Epidermal Growth Factor Receptor Expression in Spindle Cell Carcinomas of the Head and Neck.

Spindle cell carcinoma (SpCC) is an uncommon head and neck squamous cell carcinoma (SCC) variant consisting of spindled and/or pleomorphic cells with epithelial differentiation. Epidermal growth factor receptor (EGFR) is expressed by >90 % of conventional SCC, and high level expression is associated with a poorer prognosis. Anti-EGFR therapies are commonly used to treat head and neck SCC. However, no studies have evaluated EGFR expression in SpCC. Cases of SpCC were retrieved from department files. The diagnosis required either a biphasic lesion with a squamous neoplastic component, or a purely spindle cell or pleomorphic tumor with immunohistochemical positivity for epithelial markers. EGFR immunohistochemistry was performed and was quantified in quartiles. Medical records were reviewed for clinical follow up information. EGFR was expressed in 21/30 (70 %) cases, including in the squamous component in 18/19 (95 %) and the spindle cell component in only 12/30 (40 %). Where the spindle cell component was positive, the intensity and distribution were lower than for the squamous component. Recurrent tumors were predominantly (80-90 %) of the spindle cell component, and had low (or absent) EGFR expression. Kaplan-Meier survival analysis showed no statistically significant differences in overall or disease free survival between the EGFR expressing and non-expressing groups (p = 0.414 and 0.19, respectively). SpCCs of the head and neck have a poor prognosis, and markedly reduced EGFR expression. EGFR-specific therapies may not be ideal for SpCC patients, which may lack EGFR expression, but further studies are needed.

Spindle cell carcinomas of the head and neck rarely harbor transcriptionally-active human papillomavirus.

Spindle cell carcinoma is an uncommon variant of squamous cell carcinoma characterized by spindled or pleomorphic cells which appear to be a true sarcoma but are actually epithelial. Some head and neck squamous cell carcinoma variants can be human papillomavirus (HPV)-related and have improved outcomes. We sought to determine if spindle cell carcinomas are associated with transcriptionally-active HPV. Cases of spindle cell carcinoma were retrieved from department files. Transcriptionally-active HPV was determined by mRNA in situ hybridization for high risk HPV E6 and E7 transcripts and by a surrogate marker, p16 immunohistochemistry, with a 50% staining cutoff. RT-PCR for high risk HPV mRNA was performed on the cases that were technical failures by in situ hybridization. Medical records and follow up information were retrieved for all patients. Of 31 cases, 5 were from the oropharynx, 12 from the oral cavity, and 14 from the larynx or hypopharynx. One purely spindled oral cavity spindle cell carcinoma was HPV positive. It was also diffusely positive for p16. Another laryngeal spindle cell carcinoma was HPV positive in both the squamous and spindle cell components, but was negative for p16. None of the five oropharyngeal spindle cell carcinomas were positive for p16 or HPV RNA. The HPV positive patients both presented at high stage (IV) and died with disease within 2 years of diagnosis. The majority of spindle cell carcinomas of the head and neck, including those arising in the oropharynx, are not related to transcriptionally active HPV. Although the number of cases is too small for any definitive conclusions, for the rare HPV positive spindle cell carcinoma cases, positive viral status does not appear to confer any prognostic benefit.

Squamous cell carcinoma arising in recurrent respiratory papillomatosis with pulmonary involvement: emerging common pattern of clinical features and human papillomavirus serotype association.

Squamous papillomas of the lung are an uncommon feature of recurrent respiratory papillomatosis, occurring in fewer than 1% of cases. We describe a 23-year-old patient with pulmonary papillomas who developed a fatal squamous cell carcinoma of the lung. PCR-based human papillomavirus (HPV) typing showed the presence of HPV 11 DNA in both benign papillomas and invasive carcinoma. A review of the literature reveals four reports of malignant transformation of juvenile-onset recurrent respiratory papillomatosis in which HPV typing was performed. Similar clinical features are noted in all of the reports; specifically, each case has arisen in a young adult man with a history of papillomatosis since childhood. In each of the cases, HPV 11 was identified in association with the squamous cell carcinoma. Although HPV 11 is uncommonly associated with the development of invasive carcinoma at other sites, these findings suggest that it is correlated with malignant transformation in the setting of juvenile-onset recurrent respiratory papillomatosis.

Laryngeal blastomycosis: a commonly missed diagnosis. Report of two cases and review of the literature.

Blastomycosis is a relatively uncommon fungal disease that most commonly affects the lungs. Other organs may be involved, usually secondary to dissemination of the organism. Laryngeal blastomycosis may occur in isolation from active pulmonary disease. The signs, symptoms, clinical features, and pathological findings of laryngeal blastomycosis mimic those of squamous cell carcinoma. Misdiagnosis may result in inappropriate treatment with potential morbidity. Proper understanding of the clinical presentation and familiarity with the histopathologic features of this disease are therefore imperative. In this paper, we report 2 cases of laryngeal blastomycosis, 1 of which was misdiagnosed as squamous cell carcinoma, clinically and microscopically, with consequent radiotherapy and laryngectomy. In the other case, a clinical diagnosis of glottic squamous cell carcinoma was rendered. However, blastomycosis was identified in a biopsy specimen. We also review cases of isolated laryngeal blastomycosis that have been reported in the English-language literature during the last 80 years. A number of those cases were misdiagnosed clinically and microscopically as squamous cell carcinoma.

Cemento-ossifying fibroma and benign cementoblastoma.

Cementum is a calcified dental tissue that covers the roots of teeth and is part of the periodontium. Its function is to help anchor the teeth in their sockets within the alveolar bone of the jaws. Two benign mesenchymal odontogenic tumors are uniquely distinguished by elaboration of cementum or cementum-like material: cemento-ossifying fibroma and benign cementoblastoma (true cementoma). Cemento-ossifying fibroma, which is also termed periodontoma, is characterized by production of cementum and bone in a fibrous stroma. It is a painless, slow-growing tumor usually detected in the third and fourth decade of life and is more common in women. The mandible is its site of predilection. Benign cementoblastoma is intimately associated with the roots of teeth, most commonly mandibular molars. It affects young patients, usually under the age of 20 years. Pain is a common symptom in addition to bone expansion. Benign cementoblastoma bears considerable histologic resemblance to osteoblastoma.

Tubulopapillary hidradenoma-like tumor of the mandible: clinicopathologic and immunohistochemical features.

Tubulopapillary hidradenoma is a benign sweat gland tumor that appears as a well-defined, superficially located dermal nodule. It combines ductal as well as apocrine and eccrine glandular differentiation. