Immunohistochemical Detection and Molecular Characterization of IDH-mutant Sinonasal Undifferentiated Carcinomas.

Recent studies have identified recurrent isocitrate dehydrogenase 2 (IDH2) mutations in a subset of sinonasal undifferentiated carcinomas (SNUCs); however, the true frequency of IDH mutations in SNUC is unknown. We evaluated the utility of mutation-specific IDH1/2 immunohistochemistry (IHC) in a large multi-institutional cohort of SNUC and morphologic mimics. IHC using a multispecific antibody for IDH1/2 (R132/R172) mutant protein was performed on 193 sinonasal tumors including: 53 SNUCs, 8 poorly differentiated carcinomas (PDCARs) and 132 histologic mimics. Mutant IDH1/2 IHC was positive in 26/53 SNUCs (49%; 20 strongly positive and 6 weak) and 3/8 PDCARs (37.5%; 2 strong; 1 weak) but was absent in all other tumor types (0/132). Targeted next-generation sequencing (NGS) on a subset of SNUC/PDCAR (6 strong and 3 weak positive for IDH1/2 IHC; 7 negative) showed frequent IDH2 R172X mutations (10/16) and a single IDH1 R132C mutation. All 6 cases with strong positive mutant IDH1/2 staining and NGS had IDH2 R172S/G mutations. The 3 IHC-weak cases all had IDH2 R172T mutations. Among the 7 tested cases that were negative for mutant IDH1/2 IHC, NGS detected 1 case each with IDH2 R172T and IDH1 R132C mutation. IDH-mutant carcinomas also had frequent mutations in TP53 (55%) and activating mutations in KIT (45%) or the PI3K pathway (36%). Mutation-specific IDH1/2 IHC identifies IDH mutations in SNUC, however, it lacks sensitivity for the full range of IDH mutations. These findings suggest that IDH-mutant sinonasal carcinoma may represent a distinct pathobiological entity with therapeutic implications that can be identified by a combined approach of multispecific IDH1/2 IHC and sequencing.

Whole Slide Imaging Versus Microscopy for Primary Diagnosis in Surgical Pathology: A Multicenter Blinded Randomized Noninferiority Study of 1992 Cases (Pivotal Study).

Most prior studies of primary diagnosis in surgical pathology using whole slide imaging (WSI) versus microscopy have focused on specific organ systems or included relatively few cases. The objective of this study was to demonstrate that WSI is noninferior to microscopy for primary diagnosis in surgical pathology. A blinded randomized noninferiority study was conducted across the entire range of surgical pathology cases (biopsies and resections, including hematoxylin and eosin, immunohistochemistry, and special stains) from 4 institutions using the original sign-out diagnosis (baseline diagnosis) as the reference standard. Cases were scanned, converted to WSI and randomized. Sixteen pathologists interpreted cases by microscopy or WSI, followed by a wash-out period of ≥4 weeks, after which cases were read by the same observers using the other modality. Major discordances were identified by an adjudication panel, and the differences between major discordance rates for both microscopy (against the reference standard) and WSI (against the reference standard) were calculated. A total of 1992 cases were included, resulting in 15,925 reads. The major discordance rate with the reference standard diagnosis was 4.9% for WSI and 4.6% for microscopy. The difference between major discordance rates for microscopy and WSI was 0.4% (95% confidence interval, -0.30% to 1.01%). The difference in major discordance rates for WSI and microscopy was highest in endocrine pathology (1.8%), neoplastic kidney pathology (1.5%), urinary bladder pathology (1.3%), and gynecologic pathology (1.2%). Detailed analysis of these cases revealed no instances where interpretation by WSI was consistently inaccurate compared with microscopy for multiple observers. We conclude that WSI is noninferior to microscopy for primary diagnosis in surgical pathology, including biopsies and resections stained with hematoxylin and eosin, immunohistochemistry and special stains. This conclusion is valid across a wide variety of organ systems and specimen types.

Diagnostic Efficiency in Digital Pathology: A Comparison of Optical Versus Digital Assessment in 510 Surgical Pathology Cases.

