Malignant Transformation of a Desmoplastic Ameloblastoma to Squamous Cell Carcinoma: A Case Report.

Ameloblastomas are the most common odontogenic tumors, excluding odontomas. Several morphologic variants have been described including follicular, plexiform, acanthomatous, granular cell, basaloid and desmoplastic. Desmoplastic ameloblastoma differs from other conventional ameloblastomas microscopically, clinically, and radiographically. Ameloblastic carcinoma, the malignant counterpart of ameloblastoma is characterized by cytologic features of malignancy combined within the overall histologic features of conventional ameloblastoma. Malignant transformation of ameloblastoma to squamous cell carcinoma is a controversial subject. Here we report a case of a desmoplastic ameloblastoma with malignant transformation to squamous cell carcinoma in a 49 year old African American man. The patient underwent tumor resection and radiation therapy with no evidence of disease recurrence or progression 16 months post operatively. To our knowledge malignant transformation of a desmoplastic ameloblastoma to squamous cell carcinoma has not so far been reported. This observation may lend some support to the argument that desmoplastic ameloblastoma is phenotypically and biologically distinct entity.

Salivary Duct Carcinoma and Invasive Ductal Carcinoma of the Breast: A Comparative Immunohistochemical Study.

Salivary duct carcinoma (SDC) is a high-grade salivary gland malignancy with great morphological resemblance to invasive ductal carcinoma (IDC) of the breast. Rarely, female patients may have a past history of both SDC and IDC. When these patients present with distant metastasis, accurate identification of the primary tumor is particularly difficult. Additionally, rare metastasis of SDC to the breast and IDC to the salivary (parotid) gland can also present a diagnostic challenge. Our aim was to develop an immunohistochemical panel that reliably distinguishes SDC from IDC. We included all SDCs diagnosed from 1989 to 2016 (23 cases) and 29 treatment naïve and histologically similar IDCs. All cases were stained with androgen receptor (AR), estrogen receptor-alpha (ER-α), progesterone receptor (PR), HER-2, CK5/6, p63, and beta-catenin. The great majority (> 90%) of both SDCs and IDCs reacted positively to AR. The main discrepancy in the immunohistochemical profiles was a distinctly different reactivity to ER-α, PR and HER-2. While 28 IDCs (96.6%) reacted positively to ER-α and/or PR, the majority expressing both (82.8%) with a moderate to strong staining intensity, only 2 SDCs expressed ER-α (8.7%) and 5 others expressed PR (21.7%) with only one case expressing both (P value < 0.05). On the other hand, 8 SDC (34.8%) were positive for HER-2 while none of the IDCs were positive (P value < 0.05). ER-α, PR, and HER-2 may be helpful to distinguish SDC from IDC. Positive reactivity to ER-α, PR or both and negative HER-2 favors a diagnosis of IDC while ER-α, PR negative, HER-2 positive tumors are more likely SDC.

Expression of CDX2 and Thyroid Transcription Factor-1 in Oropharyngeal Undifferentiated Carcinomas: A Potential Diagnostic Pitfall.

Oropharyngeal undifferentiated carcinomas are rare and most are human papillomavirus related. Morphologically, they overlap with undifferentiated carcinomas from other organ sites, including the nasopharynx, lung, and gastrointestinal tract. Most have lymph node metastases at presentation and, especially when initially encountered in a lymph node, immunostains may be performed to determine the most likely primary site. We recently reviewed a case in consultation that strongly and diffusely expressed both thyroid transcription factor-1 (TTF-1, SPT24 clone) and CDX2, 2 widely used markers that are considered relatively lineage specific for lung/thyroid and intestinal differentiation, respectively. Unexpected expression of these markers could be misleading. However, they have not been previously assessed in oropharyngeal undifferentiated carcinoma. Here, we performed immunohistochemistry for CDX2 and TTF-1 (8G7G3/1 clone) on primary tumors and/or lymph node metastases from 11 in-house patients with previously characterized undifferentiated carcinoma of the oropharynx from 1992 to 2008. All were male with an average age of 56.7 years, and 5 (46%) initially presented with a neck mass. All were Epstein-Barr virus negative and 9 (82%) were human papillomavirus and p16 positive. CDX2 was positive in 6 of the 11 (55%) cases. However, staining was generally weak to moderate and/or nondiffuse. TTF-1 was negative in all the in-house cases and showed only rare, weakly positive cells in the consult case when TTF-1 was repeated using the 8G7G3/1 clone. Thus, CDX2 immunoreactivity is common, whereas TTF-1 expression is rare in oropharyngeal undifferentiated carcinomas. As a result, one should not rely on CDX2 as evidence of intestinal differentiation or origin in metastatic undifferentiated carcinomas in the neck, particularly when staining is not strong and diffuse. In addition, TTF-1 should be interpreted with caution especially when using the SPT24 clone.

