Xanthogranulomatous Sialadenitis, an Uncommon Reactive Change is Often Associated with Warthin’s Tumor

Abstract

Xanthogranulomatous sialadenitis (XGS) is rare in salivary glands and only reported in the literature as single cases. Here we report a cohort of four cases with XGS and summarize the clinicopathologic features of these cases. All four patients had persistent mass lesions concerning for neoplasm. In two patients (patient 1 and 3), the initial fine needle aspirations (FNAs) contained oncocytic cells consistent with or suspicious for Warthin’s tumor, but follow-up FNAs showed only inflammation and/or debris indicating tumor infarction after FNA. All patients eventually had surgical resection. Histologically, all cases contained abundant macrophages with necrosis and fibroblastic proliferation. Warthin’s tumor with a grossly identifiable tumor nodule (0.7 cm) was noted in patient 1 and a microscopic focus (0.2 cm) of Warthin’s tumor was identified in patient 3. No identifiable tumor was observed in patient 2 and 4. There are a total of 10 XGS cases in the literature (including four from this series) and Warthin tumor was identified in 50% of reported cases of XGS, suggesting that XGS is an uncommon reactive process to spontaneous or procedure-induced infarction of Warthin tumor. As a diagnostic mimicker for malignancy, a thorough examination and generous sampling of surgical resection specimen is warranted, although a benign salivary gland neoplasm, commonly Warthin’s tumor, is often identified.

Introduction

Xanthogranulomatous tissue reaction is a rare subtype of chronic inflammation characterized by suppurative granulomatous inflammation and progressive destruction of the normal parenchyma. It is most commonly seen in the kidney of middle aged patients with a female predominance [1]. The etiology of xanthogranulomatous pyelonephritis (XGP) is unknown, although XGP is often associated with chronic urinary tract obstruction. XGP may be misdiagnosed preoperatively because clinical and imaging features are often nonspecific and can mimic other pathologic conditions, including renal cell carcinoma. Microscopically, the characteristic finding is xanthomatous histiocytes with abundant foamy and lipid-laden cytoplasm, in a background of mixed inflammation comprised of variable numbers of lymphocytes, neutrophils, and plasma cells. Often there is central necrosis/microabscess, surrounded by a granulomatous response with palisading foamy histiocytes. The staining pattern of diffuse cytoplasmic positivity for macrophage marker CD68 and negative staining for epithelial markers by immunohistochemical stains is important in distinguishing XGP from carcinoma.

Only six single cases of xanthogranulomatous sialadenitis [2–8] have been reported in the literature, although xanthogranulomatous reactions have been reported at other sites including gallbladder, ovary, fallopian tube, endometrium, testis, appendix, urinary bladder, stomach, pituitary gland, colon, prostate, retroperitoneum, and adrenal gland. Here we report four patients with xanthogranulomatous sialadenitis and summarize the clinicopathologic features of these cases. Additionally, we review previously reported cases of xanthogranulomatous sialadenitis from the literature.

Materials and Methods

Four cases of xanthogranulomatous sialadenitis of the salivary gland were identified at the University of Minnesota and University of Texas Health Science Center at Houston. The pathology specimens included resections (n = 4) and fine needle aspiration (FNA, n = 8). The histologic slides, including hematoxylin and eosin (H&E) and immunohistochemical stained slides, were reviewed. Clinical information was collected from the electronic medical records. These included patient age, gender, clinical presentations, mass location, radiologic findings, gross features, therapy, and last known clinical status.

Results

Clinical Presentations and Imaging Findings

Clinical features of all four patients are shown in Table 1. Three of the four patients are female. All masses are in the parotid glands. Three patients had a clinical history of pain and swelling at the area of mass lesion (Table 1). These patients were treated with antibiotics, however, none responded/resolved after treatment, and one patient showed enlargement of the mass. Two of the four patients also showed enlarged lymph nodes. FNA was performed in three patients and all patients had surgical resection due to not responding to antibiotics treatment and/or increase in size of the mass.

Table 1.

Summary of clinical presentation, imaging, and morphologic findings

Clinical presentation	Imaging findings	FNA and/or biopsy findings	Resection findings
Patient 1: a 66-year old woman with a history of breast cancer presented with pain and swelling at submandibular area treated with antibiotics; submandibular 2 cm lymph node not responding to antibiotics	CT: 2.5 × 1.9 × 2.0 cm predominantly cystic, peripherally enhancing soft tissue density in the inferior aspect of left parotid CT: 2.3 × 2.2 × 1.0 cm mass within superficial lobe of right parotid gland	FNA#1: left parotid gland: scant bland oncocytic epithelial groups, granular debris and mixed inflammatory cells with predominance of lymphocytes consistent with Warthin’s tumor; FNA#2: acute inflammation present	Excision: Warthin’s tumor (0.7 cm); Exuberant chronic inflammation with xanthogranulomatous inflammatory reaction and fibrosis; negative for malignancy
Patient 2: a 34-year old woman presented with pain and swelling of right parotid area treated with multiple antibiotics and steroid; Ipsilateral level IIA lymph node 1.1 cm	CT: 2.3 × 2.2 × 1.0 cm mass within superficial lobe of right parotid gland	Not performed	Excision: Salivary gland with area of mixed lymphocytic, histiocytic and granulomatous inflammation; one benign intraparenchymal lymph node; negative for malignancy
Patient 3: a 59-year old man presented with tender to palpation, light pink erythema over left parotid area. Bilateral parotid mass (left greater than right); size increase; no lymphadenopathy; not responding to treatment with antibiotics	CT (2014): 2.3 × 2.1 × 2.8 cm solitary mass within inferior superficial lobe of left parotid with heterogenous enhancement MRI (2018): well-marginated 3.8 × 3.9 × 4.3 cm mass in the inferior left parotid gland	FNA#1: rare bland oncocytic epithelioid cell groups; FNA#2: non-diagnostic; FNA#3: non-diagnostic. Somewhat suggestive of oncocytic cells with a background of hemorrhage, debris, and neutrophils; FNA#4: abundant acute inflammation; FNA#5: abundant acute inflammation	Excision: Warthin’s tumor with infarction and associated xanthogranulomatous sialadenitis; benign lymph nodes; negative for malignancy
Patient 4: a 62-year old woman with a small cyst-like mass of left parotid tail	Ultrasound: partially cystic mass with acoustic enhancement measuring 1.7 × 1.6 × 1.5 cm, possible abscess	FNA: nondiagnostic. Debris only	Excision of left parotid: salivary gland with cystic lesion filled with lymphocytes, foamy histiocytes, cholesterol cleft, and giant cells. No evidence of neoplasm. Five benign lymph nodes

Morphological Findings of FNA and Surgical Excision

Table 1 details the findings of FNA and surgical excision. Three of four patients had FNAs. Two patients (patient 1 and patient 3) had sequential FNAs, while patient 3 had five FNAs before surgical resection was performed. In the initial FNA, patient 1 had scant bland oncocytic epithelial groups, granular debris and mixed inflammatory cells with predominance of lymphocytes, consistent with Warthin’s tumor (Fig. 1). Patient 3 also had scant bland oncocytic epithelial cells without prominent lymphocytes, suggestive of Warthin’s tumor by FNA (not shown). Both patients showed predominantly acute inflammation in the follow up FNAs (Fig. 1) and had persistent mass lesion which was resected. Patient 4 had only one FNA which was nondiagnostic and contained only debris. All resection specimens showed histiocytes with abundant foamy and lipid-laden cytoplasm, as well as areas of necrosis admixed with variable numbers of lymphocytes, neutrophils, plasma cells, and eosinophils (Fig. 2a, c).

Fig. 1.

Fine needle aspiration findings of left parotid from patient 1. a Bland oncocytic epithelial cells with scattered lymphocytes in the background present on the first FNA. a, c and d diff quick stain; b Pap stain. Original magnification ×600 in a, ×200 in c, and ×400 in b and d

Fig. 2.

Pathological findings of left parotid excision from patient 1. Central necrosis/cystic change (top a) is surrounded by palisading, lipid laden histiocytes admixed with lymphocytes and rare eosinophils (mid a, and b), and fibrosis (bottom a, and c). Occasional multinucleated giant cells are seen (c). The fibrosis is replacing the salivary gland parenchyma (d). H&E stain, original magnification ×100 in a, ×400 in b and c, ×40 in d