Prior work has shown that digital images and microscopic slides can be interpreted with comparable diagnostic accuracy. Although accuracy has been well-validated, the interpretative time for digital images has scarcely been studied and concerns about efficiency remain a major barrier to adoption. We investigated the efficiency of digital pathology when compared with glass slide interpretation in the diagnosis of surgical pathology biopsy and resection specimens. Slides were pulled from 510 surgical pathology cases from 5 organ systems (gastrointestinal, gynecologic, liver, bladder, and brain). Original diagnoses were independently confirmed by 2 validating pathologists. Diagnostic slides were scanned using the Philips IntelliSite Pathology Solution. Each case was assessed independently on digital and optical by 3 reading pathologists, with a ≥6 week washout period between modalities. Reading pathologists recorded assessment times for each modality; digital times included time to load the case. Diagnostic accuracy was determined based on whether a rendered diagnosis differed significantly from the original diagnosis. Statistical analysis was performed to assess for differences in interpretative times across modalities. All 3 reading pathologists showed comparable diagnostic accuracy across optical and digital modalities (mean major discordance rates with original diagnosis: 4.8% vs. 4.4%, respectively). Mean assessment times ranged from 1.2 to 9.1 seconds slower on digital versus optical. The slowest reader showed a significant learning effect during the course of the study so that digital assessment times decreased over time and were comparable with optical times by the end of the series. Organ site and specimen type did not significantly influence differences in interpretative times. In summary, digital image reading times compare favorably relative to glass slides across a variety of organ systems and specimen types. Mean increase in assessment time is 4 seconds/case. This time can be minimized with experience and may be further balanced by the improved ease of electronic chart access allowed by digital slide viewing, as well as quantitative assessments which can be expedited on digital images.

HR-HPV E6/E7 mRNA In Situ Hybridization: Validation Against PCR, DNA In Situ Hybridization, and p16 Immunohistochemistry in 102 Samples of Cervical, Vulvar, Anal, and Head and Neck Neoplasia.

Dysregulated expression of oncogenic types of E6 and E7 is necessary for human papillomavirus (HPV)-driven carcinogenesis. An HPV E6/E7 mRNA in situ hybridization (ISH) assay covering 18 common high-risk types ("HR-RISH," aka HR-HPV RNA18 ISH) has not been extensively studied in the anogenital tract or validated on automated technology. We herein compare HR-RISH to DNA polymerase chain reaction (PCR), p16 immunohistochemistry, and a previously available HPV DNA ISH assay in HPV-related anogenital and head and neck (H&N) neoplasia. A total of 102 squamous intraepithelial lesions (16 CIN1, 25 CIN3, 3 AIN1, 12 AIN3, 9 VIN3)/invasive squamous cell carcinomas (17 cervical, 2 anal, 18 H&N) as well as 10 normal and 15 reactive cervix samples were collected. HR-RISH, DNA ISH, and p16 immunohistochemistry were performed on whole formalin-fixed, paraffin-embedded sections. RNA ISH for 6 low-risk HPV types (LR-RISH) was also performed. RNA and DNA ISH assays used automated systems. HR-HPV PCR was performed on morphology-directed formalin-fixed, paraffin-embedded punches. HR-RISH was ≥97% sensitive for PCR+ and p16+ neoplasia, as well as morphologically defined anogenital high grade squamous intraepithelial lesion/invasive squamous cell carcinoma. HR-RISH was also positive in 78% of anogenital low grade squamous intraepithelial lesion, including 81% of CIN1. Furthermore, a subset of PCR-negative/invalid and p16-negative lesions was positive for HR-RISH. Only 1 problematic reactive cervix sample and no normal cervix samples stained. These results demonstrate that HR-RISH is a robust method for the detection of HR-HPV-related neoplasia and provides insight into HPV pathobiology. Performance meets or exceeds that of existing assays in anogenital and H&N lesions and may play a role in resolving diagnostically challenging CIN1 versus reactive cases.

SMARCB1 (INI-1)-deficient Sinonasal Carcinoma: A Series of 39 Cases Expanding the Morphologic and Clinicopathologic Spectrum of a Recently Described Entity.

