Showing papers in "Head and Neck Pathology in 2014"

Metastatic Tumors to the Jaws and Mouth

Abstract: Metastatic dissemination to the oral cavity is rare and is usually the evidence of a wide spread disease with an average survival rate of 7 months. In almost a quarter of the cases, oral metastasis was found to be the first indication of an occult malignancy at a distant site. Metastatic lesions can be found anywhere in the oral cavity, however, the jaw bones with the molar area is the most frequently involved site. In the oral soft tissues, the gingiva is the most common site, suggesting the possible role of inflammation in the attraction of metastatic deposits. The most common primary malignancies presenting oral metastases were the lung, kidney, liver, and prostate for men, and breast, female genital organs, kidney, and colo-rectum for women. Most patients with jawbone metastasis complain of swelling, pain, and paresthesia. An exophytic lesion is the most common clinical presentation of metastatic lesions in the oral soft tissues. Early lesions, mainly those located in the gingiva, may resemble a hyperplastic or reactive lesion. Once a lesion is recognized as metastasis, the primary tumor site should be identified following clinical, radiological and histopathological investigations. If standardized diagnostic workup fails to detect the site of origin, then the term carcinoma of unknown primary is applied. Personalized medicine tools such as tissue-of-origin assays should be applied, either by immunohistochemical testing or by molecular-profiling methods as these may lead to a more favorable outcome.

Carcinoma Ex-Schneiderian Papilloma (Malignant Transformation): A Clinicopathologic and Immunophenotypic Study of 20 Cases Combined with a Comprehensive Review of the Literature

Abstract: Schneiderian papilloma (SP) are uncommon tumors with malignant transformation even less common. The histologic criteria to define malignant transformation are not well developed nor is the immunohistochemical profile reported in a large series of carcinomas. 20 cases of malignant transformation of SP included 7 females and 13 males, aged 38–86 years (mean 60.7 years). Patients presented most frequently with a mass (n = 11) and obstructive symptoms (n = 7), present for 38.7 months (mean). Most patients had no previous history of SP (n = 13); metachronous carcinoma was identified in 7 patients an average of 34.4 months after the first diagnosis of SP, with 1–4 recurrences of SP. With a mean size of 4.1 cm, the majority of tumors involved a combination of more than one anatomic site (n = 10), followed by the maxillary sinus only (n = 5) or nasal cavity only (n = 3). Histologically, 17 were inverted and 3 exophytic type SP. There were 17 squamous cell carcinomas, 2 mucoepidermoid carcinomas and 1 sinonasal undifferentiated carcinoma, comprising from 10 to 95 % of the tumor volume. Malignant histologic features included atypical mitoses, necrosis, bone invasion, lymphovascular invasion, decreased transmigrating neutrophils, paradoxical maturation, dyskeratosis and/or perineural invasion (n = 3). Patients tended to present with advanced stage (n = 14, Stage III and IV). Immunohistochemical studies showed positive reactions in the malignancies for CK5/6 (86 %), p63 (86 %), CK7 (luminal, 50 %), p53 (83 %), and p16 (25 %). In situ hybridization detected human papillomavirus in 26 %. Surgery was often accompanied by radiation therapy (n = 13), with a mean of 2.4 years of follow-up. Five patients developed a recurrence between 0.8 and 3.3 years. Carcinomas ex-SP are less common and are associated with better outcome than previously reported. Patients tend to present with a synchronous carcinoma, developing in an inverted type SP, with squamous cell carcinoma the most common malignancy. Development of metachronous carcinomas ex-SP was always preceded by SP recurrence in this series.

Odontogenic Tumors, WHO 2005: Where Do We Go from Here?

Abstract: As our knowledge of disease improves, its classification continually evolves. The last WHO classification of odontogenic tumors was 9 years ago and it is time for revision. We offer the following critique as a constructive, thought provoking challenge to those chosen to provide contemporary insight into the next WHO classification of odontogenic cysts, tumors, and allied conditions.

Fibro-Osseous Lesions of the Craniofacial Skeleton: An Update

Abstract: 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.

Sinonasal tract and nasopharyngeal adenoid cystic carcinoma: a clinicopathologic and immunophenotypic study of 86 cases.