Gnathodiaphyseal dysplasia: Severe atypical presentation with novel heterozygous mutation of the anoctamin gene (ANO5).

Gnathodiaphyseal dysplasia (GDD; OMIM #166260) is an ultra-rare autosomal dominant disorder caused by heterozygous mutation in the anoctamin 5 (ANO5) gene and features fibro-osseous lesions of the jawbones, bone fragility with recurrent fractures, and bowing/sclerosis of tubular bones. The physiologic role of ANO5 is unknown. We report a 5-year-old boy with a seemingly atypical and especially severe presentation of GDD and unique ANO5 mutation. Severe osteopenia was associated with prenatal femoral fractures, recurrent postnatal fractures, and progressive bilateral enlargement of his maxilla and mandible beginning at ~2months-of-age that interfered with feeding and speech and required four debulking operations. Histopathological analysis revealed benign fibro-osseous lesions resembling cemento-ossifying fibromas of the jaw without psammomatoid bodies. A novel, de novo, heterozygous, missense mutation was identified in exon 15 of ANO5 (c.1553G>A; p.Gly518Glu). Our findings broaden the phenotypic and molecular spectra of GDD. Fractures early in life with progressive facial swelling are key features. We assessed his response to a total of 7 pamidronate infusions commencing at age 15months. Additional reports must further elucidate the phenotype, explore any genotype-phenotype correlation, and evaluate treatments.

p16 expression in follicular dendritic cell sarcoma: a potential mimicker of human papillomavirus-related oropharyngeal squamous cell carcinoma.

Follicular dendritic cell sarcoma is a rare mesenchymal neoplasm that most commonly occurs in cervical lymph nodes. It has histologic and clinical overlap with the much more common p16-positive human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx, which characteristically has nonkeratinizing morphology and often presents as an isolated neck mass. Not surprisingly, follicular dendritic cell sarcomas are commonly misdiagnosed as squamous cell carcinoma. Immunohistochemistry is helpful in separating the 2 entities. Follicular dendritic cell sarcoma expresses dendritic markers such as CD21 and CD23 and is almost always cytokeratin negative. However, in many cases of HPV-related oropharyngeal carcinoma, only p16 immunohistochemistry as a prognostic and surrogate marker for HPV is performed. p16 expression in follicular dendritic cell sarcoma has not been characterized. Here, we investigate the expression of p16 in follicular dendritic cell sarcoma and correlate it with retinoblastoma protein expression. A pilot study of dendritic marker expression in HPV-related oropharyngeal squamous cell carcinoma was also performed. We found that 4 of 8 sarcomas expressed p16 with strong and diffuse staining in 2 cases. In 2 of the 4 cases, p16 expression corresponded to loss of retinoblastoma protein expression. Dendritic marker expression (CD21 and CD23) was not found in HPV-related oropharyngeal squamous cell carcinomas. As such, positive p16 immunohistochemistry cannot be used as supportive evidence for the diagnosis of squamous cell carcinoma as strong and diffuse p16 expression may also occur in follicular dendritic cell sarcoma. Cytokeratins and dendritic markers are critical in separating the two tumor types.

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.

Nonkeratinizing Squamous Cell Carcinoma In Situ of the Upper Aerodigestive Tract: An HPV-Related Entity.