To more fully characterize the clinical and pathologic spectrum of a recently described tumor entity of the sinonasal tract characterized by loss of nuclear expression of SMARCB1 (INI1), we analyzed 39 SMARCB1-deficient sinonasal carcinomas collected from multiple medical centers. The tumors affected 23 males and 16 females with an age range of 19 to 89 years (median, 52). All patients presented with locally advanced disease (T3, n=5; T4, n=27) involving the sinuses (mainly ethmoid) with variable involvement of the nasal cavity. Thirty patients received surgery and/or radiochemotherapy with curative intent. At last follow-up, 56% of patients died of disease 0 to 102 months after diagnosis (median, 15), 2 were alive with disease, and 1 died of an unrelated cause. Only 9 patients (30%) were alive without disease at last follow-up (range, 11 to 115 mo; median, 26). The original diagnosis of retrospectively identified cases was most often sinonasal undifferentiated carcinoma (n=14) and nonkeratinizing/basaloid squamous cell carcinoma (n=5). Histologically, most tumors displayed either a predominantly basaloid (61%) or plasmacytoid/rhabdoid morphology (36%). The plasmacytoid/rhabdoid form consisted of sheets of tumor cells with abundant, eccentrically placed eosinophilic cytoplasm, whereas similar cells were typically rare and singly distributed in the basaloid variant. Glandular differentiation was seen in a few tumors. None of the cases showed squamous differentiation or surface dysplasia. By immunohistochemistry, the tumors were positive for pancytokeratin (97%), CK5 (64%), p63 (55%), and CK7 (48%); and they were negative for NUT (0%). Epstein-Barr virus and high-risk human papillomavirus was not detected by in situ hybridization. Immunohistochemical loss of SMARCB1 (INI1) expression was confirmed for all 39 tumors. Investigation of other proteins in the SWI/SNF complex revealed co-loss of SMARCA2 in 4 cases, but none were SMARCA4 deficient or ARID1A deficient. Of 27 tumors with SMARCB1 fluorescence in situ hybridization analysis, 14 showed homozygous (biallelic) deletions and 7 showed heterozygous (monoallelic) deletions. SMARCB1-deficient sinonasal carcinoma represents an emerging poorly differentiated/undifferentiated sinonasal carcinoma that (1) cannot be better classified as another specific tumor type, (2) has consistent histopathologic findings (albeit with some variability) with varying proportions of plasmacytoid/rhabdoid cells, and (3) demonstrates an aggressive clinical course. This entity should be considered in any difficult-to-classify sinonasal carcinoma, as correct diagnosis will be mandatory for optimizing therapy and for further delineation of this likely underdiagnosed disease.

Thyroid sclerosing mucoepidermoid carcinoma with eosinophilia: a clinicopathologic and molecular analysis of a distinct entity.

Sclerosing mucoepidermoid carcinoma with eosinophilia is a rare thyroid neoplasm of uncertain pathogenesis that resembles salivary gland mucoepidermoid carcinoma. This multi-institutional study characterizes the clinicopathologic and molecular features of this tumor by utilizing next-generation sequencing to assess common mutations and gene fusions involved in thyroid carcinogenesis as well as fluorescence in-situ hybridization for MAML2 translocations typical of salivary gland mucoepidermoid carcinoma. Nine cases (6 females and 3 males, mean age: 59 years, range 30-77 years) were identified. All cases were comprised of nests and strands of tumor cells with both squamous and mucinous differentiation embedded in a fibrohyaline stroma with an inflammatory infiltrate replete with eosinophils. All cases were p63 positive, thyroglobulin negative and showed variable expression of TTF-1. All nine cases were negative for MAML2 rearrangements. Five cases successfully tested by next-generation sequencing (ThyroSeq v.2 assay) were negative for mutations and translocations commonly involved in thyroid carcinogenesis. NTRK1 showed overexpression but no evidence of translocation. On follow-up, one patient died of persistent disease, whereas one of four remaining patients with available follow-up (mean: 7.3 years, range 4-11 years) demonstrated recurrence at 4 years. Thus, we show that sclerosing mucoepidermoid carcinoma with eosinophilia appears molecularly and morphologically distinct from follicular and C-cell-derived thyroid tumors as well as from salivary gland mucoepidermoid carcinoma. The overall and recurrence-free survival for these patients may be lower than for other well-differentiated thyroid cancers.

Spindle Cell Melanoma and Interdigitating Dendritic Cell Sarcoma: Do They Represent the Same Process?