Excisional specimens for patient 1 and patient 3 showed diagnostic material for residual Warthin’s tumor with double layer of oncocytic epithelial cells resting on dense lymphoid stroma (Fig. 3). Patient 1 had a gross tumor nodule (0.7 cm) which was microscopically classic for Warthin’s tumor. Patient 3 had no grossly identifiable tumor nodule within the mass and no tumor was identified during the first round of microscopic examination. However, a microscopic focus of Warthin’s tumor (0.2 cm) was noted after the mass lesion was entirely submitted. Warthin’s tumor in both cases was surrounded by xanthogranulomatous sialadenitis, suggesting a reaction to infarction of Warthin’s tumor. There were also cystically dilated ducts surrounded by fibroblastic stroma with inflammation but without classic double layer arrangement and lymphocyte cuffing. Mucin producing cells were visible with H&E stain and confirmed by mucicarmine stain (Fig. 3). These features can be misinterpreted as mucoepidermoid carcinoma. However, the underlying discontinuous basal cells were highlighted by p63 immunohistochemical stains (Fig. 3d). The luminal epithelial cells stained positive for CK7 (Fig. 3f). No neoplasm was identified for patient 2 and patient 4. No malignancy was identified in any patient.

Fig. 3.

Findings of surgical resection specimen from Patient 1. Characteristic Warthin’s tumor with double layer of epithelial cells resting on dense lymphoid stroma (a, H&E stain, original magnification ×400). Cystically dilated ducts surrounded by fibroblastic stroma with inflammation but without classic double layer arrangement and lymphocyte cuffing (b, H&E stain, original magnification ×200). Basal cells are highlighted by p63 immunohistochemical staining (c, original magnification ×200). The epithelial cells stained positive for CK7 (d, original magnification ×200). Rare mucin secreting cells are visible (e, H&E, original magnification ×400) and these cells stain positive for mucicarmine (f, original magnification of ×400)

Discussion

FNA is commonly used for diagnosing salivary gland lesions. In this study, three patients had FNAs before surgery. All diagnostic FNAs from our patients showed inflammation or debris, similar to the previously reported six individual cases [2–7]. In two patients (patient 1 and 3), the initial fine needle aspirations (FNAs) contained oncocytic cells consistent with or suspicious for Warthin’s tumor, but follow-up FNAs showed only inflammation and/or debris indicating tumor infarction after FNA. In the Milan system for reporting salivary gland cytopathology [9], these cases belong to the categories of “neoplastic, benign Warthin’s tumor” (patient 1) and “atypia of undetermined significance (AUS), oncocytic metaplasia vs neoplasm” (patient 3), and “non-neoplastic” (patient 4). Clinical follow up and radiologic correlation is recommended for cases diagnosed as “non-neoplastic”; repeat FNA or surgery is recommended for AUS cases, while surgery is recommended for benign neoplasm. All cases in this study had surgery. All excisional pathology demonstrated xanthogranulomatous sialadenitis.

Stephen et al. proposed xanthogranulomatous sialadenitis as a complication of FNA, while others argue that the inflammation is already present at the time of FNAs. Our findings from two patients with sequential FNAs suggest that xanthogranulomatous sialadenitis is most likely a reaction to infarction of a Warthin’s tumor induced by FNA. In two cases without evidence of Warthin’s tumor (patient 2 and 4), the xanthogranulomatous sialadenitis could result from spontaneous infarction and subsequent obliteration of a prior Warthin’s tumor. This is supported by the fact that three out of the four patients had a clinical history of pain and swelling at the area of mass lesion (Table 1). In contrast, Warthin’s tumor, the second most common benign salivary gland neoplasm, is clinically painless, slowly growing, and cystic if there is no infarction or secondary inflammation. However, the combination of cystic spaces and a poor blood supply makes the Warthin’s tumor susceptible to infarction and inflammation. The incidence of infarction following FNA in lesions were reported to be at least 9% in a retrospective study of 76 patients with Warthin’s tumor [10]. Spontaneously infarcted Warthin’s tumor can simulate malignancy [11, 12] and has been reported as diagnostic pitfalls in frozen section evaluation [13]. Therefore, xanthogranulomatous sialadenitis in a salivary gland may have a different etiology from the kidney. Most cases of xanthogranulomatous changes in the kidney have a clinical history of urinary infection and response to antibiotic treatment initially. Although all of our cases were clinically suspicious for infection, all culture were negative and none responded to antibiotic treatment.