The clinical and pathologic characteristics of human papillomavirus (HPV)-related premalignant lesions in the upper aerodigestive tract have not been adequately studied. There are a few reports of oral cavity HPV-related severe dysplasia with unique morphology (prominent apoptosis/karyorrhexis imparting a 'bowenoid' appearance) and a single case report of HPV-related squamous cell carcinoma in situ with nonkeratinizing histology distinct from the 'bowenoid' pattern that extensively involved the upper aerodigestive tract. The aim of this study was to characterize the morphologic and clinical features of HPV-related severe dysplasia/carcinoma in situ. All cases of upper aerodigestive tract severe dysplasia/carcinoma in situ (111 cases from 98 patients) at Washington University from July 2012 to March 2015 were categorized into histologic types: keratinizing, nonkeratinizing, mixed or 'bowenoid'. There were 83 (85 %) patients with keratinizing, 3 (3 %) nonkeratinizing and 12 (12 %) mixed patterns. The previously reported 'bowenoid' morphology was not identified. All 3 (100 %) nonkeratinizing and 6 (50 %) mixed cases were p16 and HPV RNA in situ hybridization (RNA ISH) positive (100 % concordance between p16 and RNA ISH). Only 2 of 73 keratinizing cases were p16 positive, 1 of which was also HPV RNA ISH positive (1.4 % of keratinizing cases HPV-related). Thus, nonkeratinizing morphology was a strong predictor of transcriptionally-active HPV in severe dysplasia/carcinoma in situ. HPV-related cases most commonly occurred in the floor of mouth and were frequently extensive (≥4 cm) or unresectable.

Histologic Typing in Oropharyngeal Squamous Cell Carcinoma: A 4-Year Prospective Practice Study With p16 and High-Risk HPV mRNA Testing Correlation.

Oropharyngeal squamous cell carcinomas (OPSCCs) associated with human papillomavirus (HPV) represent a distinct clinical and pathologic entity. The majority of HPV-related OPSCCs have a characteristic nonkeratinizing morphology. This study sought to determine the strength of the association between nonkeratinizing histology and HPV status compared with other squamous cell carcinoma variants in 4 years of routine clinical practice on a high-volume head and neck service. Primary and/or nodal metastatic tumors in all cases of OPSCC from 2010 to 2013 were typed by 1 of 3 head and neck pathologists as keratinizing, nonkeratinizing, nonkeratinizing with maturation, or another defined variant. All were assessed for p16 by immunohistochemistry with a 70% nuclear and cytoplasmic positivity cutoff as part of routine clinical practice. In addition, 70 consecutive cases from 1 year were "audited" for high-risk HPV mRNA by reverse transcription polymerase chain reaction and in situ hybridization. Of the 435 cases, the majority (90%) consisted of 1 of the 3 main types described and the rest (10%) of uncommon variants. Nonkeratinizing morphology had 99.1% and 100.0% positive predictive value for p16 and high-risk HPV mRNA positivity, respectively. Nonkeratinizing with maturation, keratinizing, and other specific squamous cell carcinoma variants were p16 positive in 91.8%, 22.8%, and 79.5%, respectively. All 47 nonkeratinizing OPSCCs tested for HPV mRNA were positive. In summary, strictly defined nonkeratinizing OPSCC (which constitutes ∼55% of all tumors) essentially implies positivity for both p16 and transcriptionally active high-risk HPV.

Diagnostic Discrepancies in Mandatory Slide Review of Extradepartmental Head and Neck Cases: Experience at a Large Academic Center.

CONTEXT: Medical error is a significant problem in the United States, and pathologic diagnoses are a significant source of errors. Prior studies have shown that second-opinion pathology review results in clinically major diagnosis changes in approximately 0.6% to 5.8% of patients. The few studies specifically on head and neck pathology have suggested rates of changed diagnoses that are even higher. Objectives .- To evaluate the diagnostic discrepancy rates in patients referred to our institution, where all such cases are reviewed by a head and neck subspecialty service, and to identify specific areas with more susceptibility to errors. DESIGN: Five hundred consecutive, scanned head and neck pathology reports from patients referred to our institution were compared for discrepancies between the outside and in-house diagnoses. Major discrepancies were defined as those resulting in a significant change in patient clinical management and/or prognosis. RESULTS: Major discrepancies occurred in 20 cases (4% overall). Informative follow-up material was available on 11 of the 20 patients (55.0%), among whom, the second opinion was supported in 11 of 11 cases (100%). Dysplasia versus invasive squamous cell carcinoma was the most common (7 of 20; 35%) area of discrepancy, and by anatomic subsite, the sinonasal tract (4 of 21; 19.0%) had the highest rate of discrepant diagnoses. Of the major discrepant diagnoses, 12 (12 of 20; 60%) involved a change from benign to malignant, one a change from malignant to benign (1 of 20; 5%), and 6 involved tumor classification (6 of 20; 30%). CONCLUSIONS: Head and neck pathology is a relatively high-risk area, prone to erroneous diagnoses in a small fraction of patients. This study supports the importance of second-opinion review by subspecialized pathologists for the best care of patients.