Abstract: Primary sinonasal tract and nasopharyngeal adenoid cystic carcinomas (STACC) are uncommon tumors that are frequently misclassified, resulting in inappropriate clinical management. Eighty-six cases of STACC included 45 females and 41 males, aged 12–91 years (mean 54.4 years). Patients presented most frequently with obstructive symptoms (n = 54), followed by epistaxis (n = 23), auditory symptoms (n = 12), nerve symptoms (n = 11), nasal discharge (n = 11), and/or visual symptoms (n = 10), present for a mean of 18.2 months. The tumors involved the nasal cavity alone (n = 25), nasopharynx alone (n = 13), maxillary sinus alone (n = 4), or a combination of the nasal cavity and paranasal sinuses (n = 44), with a mean size of 3.7 cm. Patients presented equally between low and high stage disease: stage I and II (n = 42) or stage III and IV (n = 44) disease. Histologically, the tumors were invasive (bone: n = 66; neural: n = 47; lymphovascular: n = 33), composed of a variety of growth patterns, including cribriform (n = 33), tubular (n = 16), and solid (n = 9), although frequently a combination of these patterns was seen within a single tumor. Pleomorphism was mild with an intermediate N:C ratio in cells containing hyperchromatic nuclei. Reduplicated basement membrane and glycosaminoglycan material was commonly seen. Necrosis (n = 16) and atypical mitotic figures (n = 11) were infrequently present. Pleomorphic adenoma was present in 9 cases; de-differentiation was seen in two patients. Immunohistochemical studies showed positive reactions for pan-cytokeratin, CK7, CK5/6, CAM5.2, and EMA, with myoepithelial reactivity with SMA, p63, calponin, S100 protein and SMMHC. CD117, CEA, GFAP and p16 were variably present. CK20 and HR HPV were negative. STACC needs to be considered in the differential diagnosis of most sinonasal malignancies, particularly poorly differentiated carcinoma, olfactory neuroblastoma and pleomorphic adenoma. Surgery (n = 82), often accompanied by radiation therapy (n = 36), was generally employed. A majority of patients developed a recurrence (n = 52) 2–144 months after initial presentation. Overall mean follow-up was 19.4 years (range 0.4–37.5 years): 46 patients died with disease (mean 6.4 years); 5 were alive with disease (mean 5.4 years), and 35 patients were either alive or had died of unrelated causes (mean 16.3 years). ACC of the SNT is uncommon. Recurrences are common. The following parameters, when present, suggest an increased incidence of either recurrence or dying with disease: mixed site of involvement, high stage disease (stage IV), skull base involvement, tumor recurrence, a solid histology, perineural invasion, bone invasion, and lymphovascular invasion.

Cheilitis Granulomatosa: A Review

Abstract: Cheilitis granulomatosa (CG) is a cosmetically disturbing and persistent idiopathic lip swelling. It is one manifestation of orofacial granulomatosis (OFG), which is a clinical entity describing facial and oral swelling in the setting of non-caseating granulomatous inflammation and in the absence of systemic disease such as Crohn’s disease and sarcoidosis. CG can occur by itself or as part of the Melkersson–Rosenthal syndrome, which includes facial palsy and a plicated tongue. Other proposed causes of OFG include dietary allergens such as cinnamon and benzoates. Similar orofacial swelling may be an early manifestation of Crohn’s disease or sarcoidosis, and so clinical history is important in diagnosis. The cause of CG has not been wholly elucidated, but a current hypothesis holds that a random influx of inflammatory cells is responsible. Other granulomatous and edematous causes of lip swelling must be investigated prior to diagnosis. Options for treatment include dietary modifications, antibiotics, systemic or intralesional corticosteroids, and surgery, although treatment is not always necessary. CG should be considered in the differential of persistent lip swelling.

The sinonasal tract: another potential "hot spot" for carcinomas with transcriptionally-active human papillomavirus.

Abstract: While high risk human papillomavirus (HPV) is well established as causative and clinically important for squamous cell carcinoma (SCC) of the oropharynx, its role in non-oropharyngeal head and neck SCC is much less clearly elucidated. In the sinonasal region, in particular, although it is a relatively uncommon site for SCC, as many as 20 % of SCC harbor transcriptionally-active high risk HPV. These tumors almost always have a nonkeratinizing morphology and may have a better prognosis. In addition, specific variants of SCC as well as other rare carcinoma types, when arising in the sinonasal tract, can harbor transcriptionally-active HPV. This article reviews the current literature on HPV in sinonasal carcinomas, attempts to more clearly demonstrate what tumors have it and how this relates to possible precursor lesions like inverted papilloma, and discusses the possible clinical ramifications of the presence of the virus.

HRAS mutations in epithelial-myoepithelial carcinoma.

Abstract: The molecular profile of epithelial–myoepithelial carcinomas (EMCa) has not been well studied, though a recent association with Harvey rat sarcoma viral oncogene homolog (HRAS) mutations has been noted. To confirm and validate this, we surveyed fifteen EMCa for HRAS codon 61 mutations and correlated HRAS status with clinicopathologic parameters. There were 11 females and 4 males and mean patient age was 64 (range 49–90). Parotid gland was most commonly involved (n = 10) and the most common histologic appearance was that of a ‘classic’ EMCa (7/15). Four of fifteen (26.7 %) cases demonstrated local recurrence, while 2/15 (13.3 %) demonstrated distant metastases. Other variant morphologies included EMCa arising from pleomorphic adenoma (3/15), and high grade EMCa (2/15). HRAS exon 3, codon 61 mutations, p.Q61R (n = 3) and p.Q61 K (n = 1) were identified in 4 of 15 successfully tested EMCAs (14 patients). Two cases were classic type, while the other cases consisted of one oncocytic variant, and one tumor with myoepithelial overgrowth, the latter of which showed the same mutation in both the primary and recurrence. Of note, the high grade EMCa and EMCa ex pleomorphic adenoma were negative for mutations. Given the small number of cases, there were no significant differences between mutation positive and mutation negative cases in terms of age, gender and outcome.