Together with the previously reported six patients with xanthogranulomatous sialadenitis [2–8] summarized in Table 2, only ten cases have been identified. Three of these ten patients had a history of neoplasm, one benign (pleomorphic adenoma of right parotid gland [2]) and two malignant (breast cancer in patient 1 of this study and Hodgkin lymphoma in a previous study [6], respectively). Warthin’s tumor was identified in 50% of the patients (5/10) with 2/4 in this study and 3/6 in previously reported cases. Of these five cases of Warthin’s tumor, four (including two from this series) cases demonstrated certain cytological features of Warthin’s tumor on FNAs [5, 7]. The frequent association of xanthogranulomatous sialadenitis with Warthin’s tumor suggests that it is an uncommon reactive change to spontaneous or procedure-induced infarction of Warthin tumor.

Table 2.

Summary of previously reported cases with xanthogranulomatous sialadenitis

References	Age/sex	PMH	Imaging findings	FNA findings	Resection findings
[2, 3]	60/F	Pleomorphic adenoma, right parotid gland, resected 26 years prior	MRI: Ill-defined lobulated mass involved in the inferior part of the superficial and deep lobes, with characteristics typical of an infiltrating malignancy US with Doppler: vascular changes consistent with a neoplastic circulation	FNA: necrotic tissue with inflammatory cells, no evidence of malignancy	XG sialadenitis
[4]	72/Fa	None	MRI: right sided mass wrapped around the mandible displacing the pterygoid; Bilateral cervical lymph nodes with similar signals to those seen in the mass	FNA: nondiagnostic	Excision: intense granulomatous reaction replacing the parotid tissue
[5]	56/M	None	NA	FNA#1: nondiagnostic; FNA#2: supported impression of a Warthin’s tumor	Excision: sheets of cells with clear foamy cytoplasm and small band nuclei admixed with neutrophils, lymphocytes, plasma cells, mast cells, and multinucleated giant cells
[6]	61/M	Gastric Hodgkin lymphoma	NA	FNA: features consistent with an inflammatory process	Excision: a XG reaction characterized by abundant foamy macrophages, neutrophils, lymphocytes, and plasma cells. Adjacent to the inflammatory process was a Warthin’s tumor
[7]	52/M	None	MRI: contrast-enhancing mass located within the left parotid gland; PET-CT: nodular density within the left parotid region	FNA: consistent with Warthin’s tumor	Excision: mixed inflammatory infiltration consisted of sheets of foamy macrophages centrally admixed with neutrophils, eosinophils, lymphocytes, plasma cells and scattered giant cells
[8]	73/F	Hypertension	CT: Several conglomerated high density lesions in the left submandibular gland	FNA: many lymphocytes and scattered histiocytes with tingible bodies	Primary necrobiotic XG sialadenitis

^aThree months later, abdominal T cell rich B-cell lymphoma diagnosed after emergent laparotomy

Cytomorphologically, the presence of oncocytes, lymphocytes, and cystic contents with proteinaceous debris are diagnostic of Warthin’s tumor. Histologically, Warthin’s tumor is composed of two layers of oncocytic epithelium, luminal cells and basal cells, and underlying mature lymphoid tissue often with lymphoid follicles and germinal centers. Usually Warthin’s tumor is readily recognized on H&E stained sections. Some cases can show mucinous metaplasia and/or squamous metaplasia. These cases can be mistaken as low grade mucoepidermoid carcinoma, especially on FNA. In this study, in the resection specimen of patient 1, rare mucin secreting cells are noted (Fig. 3a) and these cells stain positive for mucicarmine (Fig. 3b). However, atypia, mitosis, and perineural and vascular invasion are usually not present in Warthin’s tumor.

It is noted that none of these cases with xanthogranulomatous sialadenitis showed malignant neoplasm of the salivary gland. Only one patient was diagnosed with abdominal T cell-rich B cell lymphoma 3 months after the resection of salivary gland [4], while no malignancy was identified in the remaining nine patients. Therefore, xanthogranulomatous sialadenitis appears to not be associated with any malignant salivary gland type tumors. However, it often occurs in Warthin’s tumor, more than coincidental phenomena given the paucity of xanthogranulomatous sialadenitis.

In conclusion, xanthogranulomatous sialadenitis is an uncommon reactive change of the salivary gland. As a diagnostic mimicker for malignancy, a thorough examination and generous sampling of surgical resection specimen is warranted, although a benign salivary gland neoplasm, commonly Warthin’s tumor, is often identified.

Compliance with Ethical Standards

Conflict of interest

All authors declare that they have no competing interest.