Human papillomavirus-related head and neck squamous cell carcinoma variants.

During the last few decades, a phenotypically distinct type of head and neck squamous cell carcinoma (SCC), which is etiologically related to human papillomavirus (HPV), has emerged, and its prevalence continues to increase. The tumors are site-specific with special predilection for the oropharynx. They are morphologically and molecularly distinct and are responsive to different types of treatment modalities, with excellent clinical outcome, in spite of early lymph node metastasis. Microscopically, the carcinomas are nonkeratinizing SCCs. More recently, other variants that are believed to be etiologically related to HPV are reported. As a result, several clinical and pathologic questions have emerged. Importantly, whether the virus is biologically active in these tumors and involved in their pathogenesis, and second, what are the clinical implications with regard to patient management and outcome in these HPV-related variants. This review is an attempt to answer some of these questions based on information derived from available yet limited number of publications. The variants to be discussed include nonkeratinizing SCC (NKSCC), NKSCC with maturation (hybrid type), keratinizing SCC (KSSC), basaloid squamous carcinoma (BSCC), undifferentiated carcinoma (UC), papillary SCC (PSCC), small cell carcinoma, adenosquamous carcinoma (AdSCC), and spindle cell (sarcomatoid) carcinoma.

Low-grade papillary schneiderian carcinoma, a unique and deceptively bland malignant neoplasm: report of a case.

The sinonasal tract harbors several different types of papillomas, some of which can progress to carcinoma. The most frequent among these are inverted and oncocytic Schneiderian papillomas. The rates of progression are somewhat controversial but are approximately 5% to 10% and are almost invariably described in the literature as in situ or invasive squamous cell carcinoma. Other carcinoma types, such as mucoepidermoid and sinonasal undifferentiated carcinoma, have also been described. Almost all of the described patterns of malignancy involve frank carcinoma with overtly dysplastic nuclear features, lack of cell maturation, and increased mitotic activity. Some squamous cell carcinomas, particularly nonkeratinizing, can grow in a papillary pattern, appearing to only line the surface epithelium, but they are cytologically overtly malignant throughout. In this case report, however, we describe a novel, human papillomavirus-negative, papillary carcinoma, which presented as a left nasal and maxillary sinus exophytic and inverted-appearing, papillomatous mass with very bland cytomorphology. The initial features were not typical for any defined Schneiderian papilloma but were also not clearly diagnostic of papillary carcinoma. The tumor recurred >10 times over 18 years despite extensive surgical resection including orbital exenteration. The tumor retained a bland appearance throughout the patient's entire clinical course, but did develop a pushing pattern of stromal invasion, increased mitotic activity, vesicular nuclei with prominent nucleoli, lymph node metastases, and eventually overwhelming local recurrence and nodal metastases, resulting in death. This tumor seems best characterized as a low-grade papillary Schneiderian carcinoma and appears to represent a novel type of sinonasal carcinoma.

Histologic and systemic prognosticators for local control and survival in margin-negative transoral laser microsurgery treated oral cavity squamous cell carcinoma.