Human Papillomavirus-Associated Head and Neck Squamous Cell Carcinoma Survival: A Comparison by Tumor Site and Initial Treatment

Abstract: Recent evidence suggests that human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) patients have better survival than HPV-negative patients. However, it is unclear if similar patterns for survival exist across different tumor sites, and whether HPV-associated prognosis is modified by type of treatment. We prospectively tested 222 histologically confirmed HNSCC primary tumors for HPV DNA by PCR and HPV E6/E7 RNA by RT-PCR prior to treatment at a large urban health center. Cox proportional hazard ratio models were constructed to assess HPV-associated differences in overall and disease-specific survival adjusting for clinical and demographic covariates. HPV detection varied significantly by primary HNSCC tumor site, from 35 % for oropharynx, to 25 % for hypopharynx, 5 % for larynx, and 3 % for oral cavity (p < 0.0001), with HPV16 accounting for the majority (95 %) of HPV-positive tumors. The hazard-risk of overall and disease-specific death comparing HPV16-positive versus negative oropharyngeal HNSCC was reduced by 74 and 89 %, respectively (p values < 0.05), and was independent of other prognostic indicators; no statistically significant changes in outcomes were observed for non-oropharyngeal HNSCC sites. Prediction of overall survival was better with combined DNA and RNA HPV16 positive PCR detection. There was no difference in HPV16-associated survival whether patients received either surgery or (chemo)radiotherapy as their initial treatment modality. Improved HPV-associated HNSCC survival is limited to patients with oropharyngeal primaries. No selective treatment advantage is observed for HPV-positive tumors, although clinical trials are needed to evaluate which treatment modalities provide the most benefit for HPV-positive HNSCC.

Glandular odontogenic cysts (GOCs) lack MAML2 rearrangements: a finding to discredit the putative nature of GOC as a precursor to central mucoepidermoid carcinoma

Abstract: Glandular odontogenic cyst (GOC) is a cyst of the gnathic bones that is characterized by squamous and glandular differentiation. The histopathologic features of GOC overlap considerably with central mucoepidermoid carcinoma (MEC), suggesting that GOC could be a precursor lesion to, or even a low-grade form of, central MEC. Differentiating the two lesions may be difficult or impossible on a limited biopsy. MAML2 rearrangements have been recently found to be specific for MEC, even those arising in the jaws. An analysis of MAML2 in GOCs could help clarify its relationship with central MEC. Tissue blocks from 21 GOCs and 5 central MECs were retrieved from the surgical pathology archives of The Johns Hopkins Hospital. Each MEC exhibited solid areas and clear-cut stromal invasion. In addition, 4 of the MECs demonstrated cystic areas that were histologically similar to GOC. Break-apart fluorescence in situ hybridization for MAML2 was performed. For the MECs, analysis was performed on both the solid components and the cystic areas that resembled GOC. MAML2 rearrangements were identified in all 5 of the MECs, but in none of the 21 GOCs (100 vs. 0 %; p < 0.0001, Fisher’s Exact). In the MECs, the rearrangement was present in both the solid and GOC-like cystic areas. While central MECs consistently harbor the MAML2 rearrangement, even in low-grade cystic areas that resemble a pre-existing GOC, true GOCs do not. Accordingly, GOC does not appear to represent an early or low-grade form of central MEC, but rather an unrelated lesion. The high sensitivity and specificity of MAML2 rearrangement for MECs points to its utility as a diagnostic adjunct in separating mucinous cystic lesions of the gnathic bones.

Neuroendocrine neoplasms of the head and neck: some suggestions for the new WHO classification of head and neck tumors.

