Objectives:
To review evidence for the role of human papillomavirus (HPV) in the etiology of oropharyngeal cancers, methods of viral detection, and the resulting clinical implications.
Study Design:
...Contemporary review.
Methods:
Published journal articles identified through PubMed and conference proceedings were reviewed.
Results:
HPV‐associated squamous cell carcinomas represent a distinct disease entity from carcinogen‐associated squamous cell carcinomas. HPV oncoproteins lead to mucosal cell transformation through well‐defined mechanisms. Different methods of detecting HPV exist with variable levels of sensitivity and specificity for biologically active virus. Although virus is detected in a number of head and neck subsites, studies demonstrate improved outcomes in HPV‐associated carcinoma of the oropharynx only. The cell cycle regulatory protein p16 is upregulated by biologically active HPV and serves as a biomarker of improved response to therapy.
Conclusions:
HPV‐associated squamous cell carcinoma of the oropharynx is a biologically distinct entity from carcinogen‐associated carcinoma. Understanding the molecular mechanisms behind the improved outcomes in patients with HPV‐associated oropharyngeal carcinoma may lead to novel therapeutics for patients with carcinogen‐associated carcinomas. Laryngoscope, 2010
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.
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
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. 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.
Summary Basaloid squamous cell carcinoma of the upper aerodigestive tract is a rare, morphologically distinct variant of squamous cell carcinoma that is thought to be clinically aggressive. The ...histologic features are distinct from, but often confused with, those of human papillomavirus–related oropharyngeal nonkeratinizing squamous cell carcinoma. The role of human papillomavirus as an etiologic agent in true basaloid squamous cell carcinoma is controversial. The purpose of this study was to determine human papillomavirus prevalence and its clinicopathologic significance in upper aerodigestive tract tumors with true basaloid squamous cell carcinoma histology. Twenty-eight cases were identified, 12 in the oropharynx and 16 in the larynx and/or hypopharynx. High-risk human papillomavirus in situ hybridization and immunohistochemistry for p16 and p53 were performed. Nine (75%) of the oropharyngeal and none of the larynx/hypopharynx tumors were human papillomavirus positive. Human papillomavirus–positive tumors affected younger patients. No significant statistical differences in patients' sex, tumor stage, treatment modality, or length of follow-up were observed between the 2 groups. Viral status showed a strong, positive correlation with p16 ( P < .001) and a strong, negative correlation with p53 ( P < .0001) immunoreactivity. Overall survival was better for human papillomavirus–positive basaloid squamous cell carcinomas ( P < .05), with 86% of patients alive at 3 years compared with 35.3% of patients with human papillomavirus–negative tumors. These findings suggest that a subset of basaloid squamous cell carcinomas is virally driven. These tumors occur almost exclusively in the oropharynx, are molecularly distinct from their human papillomavirus–negative counterparts, and have a more favorable clinical outcome.
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.
Although a strong etiologic relationship between human papillomavirus (HPV) and a majority of oropharyngeal squamous cell carcinomas has been established, the role of HPV in non-oropharyngeal head ...and neck carcinomas is much less clear. Here, we investigated the prevalence and clinicopathologic significance of HPV and its reported biomarkers, CDKN2A(p16) and CDKN1A(p21), in laryngeal squamous cell carcinomas in patients treated either with primary surgery and postoperative radiation or with definitive radiation-based therapy. Nearly all of 76 tumors were keratinizing and none displayed the nonkeratinizing morphology that is typically associated with HPV infection in the oropharynx. However, CDKN2A(p16) immunohistochemistry was positive in 21 cases (28%) and CDKN1A(p21) in 34 (45%). CDKN2A(p16) and CDKN1A(p21) status strongly correlated with each other (P=0.0038). Yet, only four cases were HPV positive by DNA in situ hybridization or by reverse transcriptase PCR E6/E7 mRNA (all four were CDKN2A(p16) and CDKN1A(p21) positive). Unexpectedly, 9 additional tumors out of 20 CDKN2A(p16) positive cases harbored high-risk HPV DNA by PCR. For further investigation of this unexpected result, in situ hybridization for E6/E7 mRNA was performed on these nine cases and all were negative, confirming the absence of transcriptionally active virus. Patients with CDKN1A(p21)-positive tumors did have better overall survival (69% at 3 years) than those with CDKN1A(p21)-negative tumors (51% at 3 years) (P=0.045). There was also a strong trend towards better overall survival in the CDKN2A(p16)-positive group (P=0.058). Thus, it appears that the role of HPV is more complex in the larynx than in the oropharynx, and that CDKN2A(p16) and CDKN1A(p21) expression may not reflect HPV-driven tumors in most cases. Because of this, CDKN2A(p16) should not be used as a definitive surrogate marker of HPV-driven tumors in the larynx.
