Small-cell predominant extranodal NK/T cell lymphoma, nasal type: clinicopathological analysis of a series of cases diagnosed in a Western population.

AIMS: Extranodal NK/T cell lymphoma, nasal type (ENKTCL) is usually composed of medium- to large-sized lymphoid cells showing prominent angiotrophism and tumour cell necrosis. We report 13 cases composed predominantly of small lymphocytes diagnosed in the United States and Western Europe. METHODS AND RESULTS: Patients included seven females and six males aged 17-75 years. Ten presented with sinonasal and three with buccal disease. Nine had stage IE/IIE and four had stage IV disease. In five of seven patients with multiple biopsies at different time-intervals, the lymphoma was misinterpreted as representing chronic inflammation on an earlier biopsy. In all cases morphology showed a dense infiltrate of small lymphoid cells with minimal cytological atypia. Necrosis, angioinvasion and angiodestruction were each seen in 17%, 22% and 17% of biopsies. Median Ki67 was 5%. Four patients died of lymphoma 4-16 months after diagnosis, including three of four patients with stage IV disease; seven (54%) are alive with no evidence of disease at a median of 39 months; one patient with stage IV disease is alive at 10 months and one recurred at 17 months. CONCLUSIONS: In sinonasal biopsies with predominantly small lymphocytic infiltrates with admixed chronic inflammation, focal hypercellularity, focal surface ulceration or microscopic bone invasion by small lymphoid cells should alert pathologists to the possibility of small-cell predominant ENKTCL. Awareness of the full histological spectrum of ENKTCL, particularly in non-endemic areas, is important in avoiding a delay in diagnosis and ensuring timely initiation of therapy.

Chronic sclerosing sialadenitis (Küttner tumor) is an IgG4-associated disease.

BACKGROUND: Chronic sclerosing sialadenitis is a fibroinflammatory disease of the salivary glands, characteristically of the submandibular gland. One prior Asian study proposed that chronic sclerosing sialadenitis is a part of the spectrum of IgG4-associated disease. This association has not been confirmed in Western populations. We therefore, investigated the relationship between IgG4 and chronic sclerosing sialadenitis, and compared the histomorphologic features of this condition with those of chronic sialadenitis-not otherwise specified, Sjögren syndrome, and lymphoepithelial sialadenitis. MATERIALS AND METHODS: We evaluated 13 cases of chronic sclerosing sialadenitis and compared them with 15 cases of chronic sialadenitis-not otherwise specified, 8 lip biopsies from individuals with Sjögren syndrome, and 4 cases of lymphoepithelial sialadenitis. Immunohistochemistry for IgG, and IgG4 was carried out. IgG4-positive plasma cells were quantified and the IgG4/IgG ratio was calculated. RESULTS: Seven patients with chronic sclerosing sialadenitis were female and 6 were male. Their mean age was 61 years (range: 27 to 80). Twelve chronic sclerosing sialadenitis cases involved the submandibular gland (bilaterally in 3) and in 1 there was a parotid lesion. Three of these 12 cases had manifestations of IgG4-associated systemic disease. Morphologically these specimens had preservation of lobular architecture, hypercellular interlobular fibrosis, florid lymphoid hyperplasia, and numerous plasma cells. Obliterative phlebitis was observed in 6 cases. The histologic features of chronic sclerosing sialadenitis were reminiscent of autoimmune pancreatitis, and were either not observed or were present only focally in cases of chronic sialadenitis, Sjögren syndrome, and lymphoepithelial sialadenitis.Eleven of 12 evaluable cases showed an increased number of IgG4 plasma cells with a mean of 229/high-power field (HPF) (range 75 to 608) and an overall IgG4/IgG ratio of 0.86 (range 0.5 to 1). The only patient whose biopsy lacked IgG4-positive plasma cells had pathologic evidence of cytomegalovirus infection. Chronic sclerosing sialadenitis cases, in comparison with the other 3 groups studied, showed a significantly higher number of IgG4 positive plasma cells (P<0.05). Patients with chronic sialadenitis-not otherwise specified had a median number of only 16 IgG4-positive plasma cells/HPF (range 2 to 44), with an IgG4/IgG ratio of 0.14 (range 0.02 to 0.28). The Sjögren syndrome patients had a median of 1 IgG4-positive plasma cell/HPF (range 0 to 3), with an IgG4/IgG ratio of 0.02 (range 0 to 0.07). Patients with lymphoepithelial sialadenitis had a median of 0 IgG4-positive plasma cells per HPF. CONCLUSION: Chronic sclerosing sialadenitis has a characteristic morphologic appearance. This morphologic appearance, in conjunction with the elevated IgG4 expression, distinguishes chronic sclerosing sialadenitis from other inflammatory diseases of the salivary glands. Chronic sclerosing sialadenitis belongs to the spectrum of IgG4-related diseases.