Intranodal spindle cell lesions on biopsy are problematic for a surgical pathologist, often requiring an extensive immunohistochemical evaluation with variable and frequently unsatisfactory results. In the absence of a history of malignancy, the differential diagnosis of a spindle cell tumor must include both a primary nodal proliferation and a metastatic process. Particularly challenging are those lesions that share morphologic and immunohistochemical features; spindle cell melanomas (SCM) and interdigitating dendritic cell sarcomas (IDCS) belong to this category. At present, electron microscopy is the only method proposed to distinguish between the 2 entities; however, this method is often unavailable and impractical. In this study, we assessed the comparative immunophenotypes of 18 cases of SCM and 8 cases of IDCS, with particular emphasis on the expression of MUM-1, ß-catenin, SOX-10, MiTF, and p75. Our results showed nearly equivalent staining patterns and profiles; 12% and 17% of IDCS and SCM were labeled for MUM-1, 75% and 83% stained for ß-catenin, 0% and 24% expressed MiTF, and 100% and 94% labeled for p75, respectively. All cases of IDCS and SCM displayed strong nuclear reactivity for SOX-10. On the basis of our study and pertinent literature, the morphologic and immmunophenotypic features of SCM and IDCS appear to be virtually indistinguishable from one another, raising the question as to whether these 2 entities represent a pathobiologically similar or even identical process.

Sclerosing Microcystic Adenocarcinoma of the Head and Neck Mucosa: A Neoplasm Closely Resembling Microcystic Adnexal Carcinoma.

Microcystic adnexal carcinoma (MAC) occurs predominantly in the centrofacial skin and has been only rarely reported in mucosal surfaces. We here present a 5 case series of tumors closely resembling MAC occurring in the mucosal surfaces of the head and neck, which we have termed sclerosing microcystic adenocarcinomas. These tumors showed a predilection for women (4:1) with an average patient age of 52.6 years (range 41-73 years). Location included the tongue (n = 2), the floor of the mouth (n = 2), and the nasopharynx/clivus (n = 1). One occurred after radiation therapy and another occurred in the setting of immune compromise. Immunohistochemistry highlighted a dual cell population with luminal cells showing positivity for high and low-molecular weight keratins and surrounding myoepithelial cells showing S100 and smooth muscle actin staining. No cases had nodal involvement, and the single patient with clinical follow-up was alive and free of disease 34 months after diagnosis and definitive radiochemotherapy. Differential diagnoses for all cases diverged from those provoked by MAC in the skin and included a variety of salivary gland neoplasms such as adenoid cystic carcinoma, polymorphous low grade adenocarcinoma, and mucoepidermoid carcinoma. Recognition of sclerosing microcystic adenocarcinoma in the head and neck mucosa is critical given its bland appearance and subtle infiltration pattern, infrequency of nodal involvement, and behavioral differences from the other entities on the differential.

Large Cell Neuroendocrine Carcinoma of the Head and Neck: A Clinicopathologic Series of 10 Cases With an Emphasis on HPV Status.

Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine neoplasm first described in the lung and subsequently well documented in many other anatomic sites. It has only recently been recognized that LCNEC can also occasionally arise in the head and neck. The role of human papillomavirus (HPV), which is associated with some small cell carcinomas of the head and neck, has not been investigated for LCNEC. We sought to further characterize the histologic, immunophenotypic, and clinical features of LCNEC and also investigate the role of HPV in this newly described group of tumors. The surgical pathology archives of 2 large academic institutions were searched for cases of LCNEC arising in the head and neck. p16 immunohistochemistry and HPV in situ hybridization were performed, and clinical information was obtained from electronic medical records. Ten cases of head and neck LCNEC were identified. The tumors arose in 6 men and 4 women ranging in age from 14 to 70 years (median, 63.5 y). The primary tumor sites were the oropharynx (n=4), the sinonasal tract (n=3), and the larynx (n=3). The LCNECs consisted of nests and trabeculae of medium-large cells with abundant cytoplasm, coarse chromatin, and prominent nucleoli with very high mitotic rates. The tumor nests were often associated with necrosis, peripheral palisading, and rosette formations. The LCNECs were positive for pan-cytokeratin and at least 1 neuroendocrine marker (most often synaptophysin) and were largely negative for p63 (focal staining in 2/10) and CK5/6 (staining in 1/10). The LCNECs demonstrated aggressive clinical behavior: 8 of 10 presented with advanced disease, 5 of 10 died, with 4 more living but with persistent tumor. Three of 10 LCNECs were HPV-related (HPV-LCNEC); they arose in the oropharynx (n=2) and sinonasal tract (n=1). The HPV-LCNECs did not differ from the HPV-negative tumors in histologic appearance or behavior: 2 patients with HPV-LCNEC have died because of their disease and 1 remains alive but with widespread metastases. LCNEC is a rare but distinct form of head and neck carcinoma that exhibits aggressive clinical behavior. A subset of oropharyngeal and sinonasal LCNEC is HPV related, but the presence of HPV may not impart a more favorable prognosis. Because of its aggressive behavior, LCNEC should be distinguished from moderately differentiated neuroendocrine carcinoma and squamous cell carcinoma. The morphology of LCNEC overlaps considerably with the nonkeratinizing appearance of HPV-related squamous cell carcinoma, and as a result a high index of suspicion is needed to identify LCNEC. Immunohistochemical studies for synaptophysin and p63 are helpful tools for making this distinction.