BACKGROUND: Appreciable local recurrence rates observed in patients with margin-negative, transoral laser microsurgery (TLM)-treated oral cavity squamous cell carcinoma (SCC) necessitate identification of new prognosticators for local control and survival. A histopathologic index (Brandwein-Gensler score [BGS]) and intrinsic/iatrogenic/chronic conditions causing immune compromise are investigated. METHODS: From a prospectively assembled database of TLM-treated oral cavity SCC, specimens for 60 patients with a minimum of 2-years follow-up could undergo BGS assignment. Local control, disease-specific survival (DSS), and overall survival (OS) were study endpoints. RESULTS: "Low-BGS" was recorded in 28 patients (47%) and "high-BGS" in 32 patients (53%), whereas immune compromise was observed in 18%. In multivariate analyses, immune compromise was the only predictor for local control. T classification and immune compromise were prognostic for DSS and OS. "High-BGS" was prognostic only for OS. CONCLUSION: "High-BGS" was associated with recurrences but immune compromise was the most significant predictor of local control and survival in margin-negative, TLM-treated oral cavity SCC. Strategies that maintain/restore tumor-specific immune responses in immune compromised oral cavity SCC hosts need to be developed.

Verrucous carcinoma with dysplasia or minimal invasion: a variant of verrucous carcinoma with extremely favorable prognosis.

Verrucous carcinomas (VC) recur locally but do not metastasize in the absence of an invasive squamous cell carcinoma (SCC) component. Although excluded from the definition of pure VC, some tumors harbor only dysplasia or minimal invasion, findings of unknown clinical significance. Surgically resected VC cases from two institutions were collected and categorized into three types: VC, VC with dysplasia or minimal invasion (VCDMI), defined as SCC less than or equal to 2 mm in depth, and SCC arising in VC (SCC-VC) where the SCC was greater than 2 mm in depth. Cases were also matched with conventional SCC based on location and T and N-stages, and clinical follow up was obtained. Of the 58 total cases, 18 were VC, 26 VCDMI, and 14 SCC-VC. Only 1 of 18 (5.6 %) VC and 5 of 26 (19.2 %) VCDMI cases recurred locally (p = 0.37) versus 7 of 14 (50 %) SCC-VC (p = 0.01). All VC and VCDMI cases were node negative at presentation whereas SCC-VC had nodal metastases in 2 of 14 (14.3 %) cases. No patients with VC or VCDMI died from disease, whereas 5 of 14 (35.7 %) patients with SCC-VC died from disease. T-stage matched conventional SCC cases from institutional databases had worse outcomes than VC and VCDMI, but not after they were matched for both T and N-stages. Our findings suggest that dysplasia and/or minimal invasive SCC do not adversely affect outcomes in tumors otherwise showing diagnostic features of VC.

Prevalence of a hobnail pattern in papillary, poorly differentiated, and anaplastic thyroid carcinoma: a possible manifestation of high-grade transformation.

Papillary thyroid carcinoma is the most common thyroid carcinoma and has a generally favorable prognosis. There are several well-characterized variants, some of which are associated with more aggressive clinical behavior. Hobnail is a recently described rare variant that appears to behave more aggressively. Initial reports characterizing this variant focused on primary tumors and excluded other recognized variants, as well as poorly differentiated and anaplastic thyroid carcinomas, from analysis. Here, we evaluate the frequency of hobnail features in both primary and metastatic papillary thyroid carcinomas, including in association with other known variants, and also in poorly differentiated and anaplastic thyroid carcinomas. Primary and metastatic papillary thyroid carcinomas from a 5-year period (2007 to 2011) and all available anaplastic and poorly differentiated thyroid carcinomas from a 22-year period (1989 to 2011) were retrieved from the files. Tumors from 478 papillary, 26 anaplastic, and 18 poorly differentiated thyroid carcinomas were reviewed for hobnail features present in >10% of each tumor. Hobnail features were most commonly observed in association with poorly differentiated thyroid carcinoma (4 of 18 cases, 22%) and were seen in only 1.3% of papillary thyroid carcinoma patients (6 of 478). One of 26 anaplastic carcinomas had hobnail features (3.8%). Among the papillary thyroid carcinomas, hobnail features were often associated with other histologic variants that are known to be more clinically aggressive, had increased mitotic activity, and/or necrosis and lymph node metastases at presentation. These findings suggest that hobnail features may be a manifestation of higher-grade transformation.

Fibro-osseous lesions of the craniofacial skeleton: an update.