Abstract: As knowledge and understanding in pathology evolve, classifications and nomenclature also change to reflect those advances. The 2005 World Health Organization Classification of Head and Neck Tumours was a significant step towards diagnostic standardization of head and neck neuroendocrine carcinomas; however, in the last 10 years there have been new data supporting the recognition of “large cell neuroendocrine carcinoma” as a distinctive high grade carcinoma in the head and neck, a lesion not included in the 2005 Classification. In addition, the terms “middle ear adenoma” and “carcinoid tumor of middle ear” are still widely used to describe a neoplasm that is neither a pure adenoma nor a carcinoid tumor but a lesion with variable mixed exocrine and endocrine differentiation. Largely using the diagnostic criteria of the WHO classification of neuroendocrine carcinomas of the lung, we propose the terms “neuroendocrine carcinoma, grade 1”; “neuroendocrine carcinoma, grade 2”; “neuroendocrine carcinoma, grade 3, large cell type”; and “neuroendocrine carcinoma, grade 3, small cell type” for the classification of neuroendocrine carcinomas of the head and neck in a future WHO classification. In addition, we also proposed the term “mixed epithelial neuroendocrine tumor” of the middle ear as an alternative for “middle ear adenoma” and “carcinoid tumor of the middle ear”.

Utility of p40 in the Differential Diagnosis of Small Round Blue Cell Tumors of the Sinonasal Tract.

Abstract: The sinonasal tract may give rise to a broad range of neoplasms that share a “small round blue cell” tumor (SBRCT) appearance on routine histology, but treatment strategies depend on precise tumor classification. Immunohistochemistry for p63 is often employed in the sinonasal SRBCT differential diagnosis because it is highly sensitive for squamous cell carcinoma (SCC). However, p63 staining may be observed in other tumor types, a potential diagnostic pitfall. P40 is a more squamous-specific isoform of p63, and it may be more useful in distinguishing poorly differentiated SCC from its mimickers in the sinonasal tract. Immunohistochemistry for p40 and p63 was performed on 171 sinonasal neoplasms with SRBCT morphology: 73 SCCs (67 poorly differentiated, non-keratinizing, or basaloid types and 6 nasopharyngeal carcinomas), 46 esthesioneuroblastomas, 11 sinonasal undifferentiated carcinomas (SNUCs), 11 lymphomas, 9 melanomas, 7 alveolar rhabdomyosarcomas, 4 solid adenoid cystic carcinomas, 4 NUT midline carcinomas, 4 primitive neuroectodermal tumors (PNETs), and 2 small cell carcinomas. P40 was positive in 72 of 73 SCCs, and showed a diffuse distribution in all but one positive case. P40 immunoexpression was also observed in 13 of 46 (28 %) esthesioneuroblastomas, 6 of 11 (55 %) SNUCs, 2 of 4 (50 %) adenoid cystic carcinomas, 3 of 4 (75 %) NUT midline carcinomas, 1 of 2 (50 %) small cell carcinomas, and 1 of 4 (25 %) PNETs; in the non-SCC tumors, p40 staining was focal in most cases. P63 was positive in every p40-positive tumor. In addition, a p63+/p40− phenotype was seen 5 of 11 (45 %) lymphomas, 4 of 7 (57 %) alveolar rhabdomyosarcomas, 1 of 4 (25 %) PNETs, and 3 of 46 (7 %) esthesioneuroblastomas. All sinonasal melanomas were negative for both markers. In the sinonasal SRBCT differential diagnosis, both p40 and p63 are highly sensitive for SCC, but p40 is more specific. Notably, p40 is consistently negative in lymphomas and alveolar rhabdomyosarcomas, two tumors that are frequently p63-positive. It must be remembered, however, that even diffuse p40 immunostaining is not entirely specific for the squamous phenotype, and therefore it should be utilized as part of an immunohistochemical panel.

Giant Cell Lesions of the Craniofacial Bones

Abstract: Multinucleate giant cells of one type or another are commonly encountered in oral and maxillofacial lesions. These include the common occurrence of foreign-body-type giant cells in some reactive lesions, and giant cells associated with granulomatous inflammation as a consequence of infection. However in these cases the giant cells do not represent the primary pathology. In this brief review, we will focus on lesions that may arise in the jaws and in which osteoclasts-like giant cells are a characteristic or defining feature. The classification of this group of lesions remains problematic, because for some lesions, for example, central giant cell granulomas of the jaw, the true nature or cause of the lesions has not been established. In other cases, molecular pathology is now beginning to unravel the pathogenesis of these lesions, and also their relationships to each other. We will not include a discussion of the pathology of hyperparathyroidism except to emphasize that when an osteoclast-rich tumor is encountered within the jaw bones, consideration should be given to the exclusion of hyperparathyroidism. This is usually straightforward based on radiology and appropriate serology.

Ameloblastic Fibro–Odontoma

Abstract: A case of an amelobastic fibro–odontoma affecting a 15 year-old girl will be discussed. The characteristic radiologic and histologic features of the entity will be described.

Salivary Gland Tumor “Wishes” to Add to the Next WHO Tumor Classification: Sclerosing Polycystic Adenosis, Mammary Analogue Secretory Carcinoma, Cribriform Adenocarcinoma of the Tongue and Other Sites, and Mucinous Variant of Myoepithelioma

Abstract: This review is a continuation of suggested tumor additions to the next WHO Tumor Classification. The author will focus on four salivary gland entities that have recently become accepted in the literature as new neoplastic entities: sclerosing polycystic adenosis, mammary analogue secretory carcinoma, cribriform adenocarcinoma of the tongue and other sites, and mucinous variant of myoepithelioma.