Obituary of Philip H. Cooper, MD.

Dermatopathology lost a giant in the field with the death of Philip H. Cooper, MD, on Friday, January 30, 2015. The following obituary represents a celebration of his life and his contributions to our field.

Gnathic and peripheral ameloblastomas lack human papillomavirus DNA.

Human papillomavirus (HPV) has been associated with a variety of head and neck neoplasms, including squamous cell carcinomas and Schneiderian papillomas. Ameloblastomas can arise from either the gnathic bones or peripheral soft tissues. Peripheral sinonasal ameloblastomas share clinical features with Schneiderian papillomas. A small number of reports have described detection of HPV DNA within ameloblastomas. However, Most of these cases was reported in the 1990s, used the polymerase chain reaction technique, and only examined gnathic tumors. The current study was designed to determine whether low- or high-risk HPV DNA could be detected in gnathic or peripheral ameloblastomas using in situ hybridization. Twenty-nine examples of gnathic osseous and peripheral head and neck ameloblastomas were obtained from the authors' archives (University of Virginia and the Johns Hopkins Hospital). High-risk HPV DNA was not detected in any of the 29 tumors analyzed. Low-risk HPV DNA was identified in only 1 tumor, which was peripheral in origin, and from an immunocompromised patient. We believe that the HPV in this case represents a background "passenger" infection. This study demonstrates that HPV of either high- or low-risk subtypes is unlikely to play a role in the pathogenesis of sinonasal ameloblastomas.

Morphology in conjunction with immunohistochemistry is sufficient for the diagnosis of mammary analogue secretory carcinoma.

The recently described mammary analogue secretory carcinoma (MASC) is a low-grade salivary gland malignancy that harbors the recurrent cytogenetic abnormality t(12;15) (p13;q25) ETV6-NTRK3. Confirmation of this is currently considered the gold standard for diagnosis. Some have postulated that morphology together with supporting immunohistochemistry is sufficient to diagnose MASC. In this study we retrospectively review a series of 19 MASCs diagnosed based on histology in conjunction with immunohistochemistry; subsequently we performed in situ hybridization using an ETV6 break-apart probe. Immunohistochemistry for S100 protein and mammaglobin as well as fluorescence in situ hybridization using the Vysis ETV6 Dual Color Break-Apart FISH Probe Kit were performed on all cases. The 19 cases were from 12 females and 7 males with ages ranging from 16 to 76 years (mean = 45 years). Sixteen cases were from the parotid gland, 1 case was from a periparotid lymph node and 2 cases were from the submandibular gland. All 19 cases demonstrated moderate to strong expression of S100 protein. Eighteen cases demonstrated strong, diffuse expression of mammaglobin, while one case had only rare tumor cells that strongly expressed mammaglobin. Eighteen of 19 cases (95 %) demonstrated the ETV6 rearrangement by fluorescence in situ hybridization. Given that morphology together with immunohistochemistry is highly correlated with the ETV6 gene rearrangement, we conclude that molecular confirmation is not required to diagnose MASC.

From slide sets to sound bites: teaching and learning pathology in the digital age.

Educational evolution is particularly important in pathology, particularly cytopathology, due to the vast amounts of independent learning required to master this field. In this study, learning challenges faced by pathology residents were addressed through a variety of educational modalities including 24 short (∼10 minute) online tutorials (dubbed "Sound Bites") covering selected topics in cytopathology as well as other areas of anatomic and clinical pathology. Additionally, residents were provided with an annotated glass slide set covering pediatric pathology with an associated multiple choice self-assessment as well as multiheaded microscope slide review sessions. Use of these modalities was tracked and residents surveyed about their experiences using them. All 20 residents (100%) reported using Sound Bites either from work computers, home computers, or mobile devices. Residents reported that easy accessibility, brevity, and opportunities for self-assessment were important variables contributing to this use, and that Sound Bite use would make them more likely to benefit from in-person teaching through lectures and/or slide sessions. Within 12 months of the release of the first Sound Bite, individual Sound Bites were accessed a total of 1169 times (mean: 49 times per Sound Bite). In contrast, slide sets were only accessed about once a month and were only employed by 30% of residents (6 of 20) for independent study; only 20% (4 of 20) completed the accompanying multiple choice self-assessment. All residents attended multiheaded microscope slide review sessions. Whereas traditional educational methods remain valuable tools in pathology education, these data suggest that short, web-based tutorials represent a valuable adjuvant teaching tool.

