Well-differentiated Neuroendocrine Carcinoma of the Larynx: Confusion of Terminology and Uncertainty of Early Studies.

Well-differentiated neuroendocrine carcinoma (also known as "carcinoid") of the larynx is an exceedingly rare tumor that has an epithelial origin. These tumors are malignant and have a low, but definite, risk of metastasis. Although it can be challenging, this tumor should be differentiated from moderately differentiated neuroendocrine carcinoma (also known as "atypical carcinoid"). The clinical and pathologic features of this tumor, as well as treatment and prognosis, are reviewed in detail.

Molecular diagnostic alterations in squamous cell carcinoma of the head and neck and potential diagnostic applications.

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy that continues to be difficult to treat and cure. In many organ systems and tumor types, there have been significant advances in the understanding of the molecular basis for tumorigenesis, disease progression and genetic implications for therapeutics. Although tumorigenesis pathways and the molecular etiologies of HNSCC have been extensively studied, there are still very few diagnostic clinical applications used in practice today. This review discusses current clinically applicable molecular markers, including viral detection of Epstein-Barr virus and human papillomavirus, and molecular targets that are used in diagnosis and management of HNSCC. The common oncogenes EGFR, RAS, CCND1, BRAF, and PIK3CA and tumor suppressor genes p53, CDKN2A and NOTCH are discussed for their associations with HNSCC. Discussion of markers with potential future applications is also included, with a focus on molecular alterations associated with targeted therapy resistance.

Sinonasal tumors: a clinicopathologic update of selected tumors.

The sinonasal cavities show a wide variety of neoplasms of epithelial, mesenchymal, neural/neuroectodermal or hematopoietic origin. The differential diagnosis for these tumors may be difficult due to overlapping morphologies, variable patterns in ancillary studies, and potentially confusing terminology. In this report, an updated review of the spectrum of neoplasia is provided, using the World Health Organization 2005 classification as a guide. Classic tumors that are generally limited to the sinonasal tract are described and new information regarding molecular pathogenesis is reviewed. Also new entities that have the sinonasal tract as a site of predilection, such as sinonasal renal cell-like adenocarcinoma and NUT midline carcinoma are highlighted.

Cervical lymph node metastasis in adenoid cystic carcinoma of oral cavity and oropharynx: A collective international review.

The purpose of this study was to suggest general guidelines in the management of the N0 neck of oral cavity and oropharyngeal adenoid cystic carcinoma (AdCC) in order to improve the survival of these patients and/or reduce the risk of neck recurrences. The incidence of cervical node metastasis at diagnosis of head and neck AdCC is variable, and ranges between 3% and 16%. Metastasis to the cervical lymph nodes of intraoral and oropharyngeal AdCC varies from 2% to 43%, with the lower rates pertaining to palatal AdCC and the higher rates to base of the tongue. Neck node recurrence may happen after treatment in 0-14% of AdCC, is highly dependent on the extent of the treatment and is very rare in patients who have been treated with therapeutic or elective neck dissections, or elective neck irradiation. Lymph node involvement with or without extracapsular extension in AdCC has been shown in most reports to be independently associated with decreased overall and cause-specific survival, probably because lymph node involvement is a risk factor for subsequent distant metastasis. The overall rate of occult neck metastasis in patients with head and neck AdCC ranges from 15% to 44%, but occult neck metastasis from oral cavity and/or oropharynx seems to occur more frequently than from other locations, such as the sinonasal tract and major salivary glands. Nevertheless, the benefit of elective neck dissection (END) in AdCC is not comparable to that of squamous cell carcinoma, because the main cause of failure is not related to neck or local recurrence, but rather, to distant failure. Therefore, END should be considered in patients with a cN0 neck with AdCC in some high risk oral and oropharyngeal locations when postoperative RT is not planned, or the rare AdCC-high grade transformation.

Cervical Lymph Node Metastasis in High-Grade Transformation of Head and Neck Adenoid Cystic Carcinoma: A Collective International Review.

Adenoid cystic carcinoma (AdCC) is among the most common malignant tumors of the salivary glands. It is characterized by a prolonged clinical course, with frequent local recurrences, late onset of metastases and fatal outcome. High-grade transformation (HGT) is an uncommon phenomenon among salivary carcinomas and is associated with increased tumor aggressiveness. In AdCC with high-grade transformation (AdCC-HGT), the clinical course deviates from the natural history of AdCC. It tends to be accelerated, with a high propensity for lymph node metastasis. In order to shed light on this rare event and, in particular, on treatment implications, we undertook this review: searching for all published cases of AdCC-HGT. We conclude that it is mandatory to perform elective neck dissection in patients with AdCC-HGT, due to the high risk of lymph node metastases associated with transformation.