The Diagnostic Usefulness of Immunohistochemistry for Odontogenic Lesions

Abstract: The diagnosis of odontogenic tumors can be challenging, largely due to their rarity and consequent difficulties in gaining experience in their assessment. In most cases, careful attention to morphology, in conjunction with clinical and radiological features will allow a diagnosis to be made. However, in some cases, immunohistochemical analysis of the tumor may be useful. In this review we will outline the immunohistochemical expression profile of normal developing odontogenic tissues and a range of odontogenic tumors. In many cases the immunohistochemical markers are neither specific nor sensitive enough to be of help in diagnosis, but in some cases such analysis may prove very useful. Thus we have outlined a limited number of circumstances where immunohistochemistry may be of use to the practicing diagnostic pathologist.

Envisioning the Next WHO Head and Neck Classification

Abstract: The next WHO classification should abandon “salivary duct carcinoma”; conventional salivary duct carcinoma should be classified as “high-grade salivary duct carcinoma”. Low-grade salivary duct carcinoma should replace the current nosology of “low-grade cribriform cystadenocarcinoma”. Cystadenocarcinoma should be classified with the descriptor “Not Otherwise Specified” and should be considered an exclusionary diagnostic category. On the other hand, “Not Otherwise Specified” does not fit for hyalinizing clear cell carcinoma (HCCC). The EWSR1-ATF1 fusion is specific for HCCC within the context of salivary neoplasia. We recommend adding “hyalinizing” even though this feature is not present in all cases; the benefit of which is the mental association with a salivary clear cell malignancy. Sinonasal Renal Cell-like Adenocarcinoma (SNRCLA) is a distinct clear cell neoplasm and should be added to the next WHO classification. Future studies will bear out whether SNRCLA is even a low-grade carcinoma, or may be reclassified as “adenoma”. Lastly, the next WHO monograph should include the Risk Model in the general introductory statements on oral squamous cell carcinoma, under a subheading of “Histological Prognosticators”. The positive predictive value for developing locoregional recurrence in patients with low-stage oral cavity squamous carcinoma (OSCC) and “worst pattern of invasion type-5” (WPOI-5) is 42 %. Low-stage high-risk OSCC with a combination of features other than WPOI-5 is associated with 32 % likelihood for locoregional progression. WPOI-5 also predicts occult metastatic disease (p = 0.0001, Chi squared, 2 DF). Thus the Risk Model can also be used to make decisions regarding staged elective neck dissections.

Human Papillomavirus and Epstein Barr Virus in Head and Neck Carcinomas: Suggestions for the New WHO Classification

Abstract: In the 9 years since the last World Health Organization (WHO) classification for head and neck tumors, a great deal has changed. In particular, human papillomavirus (HPV) has emerged as the major etiologic agent and patient prognostic marker for squamous cell carcinoma, most profoundly in the oropharynx. It also casts a long shadow over all of the rest of head and neck cancer given its biologic and prognostic implications. By contrast, little has changed regarding our knowledge of Epstein–Barr virus in head and neck cancers, except as it relates to HPV in nonkeratinizing-type nasopharyngeal carcinomas. This article discusses some of the major advances in our understanding of virus-related squamous cell carcinoma of the head and neck and suggests several specific concepts and terminology for incorporation into the next WHO classification.

Acetylated Tubulin (AT) as a Prognostic Marker in Squamous Cell Carcinoma of the Head and Neck

Abstract: Acetylated tubulin (AT) expression has been proposed as a marker for sensitivity to taxane chemotherapy. We wanted to explore AT as a prognostic marker in squamous cell carcinoma of the head and neck (SCCHN). We assessed AT expression in archival tissue from our institutional tissue bank of primary SCCHN specimens. We also examined AT expression on pre-therapy tissues of patients with SCCHN receiving induction chemotherapy with docetaxel, cisplatin and 5FU (TPF IC). AT expression was assessed on archival cases of SCCHN with (N = 63) and without (N = 82) locoregional lymph node metastases (LNM). The predominant tumor site was oral cavity (52 %). Immunohistochemistry staining was based on staining intensity and percentage of tumor cells stained to create a weighted index (WI). A total of nine patients who received TPF IC were evaluable for response by RECIST and also had pre-therapy tissues available. A significant independent correlation between AT and tumor grade (p = 0.001) and primary location (p = 0.008) was noted. There was a trend of higher AT in patients with presence of LNM (p = 0.052) and a trend in improved OS for patients with an AT WI below the median compared to those above the median for patients with no LNM (p = 0.054). For patients treated with induction TPF, we observed an inverse correlation between AT expression and response to TPF IC (p = 0.0071). AT expression is correlated with tumor grade and primary site. There was an observed trend correlating AT with presence nodal metastases. The observed inverse correlation with response to taxane based chemotherapy needs validation in a larger sample size.