EWSR1 genetic rearrangements in salivary gland tumors: a specific and very common feature of hyalinizing clear cell carcinoma.

The Ewing sarcoma breakpoint region 1 (EWSR1) is translocated in many sarcomas. Recently, its rearrangement has been described in salivary gland hyalinizing clear cell carcinomas (HCCCs) and in a subset of soft tissue myoepitheliomas. This study examines the presence of the EWSR1 rearrangement in a variety of salivary gland lesions including classic myoepitheliomas and HCCCs. Using a tissue microarray and whole-mount sections, fluorescence in situ hybridization (FISH) was performed on a variety of salivary gland lesions including HCCCs. The EWSR1 rearrangement was detected in 87% of HCCCs (13 of 15); all other salivary gland lesions including classic myoepitheliomas had intact EWSR1. Patients with HCCCs with rearranged EWSR1 included 1 man, 10 women, and 2 of unknown sex. Ages ranged from 35 to 83 years; the tumor size ranged from 0.8 to 5.5 cm, and the involved locations included: palate (2), base of the tongue (2), mandible (2), submandibular gland (2), lip (1), floor of the mouth (1), sublingual gland (1), inner cheek (1), and nasopharynx (1). All HCCCs were composed of sheets and nests of monotonous cells with clear cytoplasm within a hyalinized stroma. All tested cases were immunoreactive with antibodies to p63 and were nonreactive with antibodies to more conventional myoepithelial antigens (e.g., smooth muscle actin and S100 protein). These findings show that the EWSR1 rearrangement is almost a defining feature of HCCCs and also confirm that classic salivary gland myoepitheliomas are distinct from these tumors and do not share a pathogenetic relationship with their soft tissue counterparts.

A histologic and immunohistochemical study describing the diversity of tumors classified as sinonasal high-grade nonintestinal adenocarcinomas.

Nonintestinal sinonasal adenocarcinomas (SNACs) are somewhat poorly characterized and high-grade nonintestinal SNACs have been only rarely reported. Here, we review our experience with these tumors. Twenty-seven cases of high-grade nonintestinal SNACs were identified from 22 men and 5 women. Ages ranged from 22 to 83 years (mean±1 standard deviation=54.7±18.6 y; median=60 y). Thirteen cases involved the nasal cavity and sinuses, 10 involved the nasal cavity only, and 4 involved sinuses only. Most cases had marked cytologic and nuclear pleomorphism, abundant mitotic activity, and necrosis; however, these features were not uniform. Although histologically heterogeneous, recurrent growth patterns were seen that resembled other neoplasms of the area. Tumors lacked CDX2 and CK20 immunoreactivity (aside from rare CK20 immunoreactive cells). High-grade nonintestinal SNACs are more common in men and, although they occur over a wide age range, they are much more common in older individuals. Histologically, they show a great deal of heterogeneity.

Ewing's family of tumors of the sinonasal tract and maxillary bone.

The Ewing's family of tumors (EFT) are malignant neoplasms affecting children and young adults. Most cases arise in the long bones or the pelvis. Primary EFT of head and neck is uncommon and primary sinonasal EFT is even rarer. Previous studies have not focused on the sinonasal region specifically, and the published literature on sinonasal EFT consists of sporadic case reports. Fourteen cases of sinonasal EFT were available and had H&Es for review and immunohistochemical stains for CD99, S100, keratins, synaptophysin and desmin. FISH or RT-PCR was performed for EWSR1 abnormalities on 8 cases. The 14 identified patients included 5 males and 9 females, ranging from 7-70 years of age (mean 32.4 years). Tumors involved nasal cavity (5), sinuses (5) or both (4). Five patients had dural, orbital or brain involvement. The majority involved bone radiologically and/or microscopically. All cases were composed of small cells with variable cytoplasmic clearing. Focal or prominent nesting was noted in most cases. All cases were positive for CD99. Keratins (AE1/3 and/or CAM5.2), S100 and synaptophysin were positive in 4, 3 and 5 cases, respectively. All cases were negative for desmin. The 8 cases tested by FISH or RT-PCR were positive for EWSR1 abnormalities. Follow-up in 8 patients ranged from 1-168 months (average 11.3 m) showing 1 death due to metastatic disease, 1 death due to local disease, 1 patient alive with metastases and 5 patients disease-free at last follow-up. Interestingly, however, an analysis of the literature suggests a better prognosis for sinonasal EFT than EFT overall.