Anatomy of the distal incus in humans.

The anatomy of the distal incus, including the lenticular process, was examined in histological sections from 270 normal cadaveric human temporal bones aged between less than 1 month and 100 years. All but nine of these sectioned specimens showed signs of a bony connection between the long process of the incus and the flattened plate of the lenticular process, and in 108 specimens a complete bony attachment was observed in a single 20 microm section. In these 108 ears, the bony lenticular process consisted of a proximal narrow "pedicle" connected to a distal flattened "plate" that forms the incudal component of the incudo-stapedial joint. A fibrous joint capsule extended from the stapes head to the pedicle of the lenticular process on all sides, where it was considerably thickened. Three-dimensional reconstructions made from serial 20 microm sections of four bones provided views from all directions that easily convey the anatomical features of this region. Morphometric measurements of the bony architecture of the distal incus in 103 temporal bones were made, including lengths and cross-sectional areas, estimates of the percentage of lacunae containing osteocytes, and the degree of bone resorption. These measurements, analyzed as a function of age, provided an anatomic description over a large age range that can serve as a normal baseline against which structural pathology can be compared. Although none of the bony dimensions showed significant age dependence, the estimated percentage of bony lacunae that contain osteocytes decreased significantly with age. The results have implications for the roles of specific components on the coupling of ossicular motion across the incudo-stapedial joint, and provide insights regarding bone resorption at the level of the distal incus, which occurs clinically in some patients with chronic otitis media or after stapedectomy.

Histopathologic and clinical features of medullary microcarcinoma and C-cell hyperplasia in prophylactic thyroidectomies for medullary carcinoma: a study of 42 cases.

CONTEXT: Prophylactic thyroidectomies are increasingly performed on patients at risk for developing medullary thyroid carcinoma (MTC); consequently, pathologists are more commonly encountering these specimens in routine practice. OBJECTIVE: To describe the detailed clinicopathologic features of prophylactic thyroidectomies for medullary carcinoma. DESIGN: We present a retrospective series of 42 prophylactic thyroidectomies for MTC performed for one or more of the following: family history of multiple endocrine neoplasia (MEN) or MTC, elevated serum calcitonin level, or detection of a RET proto-oncogene mutation. RESULTS: Patients included 22 men and 20 women (mean age, 26.2 years). Among those with known RET proto-oncogene mutations, affected sites included exons 10, 11, 14, and 16. In 93% (n = 39) of cases, either C-cell hyperplasia (n = 36), medullary microcarcinoma (MMC; n = 29), or medullary macrocarcinoma (n = 1) was found. C-cell hyperplasia was often multifocal (n = 30) and bilateral (n = 23) and included both nonnodular and nodular patterns. A total of 94% of C-cell hyperplasia cases and all MMC cases were microscopically detectable using hematoxylin-eosin stains. The MMCs were characterized by a complex microarchitectural pattern with a desmoplastic stromal response (n = 29) and focal amyloid deposition (n = 12). Most MMCs exhibited a solid pattern (n = 24) of round, polygonal, spindled, or plasmacytoid-shaped cells. Only 1 case of MMC showed evidence of metastatic disease to a pretracheal lymph node. CONCLUSIONS: Based upon our clinicopathologic findings and review of the literature, we conclude that thyroidectomies in at-risk patients are very frequently associated with C-cell hyperplasia and/or MMC; however, the clinical prognosis for these patients is very good.