Benign fibro-osseous lesions of the craniofacial skeleton (BFOL) are a variant group of intraosseous disease processes that share similar microscopic features characterized by hypercellular fibroblastic stroma containing various combinations of bone or cementum-like tissue and other calcified structures [1-6]. Whereas some are diagnosable histologically, most require a combined assessment of clinical, microscopic and radiologic features. Some BFOL of the craniofacial complex are unique to that location whereas others are encountered in bones from other regions. Reactive, neoplastic, developmental and dysplastic pathologic processes are included under the rubric of BFOL and treatment varies from disease to disease. This review will discuss the clinical, microscopic and radiologic aspects of the more important types of BFOL of the craniofacial complex with updated information on underlying genetic and molecular pathogenic mechanisms of disease. Four main groups of BFOLs will be addressed.

Histopathologic risk factors in oral and oropharyngeal squamous cell carcinoma variants: an update with special reference to HPV-related carcinomas.

Accurate identification of the microscopic risk factors of oral and oropharyngeal (OP) squamous cell carcinomas (SCC) and their morphologic variants is of at most importance, as these generally determine treatment modalities, prognosis and overall patient outcome. The great majority of oral and oropharyngeal squamous cell carcinomas are microscopically described as kerartinizing squamous cell carcinoma (KSCC). They bear certain resemblance to keratinizing stratified squamous epithelium. Tobacco habits and excessive consumption of alcoholic beverages have been considered to be the main etiologic agents in these carcinomas. The tumors occurred in older patients more commonly affected the oral tongue and floor of the mouth with well established morphologic risk factors including tumor grade, pattern of invasion and perineural involvement. Within the last 30 years however, the advent and expanding prevalence of high risk human papillomavirus (HPV) as an important etiologic agent for head and neck squamous cell carcinoma, particularly in the OP, has resulted in a significant change in the established morphologic criteria for risk assessment. The majority of HPV relate carcinomas of the OP are nonkeratinizing squamous cell carcinoma (NKSCC). These tumors are found to be more responsive to treatment with a favorable patient outcome and good prognosis. Consequently, alterations in treatment protocols aimed at de-escalation are currently being evaluated. More recently, other morphologic variants that are HPV positive are reported with increasing frequency in the OP and other head and neck sites. As a result, several clinical and pathologic questions have emerged. Importantly, whether the virus is biologically active in these tumors and involved in their pathogenesis, and second, what are the clinical implications with regard to patient management and outcome in the HPV-related variants. Examples of HPV-related squamous cell carcinoma variants that will be addressed here are: basaloid squamous cell carcinoma (BSCC), undifferentiated carcinoma (UCa), papillary squamous carcinoma (PSCC) and small cell carcinoma. Some studies have suggested favorable prognosis in some variants, analogous to that of the (NKSCC), while others showed poorer outcome. So far the number of studies on this subject is limited and the number of cases evaluated in each investigation is few. Because of that, it is prudent at this stage, not to alter management protocols as a result of identification of HPV in these variants and to await additional information.

Evaluation of a new grading system for laryngeal squamous intraepithelial lesions--a proposed unified classification.

AIMS: To verify the applicability, reproducibility and predictive value of a proposed unified classification (amended Ljubljana classification) for laryngeal squamous intraepithelial lesions (SILs). METHODS AND RESULTS: Six internationally recognized experts and three pathologists from Ljubljana contributed to this study by evaluating a set of laryngeal SILs using the new system: low-grade SIL, high-grade SIL, and carcinoma in situ (CIS). The overall agreement among reviewers was good. Overall unweighted and weighted κ-values and 95% confidence intervals were 0.75 (0.65-0.84) and 0.80 (0.71-0.87), respectively. The results were stratified between the international reviewers and the Ljubljana pathologists. The former had good overall agreement, and the latter had very good agreement. Kaplan-Meier survival curves showed a significant difference (P < 0.0001) between patients with low-grade and high-grade SILs; 19 of 1204 patients with low-grade SILs and 30 of 240 patients with high-grade SILs progressed to malignancy in 2-15 years and in 2-26 years, respectively. CONCLUSIONS: The proposed modification to the Ljubljana classification provides clear morphological criteria for defining the prognostic groups. The criteria facilitate better interobserver agreement than previous systems, and the retrospective follow-up study demonstrates a highly significant difference in the risk of malignant progression between low-grade and high-grade SILs.