An Immunohistochemical Panel for Reliable Differentiation of Salivary Duct Carcinoma and Mucoepidermoid Carcinoma

Abstract: Salivary duct carcinoma is a highly aggressive salivary gland malignancy that may be misdiagnosed as high-grade mucoepidermoid carcinoma. We utilized tissue microarrays with 78 examples of mucoepidermoid carcinoma and 47 salivary duct carcinomas to evaluate the utility of an immunohistochemical panel consisting of androgen receptor, Her2/neu, p63, and cytokeratin 5/6 in distinguishing these entities. Among all cases in the cohorts, androgen receptor was highly specific for salivary duct carcinoma, while cytokeratin 5/6 and p63 were specific for mucoepidermoid carcinoma. While the rate of unequivocal Her2/neu overexpression among the salivary duct carcinomas was low (8.9 %), discrimination of salivary duct carcinoma was enhanced when this marker was used in combination with androgen receptor due to profound sensitivity. The immunohistochemical panel was particularly efficacious at distinguishing the problematic subset of high-grade mucoepidermoid carcinomas from salivary duct carcinoma. Utilization of this set of immunohistochemical markers allows reliable differentiation of salivary duct and mucoepidermoid carcinoma, a distinction with important prognostic and therapeutic implications.

Current Views and Perspectives on Classification of Squamous Intraepithelial Lesions of the Head and Neck

Abstract: The current state in the field of classifying oral and laryngeal precursor lesions, as proposed in the WHO 2005 Blue Book is not ideal. The results of various inter-observer studies have shown that the currently used grading systems, with different basic concepts and different terminology, cannot continue to be reliably used in the future. The different etiology of cervical and head and neck precursor lesions requires a classification designed to cater to the specificities of the head and neck region. Trying to harmonize different classifications of the oral and laryngeal precursor lesions, we have proposed four crucial steps to set up a unified classification of squamous intraepithelial lesions (SILs): (a) the classification should contain two grades, low-grade and high-grade lesions and, specifically for the larynx, an additional grade—carcinoma in situ (CIS) which must be separated from high-grade laryngeal SILs; (b) the terminology should be unified; our preference is for the term SIL over squamous intraepithelial neoplasia; (c) all leading morphological criteria for low- and high-grade lesions, as well as for CIS, should be clearly defined; (d) agreement between clinicians and pathologists should be achieved on the most appropriate choice of treatment of different grades of SILs in separate head and neck areas.

Small Cell Neuroendocrine Carcinoma of the Oropharynx Harbouring Oncogenic HPV-Infection

Abstract: Small cell carcinoma/neuroendocrine carcinoma (SCNEC) of the oropharynx is uncommon. Recently, an association has been reported between oropharyngeal SCNEC and high-risk human papillomavirus (HPV) infection. While HPV infection confers a better prognosis for oropharyngeal squamous cell carcinoma, HPV infection does not appear to influence the biological behaviour of SCNECs, which are generally associated with poor clinical outcomes. We document two cases of SCNEC arising in the oropharynx with evidence of high-risk HPV infection. The cases highlight the expanding range of malignant oropharyngeal neoplasms that harbour oncogenic HPV infection and support the concept that, irrespective of HPV infection, neuroendocrine differentiation portends a poor prognosis.

Among sinonasal tumors, CDX-2 immunoexpression is not restricted to intestinal-type adenocarcinomas.

Abstract: Intestinal-type adenocarcinoma (ITAC) is a rare form of sinonasal cancer characterized by an association with exposure to industrial dusts, aggressive clinical behavior, and histologic/immunophenotypic similarity to tumors of the gastrointestinal tract. ITAC is sometimes very poorly differentiated and difficult to distinguish from other sinonasal neoplasms, particularly in a limited biopsy. CDX-2 and cytokeratin 20 are consistently immunoreactive in ITAC and as a result, these immunostains are often used to support the diagnosis. However, CDX-2 and cytokeratin 20 have not been tested on a broad range of sinonasal tumors, so their specificities remain unknown. Immunohistochemistry for CDX-2 and cytokeratin 20 was performed on 6 sinonasal ITACs as well as 176 non-intestinal-type sinonasal neoplasms. CDX-2 and cytokeratin 20 were positive in all 6 cases of ITAC. CDX-2 immunoexpression was also observed in 17 of 176 (10 %) non-intestinal-type tumors including 6 of 16 (38 %) sinonasal undifferentiated carcinomas, 8 of 81 (10 %) squamous cell carcinomas (including 5 of 39 non-keratinizing variants), 2 of 20 (10 %) salivary-type adenocarcinomas, and 1 of 2 (50 %) small cell carcinomas. In contrast, among non-intestinal types of sinonasal tumors, cytokeratin 20 was only focally observed in 1 of 176 non-intestinal tumors (a non-keratinizing squamous cell carcinoma). All cases of non-intestinal surface-derived adenocarcinoma and esthesioneuroblastoma were negative for both markers. Both CDX-2 and cytokeratin 20 are highly sensitive for the diagnosis of sinonasal ITAC, but cytokeratin 20 is more specific. CDX-2 staining may be observed in other high grade tumor types, especially sinonasal undifferentiated carcinoma and non-keratinizing squamous cell carcinoma. As a result, in the setting of a poorly differentiated sinonasal carcinoma the diagnosis of ITAC should not be based on CDX-2 immunoexpression alone. Clear-cut glandular differentiation and cytokeratin 20 immunoexpression are more reliable features.