Fine-needle aspiration biopsy findings in sclerosing polycystic adenosis of the parotid gland.

Sclerosing polycystic adenosis (SPA) is a recently described, rare lesion of the salivary gland analogous to fibrocystic disease of the breast. Recognition of this benign entity is important since the differential diagnosis includes other more common benign and malignant salivary gland neoplasms, particularly mucoepidermoid carcinoma and tumors with cystic and oncocytic features. While the histomorphology of SPA is well documented, there is only one other cytologic description of SPA in the English-language literature. Here we describe the fine-needle aspiration biopsy findings in a case of SPA of the parotid gland in an 84-year-old woman. The aspirate was characterized by flat cohesive sheets of epithelial cells with moderate amounts of finely granular oncocytic cytoplasm and enlarged round nuclei with indistinct nucleoli. Some epithelial groups formed glandular structures with lumens, and the background contained small amounts of delicate mucoproteinaceous material. Occasional markedly vacuolated cells were present as well as many cells with apocrine change manifested by well-defined apical snouting. Familiarity with the cytomorphologic features of SPA, including its characteristic apocrine changes, is important for distinguishing it from other more clinically significant salivary gland lesions.

Endocrine mucin-producing sweat gland carcinoma: twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is an underrecognized low-grade carcinoma with predilection to the eyelid. Only 4 cases of this entity have been described in the literature. Here, we describe 12 cases of EMPSGC. The lesions were twice as frequent in females than males with an average age of 70 years (range, 48-84 years). Clinically, they presented as a slowly growing cyst or swelling. The most common site of occurrence was the lower eyelid (8 cases). Two lesions occurred on the upper eyelid and 2 on the cheek. Histologically, they were well-circumscribed, typically multinodular tumors with solid or partially cystic nodules, frequently showing areas of papillary architecture. Focal cribriform arrangements were also present. The nodules were formed by uniform small- to medium-sized oval to polygonal epithelial cells with lightly eosinophilic to bluish cytoplasm. The nuclei were bland with diffusely stippled chromatin and inconspicuous nucleoli. Intracytoplasmic and extracellular mucin was usually present. Mitotic activity was present but never brisk. All tumors examined immunohistochemically expressed at least one neuroendocrine marker, synaptophysin or chromogranin. CD57 and neuron specific enolase, secondary markers of neuroendocrine differentiation, were expressed in most cases. All tumors tested expressed estrogen and progesterone receptors, cytokeratin 7, low molecular cytokeratin Cam5.2, and epithelial membrane antigen and were negative for cytokeratin 20 and S-100 protein. Calponin, smooth muscle actin, and p63 immunohistochemical stains did not disclose myoepithelial cells around larger tumor nests in most cases, supporting the notion that EMPSGC is an invasive carcinoma. In 10 cases, cystic areas lined by benign epithelium indistinguishable from eccrine ducts were present. In some foci, the benign ductal epithelium was undermined or replaced by carcinoma in situ with similar cytologic features to the solid or papillary areas of EMPSGC. Myoepithelial cells were preserved in the areas of in situ carcinoma. In 6 cases, EMPSGC was associated with invasive mucinous carcinoma. In situ carcinoma and mucinous carcinoma also expressed neuroendocrine markers. Clinical follow-up showed no recurrences or metastases, consistent with low-grade carcinoma. The series provides histologic evidence for a multistage progression of noninvasive sweat gland neuroendocrine carcinoma to EMPSGC and then to mucinous carcinoma of the eyelid. Although the data from this series support the notion that the prognosis of EMPSGC and mucinous carcinoma is good, longer follow-up is needed for better understanding of their pathogenesis and clinical behavior.

Expression of tumor necrosis factor receptor-associated factor 1 in nasopharyngeal carcinoma: possible upregulation by Epstein-Barr virus latent membrane protein 1.

