, as seen in the common mucocele of the minor salivary glands. A case of granulomatous inflammation of the submandibular gland caused by obstruction is presented. The etiology of granulomatous sialadenitis is reviewed.     

Sialadenitis in nonobese diabetic mice: transfer into syngeneic healthy neonates by splenic T lymphocytes

In the present study, we showed that both male and female nonobese diabetic (NOD) mice simultaneously develop frequent lymphocyte infiltrations in salivary submandibular glands (sialadenitis), very similar to those reported in the salivary glands of patients with Sj?gren syndrome. These lesions were observed only in mice with pancreas exhibiting insulitis. The incidence of sialadenitis increased with the severity of insulitis. At the initial stage, small focal infiltrates were predominantly located around blood vessels. In older animals, inflammatory cells surrounded blood vessels and ducts. Most of the infiltrating cells proved to be L3T4+, whereas Lyt-2+ cells were comparatively few. Autoantibodies against duct epithelial cells were shown, but the degree of tissue invasion was not related to the existence of such antibodies. Antinuclear antibodies were also observed. These salivary gland infiltrates could be transferred in vivo to NOD neonates of both sexes by splenic T lymphocytes as well as by total spleen cells. These results suggest that sialadenitis in NOD mice is T cell mediated and may be related to insulitis.     

Histochemical and biochemical determination of calcium in salivary glands with particular reference to chronic submandibular sialadenitis

Although salivary calcification is relatively common, little is known about the localization and content of the calcium of normal and diseased human salivary glands. We investigated this in chronic submandibular sialadenitis with a variable mixture of relatively normal and extremely atrophic parenchyma and in normal submandibular, parotid and palatal glands. Calcium was localized histochemically in mucous acinar cells of submandibular and palatal glands at moderate to high levels, in serous acinar cells of submandibular and parotid glands at low to moderate or occasionally high levels, in mucous ductal cells at moderate to high levels, and in extremely atrophic parenchyma at low levels or not at all. Calcium was determined biochemically at relatively high levels in the different glands in the order palatal, submandibular, sialadenitis and parotid. However, the differences were small. The results indicate that most salivary calcium is associated with secretory granules; this is the likely source of the calcium involved in salivary calcification     

Sclerosing variant of follicular lymphoma arising from submandibular glands and resembling "Küttner tumor": a report of 3 patients

We present 3 patients with a sclerosing variant of follicular lymphoma that arose from the submandibular gland and resembled "Küttner tumor." All 3 patients developed a painless unilateral tumor in the submandibular region. Histologically, all 3 lesions were categorized as follicular lymphoma grade 2. The neoplastic follicles were found to be separated by thick connective tissue, and periductal chronic inflammation with periductal fibrosis and duct ectasia was found in the residual atrophic gland. Immunohistochemistry revealed that all of the lesions contained a monoclonal tumor cell population. The immunophenotyopes of the lymphoma cells were CD 10+, CD 20+, CD 79a+, BCL-6+, CD 3-, CD 5-, CD 21-, CD 23-, CD 43-, CD 45RO-, BCL-2-, and Cyclin D1-. Two of the 3 patients exhibited clonal bands for the IgH gene by polymerase chain reaction assay. "Küttner tumor," which is a common fibrosing, chronic inflammatory lesion of the submandibular gland, is sometimes diagnosed as a malignant tumor. This study indicates that this sclerosing variant of follicular lymphoma should be added to the list of different diagnoses for "Küttner tumor."     

The genetic control of sialadenitis versus arthritis in a NOD.QxB10.Q F2 cross.

The non-obese diabetic (NOD) mouse spontaneously develops diabetes and sialadenitis. The sialadenitis is characterized by histopathological changes in salivary glands and functional deficit similar to Sj?gren's syndrome. In humans, Sj?gren's syndrome could be associated with other connective tissue disorders, such as rheumatoid arthritis. In the present study the genetic control of sialadenitis in mice was compared to that of arthritis. We have previously reported a NOD locus, identified in an F2 cross with the H2(q) congenic NOD (NOD.Q) and C57BL/10.Q (B10.Q) strains, that promoted susceptibility to collagen-induced arthritis. The sialadenitis in NOD.Q showed a similar histological phenotype as in NOD, whereas no submandibular gland infiltration was found in B10.Q. The development of sialadenitis was independent of immunization with type II collagen and established arthritis. To identify the genetic control of sialadenitis, a gene segregation experiment was performed on an (NOD.QxB10.Q)F2 cross and genetic mapping of 353 F2 mice revealed one significant locus associated with sialadenitis on chromosome 4, LOD score 4.7. The NOD.Q allele-mediated susceptibility under a recessive inheritance pattern. The genetic control of sialadenitis seemed to be unique in comparison to diabetes and arthritis, as no loci associated with these diseases have been identified at the same location.     

Sclerosing rhabdomyosarcoma of the parotid gland in an adult

Primary rhabdomyosarcoma of salivary glands is an extremely rare neoplasm, mostly seen in children. A newly described subtype of rhabdomyosarcoma, sclerosing rhabdomyosarcoma, has not yet been reported in this location. We report on a parotid gland tumor characterized by infiltrative growth of primitive type of neoplastic cells showing strong and diffuse nuclear positivity for MyoD1 and myogenin and by prominent hyalinized/chondroid matrix with some myxoid foci. The tumor recurred several times, and in recurrent tumors, differentiation into strap myoid cells appeared. There were no distant metastases during the 5-year follow-up.Sclerosing rhabdomyosarcoma may cause differential diagnostic problems because it could be confounded for osteosarcoma, chondrosarcoma, and some other types of sarcoma, and as in our case, for myxofibrosarcoma and myoepithelial carcinoma. Its location in the head and neck is of special interest because 6 of 14 previously described adult cases of sclerosing rhabdomyosarcoma and 7 of 18 pediatric cases also occurred in this region. To our knowledge, this is the first reported case of primary sclerosing rhabdomyosarcoma of the parotid gland.