Intraoral Basal Cell Carcinoma, a Rare Neoplasm: Report of Three New Cases with Literature Review

Abstract: Intraoral basal cell carcinoma (IOBCC) is an extremely rare entity that bears close microscopic resemblance to and is often confused with the peripheral ameloblastoma (PA). Basal cell carcinomas are thought to arise from pluripotential basal cells present within surface epithelium and adnexal structures, so theoretically they can arise within the oral cavity. Many of the early cases reported as IOBCC actually represent PA. Most of the well documented cases arise from the gingiva. The histologic features of basal cell carcinoma that help separate it from a PA include: tumor arising from surface epithelium, scattered mitotic figures and apoptotic cells, presence of mucoid ground substance and tumor infiltrating widely throughout the connective tissue and often exhibiting a prominent retraction artifact. Clinically IOBCC resemble carcinomas, compared to the benign and innocuous appearance of the PA and typically presents as surface ulcerations varying from rodent ulcer to an ulcerated erythroplakia appearance. This contrasts with the classic “bump on the gum” appearance of PAs with usually intact surface and appearing as small discrete, sessile, exophytic lesions. Importantly, the proliferative basaloid epithelium demonstrates positive immunoreactivity for the anti-epithelial antibody, Ber-EP4, a cell surface glycoprotein. The IOBCC has the potential for local recurrence and aggressive behavior and should be treated with wide surgical excision and close clinical follow up. We present 3 rare cases of IOBCC and discuss the salient histologic, immunohistochemical and clinical features.

NUT Midline Carcinoma: A Case Report with a Novel Translocation and Review of the Literature

Abstract: NUT midline carcinoma (NMC) is a rare, genetically defined, highly lethal undifferentiated carcinoma occurring in the midline location of the neck, head or mediastinum. We present the case of a 23 year-old otherwise healthy Chinese male immigrant who presented with complaints of sore throat and right sided neck mass. The initial treatment was for likely EBV infection with streptococcal superinfection. Although continued investigation was pursued shortly after initial presentation, the mass had enlarged and become necrotic with significant nodal involvement. The mass was diagnosed as an NMC tumor with a novel three-way translocation t(9;15;19; q34;q13;p13.1). Despite aggressive treatment, the patient’s condition progressed rapidly and he died within 3 months of initial diagnosis. Standard therapeutic interventions have been ineffective in the treatment of NMC. Earlier diagnosis could allow characterization of the natural progression of this entity, and allow more time for intervention or development of novel therapies, potentially related to molecular targets. This continues to require a high index of suspicion and early imaging with cytogenetic and immunohistochemical confirmation.

Malignant Odontogenic Tumors: An Update on Selected Tumors

Abstract: This is an update on selected odontogenic malignancies. The article deals with aspects of recognized odontogenic carcinomas, odontogenic sarcoma and a yet unrecognized entity, sclerosing odontogenic carcinoma. Odontogenic malignancies are exceedingly rare, complicating a thorough understanding of the biologic behavior, reproducible standardized diagnostic criteria, appropriate classification and clinical management. Without the knowledge of the tumor’s biologic behavior, adequate clinical management is difficult and patient outcomes uncertain. The histopathologic features are emphasized as well as the more recent biomarker findings. These recent advances may facilitate further understanding of this group of malignancies and provide useful stratification to guide patient management.