Cervical Lymph Node Metastasis in Adenoid Cystic Carcinoma of the Larynx: A Collective International Review.

Adenoid cystic carcinoma (AdCC) of the head and neck is a well-recognized pathologic entity that rarely occurs in the larynx. Although the 5-year locoregional control rates are high, distant metastasis has a tendency to appear more than 5 years post treatment. Because AdCC of the larynx is uncommon, it is difficult to standardize a treatment protocol. One of the controversial points is the decision whether or not to perform an elective neck dissection on these patients. Because there is contradictory information about this issue, we have critically reviewed the literature from 1912 to 2015 on all reported cases of AdCC of the larynx in order to clarify this issue. During the most recent period of our review (1991-2015) with a more exact diagnosis of the tumor histology, 142 cases were observed of AdCC of the larynx, of which 91 patients had data pertaining to lymph node status. Eleven of the 91 patients (12.1%) had nodal metastasis and, based on this low proportion of patients, routine elective neck dissection is therefore not recommended.

Allelic loss in parathyroid neoplasia can help characterize malignancy.

Parathyroid carcinoma can be difficult to diagnose, and the final pathologic diagnosis relies on clinicopathologic correlation. Clinical features of malignancy include high preoperative calcium levels and an intraoperative impression that the gland is adherent to local structures. Histologic features of malignancy include increased mitoses, vascular invasion, and broad bands of fibrosis. This study used molecular genotyping to assess parathyroid neoplasia for loss of heterozygosity across a panel of known tumor suppressor genes that have been previously identified as being important in the pathogenesis of parathyroid diseases. Parathyroid adenomas, hyperplasia, and carcinomas were included in the study, and a fractional allelic loss was calculated for each lesion. Losses of 1q25, 7q13.3, 10q23, 13q14.3, and 11p15.5 were particularly prevalent. In addition, almost all adenomas and carcinomas had loss of the markers for 1p. The benign parathyroid diseases (adenomas and hyperplasia) had low mean fractional allelic loss (11% and 15%, respectively). The parathyroid carcinomas, in contrast, showed high mean fractional allelic loss (63%). This difference in the mutational profile suggests that this type of assay may be useful as an adjunctive diagnostic test in cases of parathyroid neoplasia.

Idiopathic midline destructive disease: fact or fiction.

The differential diagnosis of a progressive destructive lesion of the midface and upper airway region includes both neoplastic and non-neoplastic entities; of these, the majority of cases prove to be either Wegener's granulomatosis or lymphoma. Historically, these sorts of necrotizing midfacial lesions were diagnosed clinically, and as a consequence a variety of overlapping categories of disease sprang up. As pathologic examination of biopsy material became both more widespread and (particularly in the last several years) more sophisticated, many lesions previously thought to be of mysterious origins have proven to be examples of lymphoma (in particular, sinonasal natural killer cell or T cell [NK/T] lymphomas). At present, the evaluation of a patient with a progressive destructive process involving the midface region should include imaging studies (to delineate the extent of disease) as well as biopsy (with sampling of lesional tissue for application of sophisticated testing--including immunohistochemical studies, flow cytometry, or molecular studies as necessary--to exclude the possibility of a NK/T cell lymphoma). There remain occasional patients whose necrotizing midfacial lesions continue to be difficult to classify despite the application of extensive testing; such patients are sometimes described as suffering from the nebulous entity of "idiopathic midline destructive disease". While it remains to be seen whether such patients will ultimately be assigned to other diagnostic groups (as, for example, occult toxic injuries--as in the case of cocaine abusers who are not forthcoming with regard to their drug usage), it seems likely that "idiopathic midline destructive disease" is a diagnostic term of questionable validity which should be used only with extreme reticence in modern practice.

Rhabdomyoblastic Differentiation in Head and Neck Malignancies Other Than Rhabdomyosarcoma.