Encapsulated papillary oncocytic neoplasms of the thyroid: morphologic, immunohistochemical, and molecular analysis of 18 cases.

Encapsulated papillary oncocytic neoplasms (EPONs) of the thyroid are rare tumors, whose relationship to other thyroid tumors has not been thoroughly elucidated. Earlier, they have been regarded as variants of papillary thyroid carcinoma (PTC), hyperplastic lesions, and follicular neoplasms. Eighteen EPONs were retrieved from our surgical pathology files and reviewed for defining morphologic features. Cases having the typical nuclear features of PTC were excluded. Immunohistochemistry (IHC) for CK19, HBME1, and CD56 was carried out. Microdissection, polymerase chain reaction, and sequencing of exon 15 of the BRAF gene were completed. Cases were evaluated for rearranged in transformation/papillary thyroid carcinoma RET/PTC rearrangement by fluorescent in situ hybridization (FISH). The majority of the tumors exhibited a distinctive histologic appearance. They were composed of true papillae lined by a single layer of predominantly cuboidal cells with oncocytic cytoplasm; hobnailing was typically prominent. Three tumors showed taller cells with uniformly apical nuclei and no hobnailing. Ten of 18 cases showed vascular and/or capsular invasion; hence, if the diagnostic criteria used to evaluate follicular neoplasms are applied, more than half of the tumors would be considered minimally invasive carcinomas. No cases were immunoreactive with antibodies to HBME1, whereas only 1 of 13 was immunoreactive for CK19. Six of 7 interpretable cases were immunoreactive for CD56. No BRAF point mutations or RET/PTC rearrangements were identified in the examined cases. All patients were alive at the time of last follow-up and no locally recurrent disease had been reported; however, 1 case was remarkable for a lymph node metastasis. Our results confirm that EPONs are histologically, immunohistochemically, and molecularly distinct from papillary thyroid carcinoma and seem to be most related to follicular neoplasms.

BCL2 chromosomal translocation is not a general feature of the interdigitating dendritic cell sarcoma.

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare neoplasia of interdigitating dendritic cells. Two single case reports documenting IDCS harboring t(14;18) translocation involving immunoglobulin heavy chain (IGH) and BCL2 have been reported recently; however, one of the 2 IDCS has a synchronous follicular lymphoma, the absence or presence of a follicular lymphoma in the remaining case is not mentioned. In this study, by using polymerase chain reaction and fluorescence in situ hybridization techniques, we have showed that there is neither t(14;18)/IGH-BCL2 nor IGH gene rearrangement in 4 de novo IDCS without a concurrent or known history of a B-cell lymphoma, including follicular lymphoma, indicating that BCL2 chromosomal translocation is not a general feature of de novo IDCS.

Adenocarcinoma of the upper aerodigestive tract.

Although squamous cell carcinoma is the most frequent malignant diagnosis made with upper aerodigestive tract specimens, a myriad of neoplasms can occur throughout the area. Very uncommonly, one encounters adenocarcinomas that cannot be better classified as salivary gland-type neoplasia. This manuscript reviews these tumors, including sinonasal intestinal-type adenocarcinomas, sinonasal low-grade and high-grade nonintestinal adenocarcinomas and nasopharyngeal papillary adenocarcinomas. Clinical, histologic, and immunohistochemical features and differential diagnoses are discussed.

Human papillomavirus-associated squamous cell carcinoma of the upper aerodigestive tract.

The association of human papillomavirus with the development of head and neck squamous cell carcinomas has been better elucidated over the past 20 years. In this review article, we examine the role of the virus in the development of these tumors. We discuss the clinical and pathologic features of human papillomavirus-associated squamous cell carcinomas of the head and neck. Immunohistochemical findings and those of other ancillary techniques are also reviewed. We further review the prognosis and treatment of these tumors. Finally, a detailed discussion is provided regarding the differential diagnosis that must be considered when confronting these squamous neoplasms.