Keratinizing-type squamous cell carcinoma of the oropharynx: p16 overexpression is associated with positive high-risk HPV status and improved survival.

It is well established that nonkeratinizing squamous cell carcinoma (SCC) of the oropharynx is causally related to transcriptionally active human papillomavirus (HPV) and has better survival as compared with carcinomas with a keratinizing phenotype (KSCC). Although the great majority of KSCCs are unrelated to HPV, transcriptionally active HPV is detected in a minority of oropharyngeal cases. To date, it has not been established whether the HPV status in KSCC also confers a survival advantage as it does in HPV-related nonkeratinizing SCC. This study compares clinical outcomes between patients with HPV-positive versus HPV-negative oropharyngeal KSCC. Among a total of 54 cases, 7 (13%) were diffusely and strongly positive for p16. HPV E6/E7 RNA was positive in 5 of the 6 (83%) p16-positive cases that were tested and in only 1 of the 47 (2%) p16-negative cases. Only 1 of the 7 (14%) p16-positive patients developed disease recurrence and died in the follow-up period. Kaplan-Meier survival analysis showed significantly better overall and disease-specific survival in the p16-positive than in the p16-negative patients (P=0.01 and 0.046, respectively). These data, although with relatively small patient numbers, suggest that HPV-related SCC in the oropharynx is associated with highly favorable outcomes, regardless of the keratinizing or nonkeratinizing phenotype.

Tophaceous pseudogout of the temporomandibular joint: a series of 3 cases.

OBJECTIVE: We report a series of 3 cases of tophaceous pseudogout of the temporomandibular joint (TMJ). STUDY DESIGN: Three patients, two men and one woman, ranging in age between 60 and 75 years, presented with unilateral painful swelling of the TMJ area associated with limitation of mouth opening. RESULTS: Radiographic and computed tomographic images showed opaque masses in the supracondylar region of the TMJ. The preoperative clinical impression was a "neoplastic lesion" in the 3 cases. Microscopic examination revealed numerous deeply basophilic masses of calcified deposits, exhibiting birefringence under polarized light and morphologically consistent with calcium pyrophosphate dihydrate deposition, referred to in these cases as "tophaceous pseudogout." CONCLUSION: Tophaceous pseudogout is a rare benign arthropathy that presents with clinical and radiographic features mimicking neoplastic conditions of the TMJ. Therefore, it is recommended that tophaceous pseudogout be considered in the differential diagnosis when a TMJ is involved with "neoplasm-like" lesions clinically and radiographically.

Extensive HPV-related carcinoma in situ of the upper aerodigestive tract with 'nonkeratinizing' histologic features.

Over the past several decades, it has become clear that human papillomavirus (HPV) is important for the development and progression of many head and neck squamous cell carcinomas, particularly those arising in the oropharyngeal tonsillar crypts. Yet, our understanding of HPV's role in premalignant squamous lesions remains relatively poor. This is in part because premalignant lesions of the oropharyngeal tonsillar crypt tissue, where most HPV-related carcinomas arise, are difficult if not impossible to identify. Recent evidence does suggest a role for HPV in a subset of premalignant lesions of the surface epithelium, especially the oral cavity, despite the rarity of HPV-related invasive squamous cell carcinomas at this site. Furthermore, these HPV-related oral cavity dysplasias appear to have unique, bowenoid histologic features described as 'basaloid' with full-thickness loss of squamous maturation, mitotic figures and apoptosis throughout. Here, we present a unique case of an HPV-related premalignant lesion (squamous cell carcinoma in situ) extensively involving the surface epithelium of the oral cavity, oropharynx and larynx that had 'nonkeratinizing' histologic features typical of HPV-related invasive squamous cell carcinoma. This case was strongly p16 positive by immunohistochemistry and harbored transcriptionally active HPV as demonstrated by E6/E7 RNA in situ hybridization. Furthermore, the patient had an excellent response to radiation treatment.