Rhabdomyosarcoma is a relatively common soft tissue sarcoma that frequently affects children and adolescents and may involve the head and neck. Rhabdomyosarcoma is defined by skeletal muscle differentiation which can be suggested by routine histology and confirmed by immunohistochemistry for the skeletal muscle-specific markers myogenin or myoD1. At the same time, it must be remembered that when it comes to head and neck malignancies, skeletal muscle differentiation is not limited to rhabdomyosarcoma. A lack of awareness of this phenomenon could lead to misdiagnosis and, subsequently, inappropriate therapeutic interventions. This review focuses on malignant neoplasms of the head and neck other than rhabdomyosarcoma that may exhibit rhabdomyoblastic differentiation, with an emphasis on strategies to resolve the diagnostic dilemmas these tumors may present. Axiomatically, no primary central nervous system tumors will be discussed.

Osteoclast-type giant cell neoplasm of salivary gland. A microdissection-based comparative genotyping assay and literature review: extraskeletal "giant cell tumor of bone" or osteoclast-type giant cell "carcinoma"?

Primary salivary gland tumors resembling giant cell tumor of bone are very rare and have unsettled histogenesis. Both mesenchymal and epithelial origins have been suggested. We review 14 cases in the English-language literature and report another case, the first of which to be studied by microdissection-based microsatellite analysis. One-half of the tumors have been associated with a carcinoma, usually salivary duct carcinoma and carcinoma ex pleomorphic adenoma. Significant differences between this tumor and giant cell tumor of bone were observed. Unlike giant cell tumor of bone, in which the nuclei of the mononuclear and giant cells are similar, those of salivary gland show obvious differences between the nuclei of mononuclear cells and osteoclastic giant cells. In addition and in contrast to giant cell tumor of bone, the mononuclear cells of giant cell tumor of salivary gland express epithelial markers (epithelial membrane antigen, EMA; carcinoembryonic antigen, CEA) and androgen receptor. Genotypically, the microsatellite pattern of the giant cell component is more akin to the carcinomatous component and does not resemble giant cell tumor of bone. Biologically, giant cell tumor of salivary gland tends to be more aggressive than giant cell tumor of bone. We conclude that giant cell tumor of salivary gland is an unusual carcinoma that is not related to giant cell tumor of bone.

Small-cell neuroendocrine carcinoma displays unique profiles of tumor-suppressor gene loss in relationship to the primary site of formation.

Small-cell neuroendocrine carcinoma (SCNC) is a well characterized malignancy with distinctive cellular morphology and aggressive biologic behavior most frequently encountered in the lung but also noted for origin from other sites. The basis for this difference in incidence and the impact of primary site location on the molecular pathogenesis of the neoplasm is not well understood. To address this issue and to identify reliable molecular markers of potential diagnostic value for primary site localization of this tumor, we have compared the genetic profile of cancer-related gene damage of SCNC arising from a variety of organ sites. The analysis involved microdissected paraffin-embedded formalin fixed specimens of SCNC. Tumors were organized into 3 groups: lung (n = 18), head and neck region (n = 5), and gastrointestinal tract (n = 5). Genotyping evaluated allelic imbalance (loss of heterozygosity) involving genomic regions containing p53 (17p13), L-myc (1p34), OGG1 (3p26), MCC/APC (5q21), p16 (9p21), PTEN (10q23), and point mutational change in K-ras-2 (12p12) using polymerase chain reaction-based microsatellite analysis and DNA sequencing. Distinct genotypic profiles of allelic imbalance using this panel was seen for each group of SCNC enabling primary site determination to be suggested based on genotypic profiling of microdissected tissue samples. Despite similarity in histologic appearance, our study suggests that SCNC have a unique pattern of acquired allelic damage that is determined in part by primary site of tumor development. These attributes can be effectively used for primary localization of metastatic SCNC, thereby assisting in the diagnosis and classification of this neoplasm.

Loss of heterozygosity mutations of tumor suppressor genes in cytologically atypical areas in chronic lymphocytic thyroiditis.

The relationship between chronic lymphocytic thyroiditis (CLT) and papillary thyroid carcinoma (PTC) is a subject of controversy. Some investigators suggest a causal relationship, whereas others regard the two as only a coincidental occurrence. An additional complicating factor is the presence of atypical nuclei frequently found within lymphoid infiltrates in CLT, which resemble those in PTC. The finding of the RET-PTC translocations in CLT has been reported by two independent groups of investigators, suggesting that the areas of nuclear atypia in CLT are neoplastic rather than reactive. In the present study, we report additional molecular findings that support the hypothesis that the atypical nuclear changes in CLT may be preneoplastic or neoplastic. We microdissected small areas with atypical nuclei in glands with CLT and observed loss-of-heterozygosity mutations of tumor suppressor genes. These genetic mutations are evidence of clonal preneoplastic or neoplastic changes in the follicular cells of CLT. The clinical malignant potential of these minute foci is likely to be very small but remains to be determined.