EBV infection is associated with virtually all cases of undifferentiated NPC, and the EBV-encoded LMP1 is expressed in a proportion of cases. LMP1 has transforming functions similar to members of the TNF receptor family and activates intracellular signaling cascades through interaction with TRAFs. In B cells, expression of TRAF1 is in turn upregulated by LMP1. LMP1 signaling in epithelial cells may be affected by the presence or absence of TRAF1. By immunohistochemistry, we detected TRAF1 expression in 17 of 42 (40%) EBV+ undifferentiated NPCs. All 7 LMP1+ NPC biopsies were also TRAF1+. Using an RNAse protection assay, high-level TRAF1 expression was detected in an LMP1-expressing NPC-derived cell line (C15) and expression was weaker in 2 LMP1- cell lines (C17, C19). Finally, LMP1 upregulated TRAF1 expression in an EBV- keratinocyte cell line. Our results demonstrate that TRAF1 is expressed in NPC tumor cells in vivo and suggest that TRAF1 expression may be upregulated by LMP1 in NPC. An antiapoptotic function has been proposed for TRAF1, and this may be relevant for the pathogenesis of NPC.

Ligneous (pseudomembranous) inflammation involving the female genital tract associated with type-1 plasminogen deficiency.

Ligneous (pseudomembranous) inflammation of the female genital tract is a rare and unusual condition characterized by extensive subepithelial fibrin deposition and associated inflammation. Ligneous inflammation in extragenital sites, predominantly the conjunctiva, has been linked to plasminogen deficiency. Individuals with plasminogen deficiency are unable to remove fibrin deposited in injured mucosal tissue. Severe systemic ligneous inflammation involving the female genital tract that is linked to hypoplasminogenemia has not previously been described. We present a patient with ligneous inflammation of her genital, middle ear, and oral mucosa that was associated with type-1 homozygous plasminogen deficiency due to a novel missense mutation in the plasminogen gene.

Expression of the Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) in EBV-associated nasopharyngeal carcinoma.

The Epstein-Barr virus (EBV) is associated with virtually all cases of undifferentiated nasopharyngeal carcinoma (NPC) and has been classified as a group I carcinogen. In addition to its potential role in the pathogenesis of NPC, EBV also provides a possible target for immunotherapy of NPC, since a limited number of viral genes are expressed in the neoplastic cells. The EBV-encoded latent membrane protein 2A (LMP2A) is considered a promising target since it provides epitopes recognized by EBV-specific T-cells. Using immunohistochemistry, the present study shows that LMP2A is expressed at the protein level in the neoplastic cells of 16 of 35 (45.7%) NPC biopsies. This finding provides further evidence suggesting that NPC tumour cells may be susceptible to lysis by cytotoxic T-cells directed against LMP2A and should encourage efforts to develop immunotherapeutic approaches for the treatment of NPC.

Myospherulosis following sinus surgery: pathological curiosity or important clinical entity?

OBJECTIVES/HYPOTHESIS: Myospherulosis is a foreign body reaction to lipid material used on nasal packing at the conclusion of sinus surgery. This reaction has been associated with postoperative adhesion formation. The purpose of the study was to determine whether the occurrence of myospherulosis has an adverse effect on clinical outcome following sinus surgery. STUDY DESIGN: Case-control study at an academic medical center. METHODS: Thirty-two cases of myospherulosis were identified in 28 patients (4 with bilateral disease) who underwent sinus surgery between 1989 and 1999. Cases were staged according to histological and radiological grading systems. Clinical outcome was compared with a control group of 28 patients who had similar surgery during the same time period. RESULTS: Patients with myospherulosis were found to have a significantly higher likelihood of developing postoperative adhesions compared with control subjects (50% vs. 18%, respectively [P =.023]). Histological stage, based on the extent of lipid vacuoles and spherules (erythrocyte remnants) present in the surgical specimen, was found to correlate with disease severity based on preoperative sinus computed tomography staging (P =.009). Patients with myospherulosis tended to have a shorter interval between their last two surgeries than did control subjects (2.2 +/- 2.1 vs. 4.5 +/- 7.1 y, respectively [P =.086]). Patient age, sex, comorbid conditions, CT stage, and number of previous operations were not predictive for the occurrence of myospherulosis. CONCLUSIONS: Patients who develop myospherulosis from lipid-based packing material used during sinus surgery are more likely to form postoperative adhesions. These adhesions appear to be clinically relevant and may hasten the need for revision surgery.