Summary Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor that has morphologic features similar to secretory carcinoma of the breast and that also harbors the ...same ETV6 translocation. Diffuse mammaglobin and S-100 immunoreactivity are used to differentiate MASC from its morphologic mimics, especially acinic cell carcinoma and adenocarcinoma, not otherwise specified. However, the combination of mammaglobin and S-100 immunoreactivity has not been well studied in other types of salivary gland carcinomas that may have focal areas reminiscent of MASC. Here we evaluated mammaglobin and S-100 immunoreactivity in 15 cases each of polymorphous low-grade adenocarcinoma, adenoid cystic carcinoma and mucoepidermoid carcinoma, and also in 2 cases of adenocarcinoma, not otherwise specified, and 1 mucinous adenocarcinoma. Cases with significant co-expression of mammaglobin and S-100 (moderate or strong immunoreactivity in >25% of tumor cells) were further analyzed by fluorescence in situ hybridization using the ETV6 (12p13) break-apart probe. Nine cases (60%) of polymorphous low-grade adenocarcinoma and two (13.3%) of adenoid cystic carcinoma met the criteria for significant co-expression of mammaglobin and S-100. All were negative for the ETV6 translocation by fluorescence in situ hybridization. Although mammaglobin and S-100 positivity was seen in the majority of polymorphous low-grade adenocarcinomas and a minority of adenoid cystic carcinomas, none were positive for the ETV6 translocation characteristic of MASC. This indicates a need for caution in the use of immunohistochemistry for diagnosing MASC, especially in the absence of cytogenetic confirmation.
In the human papillomavirus (HPV) era, the best way to assess oropharyngeal squamous carcinomas (SCC) for risk stratification is not clear. Many recommend use of both p16 immunohistochemistry and HPV ...in situ hybridization (ISH). A significant minority of tumors are p16 positive and HPV ISH negative, the significance of which is unclear.
Two hundred thirty-nine oropharyngeal SCC were tested by immunohistochemistry for p16 and by ISH for high-risk HPV. For p16 positive, HPV ISH negative cases, PCR was conducted for HPV. The findings were correlated with pathologic and clinical findings.
Of the 239 cases, 187 (78%) were positive for p16. Of these, 139 (74%) were positive for HPV by ISH. Of the remaining 48 cases, 45 had material for PCR. Nineteen were positive for HPV, leaving a group of 26 p16 positive and HPV undetectable SCCs. In the p16 positive cohort, there was no difference in survival between HPV ISH positive and negative cases. Comparing the HPV ISH positive and HPV ISH and PCR negative SCC, there was again no difference in survival. p16 positive, HPV negative SCC still had significantly better survival than p16 negative SCC in univariate and multivariate analysis.
Outcomes for p16 positive, HPV negative oropharyngeal SCC are not significantly different from p16 positive, HPV positive tumors and are significantly better than for p16 negative tumors. These results suggest that p16 immunohistochemistry alone is the best test to use for risk stratification in oropharyngeal SCC.
Abstract 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.
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.
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