Salivary duct carcinoma.

Salivary duct carcinoma (SDC) is a highly malignant tumor that is histologically similar to ductal carcinoma of the breast. This article presents the clinicopathologic features of 15 patients with SDC arising in the salivary glands. The majority of patients were male and aged 65 years or older. The tumor was most often located in the parotid gland. Pain, facial palsy, and presence of calcification in the CT scan were diagnostic features suggestive of SDC. Histologically, 27% of the tumors arose from pre-existing pleomorphic adenoma. Perineural and lymphatic invasion were common findings. There was an extensive cervical lymph node involvement (73%). Distant metastasis was the most common cause of failure. Although SDC exhibits an unpredictable clinical course, total parotidectomy with neck dissection and adjunctive radiation therapy appear to be appropriate for local and regional control of this aggressive neoplasm.

Giant cell tumor of the skull: a case report and review of the literature.

BACKGROUND: Giant cell tumors are benign lesions that typically occur at the epiphyses of long bones that typically present with pain or swelling. Most data on giant cell tumors in the skull consist of case reports, and many large series of giant cell tumors have no examples in the skull. METHODS: We report a case of giant cell tumor of the skull and review the literature on these lesions. RESULTS: A 24-year-old woman presented with localized tenderness and mild swelling over the left inferior parietal and occipital bones. She was neurologically intact with a nonmobile, tender, palpable mass over the left subocciptal area. A computed tomography (CT) scan showed a radiolucent, expansile, lytic lesion involving the left occipital bone. The patient underwent a left occipital craniectomy with resection of the bone and epidural mass. Permanent histopathologic sections and immunostains revealed a giant cell tumor. CONCLUSIONS: Giant cell tumors are generally benign, locally aggressive lesions for which surgical excision is the treatment of choice. This report contributes to the scarce literature on these tumors in the skull.

Laryngeal paraganglioma: an updated critical review.

Laryngeal paragangliomas are rare submucosal lesions that arise from paraganglion cells located in the false vocal fold and subglottic larynx. To date, 76 recognized cases have been reported in the world literature. Symptoms arise when the lesions become large enough to impair function. Supraglottic paragangliomas cause hoarseness and deglutition disorders, whereas subglottic tumors become symptomatic when they obstruct the airway. Evaluation of these tumors includes obtaining a complete history. Familial paragangliomas and hypertension should be sought but are rarely, if ever, associated with laryngeal paragangliomas. MRI can detect these lesions and permit characterization of the vascularity of the lesion. Adding 111In pentetreotide scanning can distinguish neuroendocrine tumors from other submucosal laryngeal lesions, making the preoperative diagnosis clearer and obviating the need for biopsy. The biggest dilemma regarding laryngeal paragangliomas is making the correct pathologic distinction between paraganglioma, typical carcinoid, atypical carcinoid and medullary thyroid cancer. Immunohistochemical markers, supplementing standard histopathologic evaluation, can distinguish paragangliomas from the aforementioned tumors. This distinction is critical as the prognosis for treated paragangliomas is excellent compared to that for other neuroendocrine neoplasms. Almost all alleged malignant paragangliomas of the larynx are in reality atypical carcinoid tumors that have been misdiagnosed. Treatment should always comprise excision. Thyrotomy has the best chance of achieving a sustained cure without damaging phonation or deglutition. Laser excision has been used successfully but there is no great experience with this modality. Surgery is preferable to radiation for paragangliomas in all locations but especially so in the larynx, due to issues such as swelling, airway protection and destruction of cartilage. With increased clinical suspicion and the use of modern imaging techniques, laryngeal paragangliomas should be routinely diagnosed and treated without loss of laryngeal functions.

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

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.

Intraosseous carcinoma of the jaws--a clinicopathologic review. Part I: Metastatic and salivary-type carcinomas.

This is the first part of a 3-part comprehensive review of intraosseous carcinoma of the jaws. We have outlined 4 groups of intraosseous carcinoma of the jaws (metastatic, salivary-type, odontogenic, and primary intraosseous carcinoma), emphasizing the need for accurate diagnosis and the problems associated with changing classification systems, standardization of diagnostic criteria and nomenclature, and the accuracy of existing literature. In this first part, the features of metastatic and the very rare salivary-type carcinomas of the jaws are examined with particular emphasis on histologic and immunohistochemical characteristics, diagnostic difficulties, and uncertainties.