DOG1: a novel marker of salivary acinar and intercalated duct differentiation.

Anoctamin-1 (ANO1) (DOG1, TMEM16a) is a calcium-activated chloride channel initially described in gastrointestinal stromal tumors, but now known to be expressed in a variety of normal and tumor tissues including salivary tissue in murine models. We herein perform a comprehensive survey of DOG1 expression in 156 cases containing non-neoplastic human salivary tissues and tumors. ANO1 mRNA levels were significantly higher (8-fold increase, P<0.0001) in normal parotid tissue (n=6) as compared with squamous mucosa (n=15). By immunohistochemistry, DOG1 showed a diffuse moderate (2+) apical membranous staining pattern in normal serous acini, 1+ apical membranous pattern in mucous acini, and variable 1-2+ apical staining of distal intercalated ducts. Myoepithelial cells, striated and excretory ducts were invariably negative. All acinic cell carcinomas (n=28) were DOG1 positive demonstrating a complex mixture of intense (3+) apical membranous, cytoplasmic and complete membranous staining. Most ductal tumor types were negative or only showed a subset of positive cases. Within the biphasic tumor category, adenoid cystic carcinomas (18/24 cases) and epithelial-myoepithelial carcinomas (8/15 cases) were frequently positive, often showing a distinctive combined apical ductal and membranous/cytoplasmic myoepithelial staining profile. Thus, DOG1 staining is a marker of salivary acinar and to a lesser extent intercalated duct differentiation. Strong staining can be used to support the diagnosis of acinic cell carcinoma. DOG1 may also be a marker of a 'transformed' myoepithelial phenotype in a subset of biphasic salivary gland malignancies.

Microsecretory Adenocarcinoma of Salivary Glands: An Expanded Series of 24 Cases.

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor with a characteristic histologic and immunophenotypic profile and recurrent MEF2C-SS18 fusions. Because only six cases of MSA have been published, its complete clinicopathologic spectrum is unclear, and its biologic behavior has not been documented. Here, we present an updated and expanded experience of 24 MSA cases. All cases of MSA were obtained from the authors' files. Immunohistochemistry for S100, SOX10, p63, p40, SMA, calponin, and mammaglobin was performed. Molecular analysis was performed by targeted RNA sequencing, SS18 break apart fluorescence in situ hybridization, and/or reverse transcriptase polymerase chain reaction for MEF2C-SS18 fusion. Clinical follow-up was obtained from medical records. A total of 24 MSA cases were collected, from 13 women and 11 men, ranging from 17 to 83 years (mean 49.5 years). The vast majority (23 of 24) arose in the oral cavity, with the palate (n = 14) and buccal mucosa (n = 6) as the most frequent subsites. Tumors showed consistent histologic features including: (1) microcystic tubules, (2) flattened intercalated duct-like cells, (3) monotonous oval hyperchromatic nuclei, (4) abundant basophilic luminal secretions, (5) fibromyxoid stroma, and (6) circumscribed borders with subtle infiltration. The tumors were very consistently positive for S100 (24 of 24), p63 (24 of 24), and SOX10 (14 of 14) and negative for p40 (0 of 21), calponin (0 of 12) and mammaglobin (0 of 16), while SMA (4 of 20) was variable. MEF2C-SS18 fusion was demonstrated in 21 of 24 cases; in the remaining 3 cases with insufficient RNA, SS18 break apart FISH was positive. Treatment information was available in 17 cases, all of which were managed with surgery only. In 14 cases with follow-up (1-216 months, mean 30), no cases recurred or metastasized. MSA is a distinct salivary gland neoplasm with remarkably consistent clinical, histologic, immunophenotypic, and genetic features that generally behaves in an indolent manner following surgery alone. These observations solidify MSA as a unique, low-grade salivary gland carcinoma that warrants inclusion in the next version of the WHO classification of head and neck tumors.

Indication and method of frozen section in vaginal radical trachelectomy.

Vaginal radical trachelectomy (VRT) is a fertility-sparing surgical technique used as an alternative to radical hysterectomy in early stage cervical carcinoma. With the advent of VRT, preoperative evaluation of the surgical margin has become imperative, because if the tumor is found within 5 mm of the endocervical margin, additional surgical resection is required. In a study published earlier from our center, we came to the conclusion that a frozen section should be conducted only when a cancerous lesion is grossly visible, and that it could be omitted in normal-looking specimens or VRT with nonspecific lesions. Since then, 53 VRT have been performed in our center, and frozen sections were conducted according to these recommendations. Fifteen VRT were grossly normal, 24 had a nonspecific lesion and 14 showed a grossly visible lesion. Final margins were satisfactory on all 15 grossly normal specimens. Of the 24 VRT with nonspecific lesions, 2 cases for which no frozen section was performed had unsatisfactory final margins (<5 mm). Of the 14 VRT with grossly visible lesions, 3 cases were inadequately evaluated by frozen section due to sampling errors, which led to unsatisfactory final margin assessment. These results confirm that a frozen section can be omitted on normal looking VRT specimens, but contrary to results published earlier, we recommend that a frozen section be performed on all VRT with nonspecific lesions. As for VRT with a grossly visible lesion, frozen section evaluation is still warranted, and we recommend increasing the sampling to improve the adequacy of frozen sections.

Primary Larynx Cryptococcus neoformans Infection: A Distinctive Clinical Entity.