Mammary Analogue Secretory Carcinoma of the Parotid Gland as a Secondary Malignancy in a Childhood Survivor of Atypical Teratoid Rhabdoid Tumor

Abstract: We report the first case of mammary analogue secretory carcinoma (MASC) arising as a secondary malignancy in a 14 years old child with a history of atypical teratoid rhabdoid tumor (ATRT). Although MASC and ATRT are both rare malignancies, they do not share the same genetic and molecular profiles. MASC is a salivary malignancy characterized by a t(12;15)(p13;q25) translocation, resulting in an ETV6-NTRK3 fusion product encoding for a tyrosine kinase. ATRT is a highly malignant pediatric tumor characterized by a chromosome 22 mutation in the hSNF5/INI1 gene, encoding for a chromatin remodeling protein. Additionally, although mucoepidermoid carcinoma has been described as a secondary malignancy post-therapy for head and neck tumors, MASC has only been reported as a primary malignancy. Our patient was treated with a complete resection of his left sided ATRT at age 3 followed postoperatively with chemoradiotherapy. At age 14 he underwent a parotidectomy for his 1 year history of a left sided preauricular mass and was subsequently diagnosed with MASC. We not only report a case of two rare malignancies in one patient, but also the first case of MASC arising as a secondary malignancy.

Mucoepidermoid Carcinoma Does Not Harbor Transcriptionally Active High Risk Human Papillomavirus Even in the Absence of the MAML2 Translocation

Abstract: High risk human papillomavirus (HPV) is firmly established as an important cause of oropharyngeal carcinoma. Recent studies have also implicated HPV as a cause of mucoepidermoid carcinoma (MEC)—a tumor of salivary gland origin that frequently harbors MAML2 translocations. The purpose of this study was to determine the prevalence of transcriptionally active HPV in a large group of MECs and to determine whether HPV infection and the MAML2 translocation are mutually exclusive events. Break-apart fluorescence in situ hybridization for MAML2 was performed on a tissue microarray containing 92 MECs. HPV testing was performed using RNA in situ hybridization targeting high risk HPV mRNA E6/E7 transcripts. Of the 71 MECs that could be evaluated by FISH, 57 (80 %) harbored the MAML2 rearrangement. HPV was not detected in any of the 57 MECs that contained a MAML2 rearrangement, in any of the 14 MECs that did not contain the rearrangement, or in any of the 21 MECs where MAML2 status was unknown. High risk HPV does not appear to play any significant role in the development of MEC. It neither complements nor replaces MAML2 translocation in the tumorigenesis of MEC.

Odontogenic carcinoma with dentinoid: a new odontogenic carcinoma.

Abstract: Dentinoid is an integral part of some odontogenic tumors. This article describes the clinico-pathological features of three cases of odontogenic carcinomas with dentinoid (OCD). A comparison of these with previously reported cases of dentinoid-producing epithelial odontogenic tumors allowed us to identify another six cases that may be considered as examples of OCD. Six cases occurred in the mandible and three in the maxilla, all developing behind the canines. There was no sex predilection (five men and four women; age range 14–61 years, mean 38.1). Pain or discomfort was mentioned in five cases, four of which showed tooth resorption. All cases appeared initially as well-defined radiolucencies, five of which showed variable amounts of calcified material. Recurrences were recorded in three instances, but no evidence of metastasis has been found. Seven cases were composed predominantly or entirely of clear cells, usually with minimal cellular atypia and variable mitotic activity; however, in all cases there was evidence of tumor infiltration into adjacent tissues, including the presence of perineural invasion in two tumors. Those cases in which no reference was made to the presence of clear cells exhibited evident mitotic activity and cellular pleomorphism. The epithelium in OCD does not produce buds or enamel organ-like structures such as those found in ameloblastic fibro-dentinoma and this tumor does not contain a mesenchyme-like connective tissue resembling dental papilla as observed in several mixed odontogenic tumors. Based on the existing data and the present series of cases, OCD appears to represent a distinct entity.

Calcifying Epithelial Odontogenic Tumour with Clear Langerhans Cells: A Novel Variant, Report of a Case and Review of the Literature

Abstract: Clear cell calcifying epithelial odontogenic tumour (CCEOT) is a rare variant of calcifying epithelial odontogenic tumor (CEOT). While it is not surprising to find clear cells in odontogenic lesions, the exact nature of the clear cells in CCEOT has not been elucidated. Herein, we report a case of peripheral CCEOT of anterior mandible in a 37 year old black female. Histologically, the tumour consisted of cords and small nests of clear cells surrounded by dense deposits of amyloid and basophilic calcifications. The cells possessed abundant clear cytoplasm and eccentrically located indented nuclei. Admixed with the clear cells were eosinophilic cuboidal to polyhedral cells. The clear cells were PAS negative and immunoreactive for S100 protein, CD1a and Langerin. The clear cells were negative for MNF-116, SMA, Desmin and CK-19. It is therefore recommended to recognize two variants of CCEOT, namely, CEOT with clear cell change and CEOT with clear Langerhans cells (LC). We further suggest that the contradictory term “non-calcifying variant of calcifying epithelial odontogenic tumour with LC” to be abandoned, as the current case clearly indicates that LC could be seen in CEOT irrespective of the presence or absence of calcifications.