Fine-needle aspiration biopsy of a cystic pleomorphic adenoma with extensive adnexa-like differentiation: differential diagnostic pitfall with mucoepidermoid carcinoma.

Although fine-needle aspiration biopsy (FNAB) is a highly accurate tool for the diagnosis of pleomorphic adenomas, even this common salivary gland neoplasm can be diagnostically challenging and cause pitfalls in cytodiagnosis. In particular, the presence of either cystic degeneration or squamous and mucinous metaplasia can lead to a false positive diagnosis of malignancy. Here we present the case of a 16-year-old female who presented with a painless, slowly growing mass in the superficial lobe of the right parotid gland. Magnetic resonance imaging of the parotid demonstrated a mass with heterogeneous postcontrast enhancement and a central, nonenhancing area suggestive of necrosis. FNAB of the lesion yielded proteinaceous debris and numerous whorls of keratin, small cohesive clusters of basaloid and squamoid epithelial cells, and many vacuolated and foamy cells. Initially and after consultation at an outside institution, the FNAB was reported as an "atypical neoplasm, cannot exclude mucoepidermoid carcinoma." A total, nerve-sparing parotidectomy and level II neck dissection revealed a pleomorphic adenoma with central cystic degeneration and extensive mixed appendageal differentiation. While foci of squamous metaplastic changes may occur in pleomorphic adenomas, the combination of cystic degeneration and extensive appendageal differentiation with numerous keratotic cysts is rare, and it presents the potential for misinterpretation of the FNAB as indicative of malignancy in general, and mucoepidermoid carcinoma in particular.

Wegener's granulomatosis of the orbit: a clinicopathological study of 15 patients.

OBJECTIVES: Wegener's granulomatosis is a granulomatous and necrotizing vasculitis that classically involves the respiratory and renal systems. The goal of the study was to define clinical and pathological characteristics in a subgroup of patients with the changes of Wegener's granulomatosis involving the orbit. STUDY DESIGN: Retrospective study. METHODS: A database search identified 15 patients with the histological changes of Wegener's granulomatosis of the orbit presenting over a 23-year period. A review of the histological specimens, radiological studies, and patient charts was performed. Additional follow-up data were obtained through patient interviews. RESULTS: Of 15 patients (median age, 54 y) with Wegener's granulomatosis of the orbit identified, the disease was limited to the orbit in 12 patients; 3 patients had additional sinonasal involvement. All patients underwent various surgical procedures followed by medical treatment (cyclophosphamide and prednisone). Specimens showed characteristic histopathological features of Wegener's granulomatosis. Follow-up data were available for 12 patients with a median period of 5 years. In the group with only orbital involvement, none of the patients developed systemic progression of Wegener's granulomatosis. Only one patient had multiple local recurrences and later developed contralateral orbital Wegener's granulomatosis. CONCLUSIONS: Wegener's granulomatosis limited to the orbit is a localized form of the disease without systemic progression. Diagnostic surgical procedures followed by aggressive medical treatment results in good outcome, although local recurrence may occur.

Massa cervical atípica em criança / An unusual pediatric cervical mass

Reporta-se o caso de lactente, com 19 meses de idade, que se apresentou com massa cervical assintomática de dois meses de evolução e que foi submetida a cirurgia. Os achados clinico-patológicos foram consistentes, com cisto de duplicação laríngea. Apresenta-se revisão do diagnóstico diferencial e das características histopatológicas do cisto de duplicação laríngea.

A 19-month-old female who presented with a mo month history of an asymptomatic neck mass and who underwent surgery is reported. The clinicopathologic findings are consistent, with a laryngeal duplication cyst. A review of the differential diagnosis and histopathologic characteristics of laryngeal duplication cyst is presented.