Cryptococcus neoformans can directly infect the vocal cords. Endoscopic findings were undistinctive from most infiltrative diseases. Tissue biopsy was essential for the diagnosis. Inhaled corticosteroids can predispose to the infection, and fluconazole 400 mg daily for at least 6 weeks appeared to be minimal to achieve a permanent cure.

Incidence of human papillomavirus in oropharyngeal squamous cell carcinomas: now and 50 years ago.

The increasing incidence of oropharyngeal squamous cell carcinomas is believed to be due to the growing proportion of human papillomavirus-positive oropharyngeal squamous cell carcinoma. To examine the time trend in the incidence of human papillomavirus, oropharyngeal squamous cell carcinomas diagnosed from 1956 to 1969 (n = 43) and from 2007 to 2009 (n = 54) were tested by p16 immunohistochemistry and in situ hybridization for human papillomavirus. Morphologically, in these 2 time periods, the predominant type of oropharyngeal squamous cell carcinoma changed from keratinizing to nonkeratinizing, with increase in nonkeratinizing cases from 28% to 67% (P < .001). Also, there was an increase in surgical resections versus biopsies (11% versus 46%; odds ratio, 6.6; P < .001) and base of tongue versus tonsillar location (20% versus 40%; odds ratio, 2.6; P = .04). The proportion of human papillomavirus-positive oropharyngeal squamous cell carcinoma increased from 35% to 72% (odds ratio, 4.9; P < .001). This increase was most apparent in men (odds ratio, 4.2; P < .001). This study provides the earliest historic baseline for human papillomavirus incidence in oropharyngeal squamous cell carcinoma and may serve as a reference point for evaluating the results of human papillomavirus infection preventive measures, such as human papillomavirus vaccination.

Squamous cell carcinoma metastatic to neck from an unknown primary: the potential impact of modern pathologic evaluation on perceived incidence of human papillomavirus-positive oropharyngeal carcinoma prior to 1970.

OBJECTIVES/HYPOTHESIS: From the 1950s through the 1960s, an unknown number of oropharyngeal squamous cell carcinomas (SCCs) presented with metastases to cervical lymph nodes from an unknown primary (SCCUP) and were not recognized as oropharyngeal in origin. At present, pathologic evaluation of SCCUP for human papillomavirus (HPV) improves discovery of occult oropharyngeal SCC and may partially explain increased incidence of HPV-positive oropharyngeal SCC. STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective study of 13 cases of SCCUP diagnosed from 1956 to 1969 was performed. The probability of these cases of metastatic SCC to originate from the oropharynx was assessed by characterizing their morphology (keratinizing vs. nonkeratinizing) and HPV status by in situ hybridization and p16 immunostaining. RESULTS: Two cases of nonkeratinizing SCC positive for HPV by in situ hybridization and p16 immunohistochemistry were identified. These cases were most likely of oropharyngeal origin. CONCLUSIONS: These two cases can be added to the other 15 cases of HPV-positive primary oropharyngeal SCC identified in our department from 1956 to 1969. When determining the incidence of HPV-positive oropharyngeal SCC before the 1970s, a correction factor of about +13% (2/15) accounting for modern pathologic workup of SCCUP during the last couple of decades may be appropriate.

Mucoepidermoid carcinoma: a five-decade journey.

Several decades after a comprehensive description of mucoepidermoid carcinoma (MEC), there is no uniformly accepted grading system. The most recent debate regarding the histologic grading of MECs, centers on the wide range of reported prevalence of cyclic AMP response element-binding protein (CREB)-regulated transcription coactivator (CRTC1-MAML2) rearrangement in high-grade (HG) MECs. We hypothesize that difficulties in morphologic classification may partially explain problems in grading MECs. We believe that HG MECs, as diagnosed over the last several decades, represent a blend of true MECs with unrelated clinicopathologic entities. To examine the historic aspects of this problem, and to identify neoplasms that most commonly mimic "high-grade" MEC, we reviewed 46 cases of alleged MEC diagnosed in our department from 1956 to 1974. The diagnosis of MEC was confirmed in 22 cases and was changed in 24 cases. Compared to cases of confirmed MEC, cases with changed diagnoses had higher incidence of lymph node metastases, perineural invasion, and shorter overall survival. Adenosquamous carcinoma, squamous cell carcinoma, and salivary duct carcinoma emerged as the most common mimics of HG MEC. The single most common diagnostic issue in these cases is the level of keratinization acceptable for MEC. Twenty cases of confirmed MEC were tested for CRTC1-MAML2 rearrangement and 5 low-grade MECs, 7 intermediate grade MECs, and 2 cases of HG MEC were translocation-positive.

Mixed ovarian large cell neuroendocrine carcinoma, mucinous adenocarcinoma, and teratoma: a report of two cases and review of the literature.

Large cell neuroendocrine carcinoma of the ovary is a rare recently established entity. Few cases have been reported in the literature, and they are usually associated with another type of surface epithelial tumor. The association of a large cell neuroendocrine carcinoma with a surface epithelial tumor and a teratoma is even rarer, with only two cases previously described. We report the cases of two patients in their fifties who presented with a growing abdominal mass and died of metastatic disease within less than a year. Histological assessment revealed large cell neuroendocrine carcinoma admixed with mucinous adenocarcinoma and teratoma. Different hypotheses regarding the origin of large cell neuroendocrine carcinoma of the ovary are discussed. The immunohistochemical pattern of staining for cytokeratin 7 and cytokeratin 20 suggests that the composite epithelial tumors originated from the pre-existing teratoma.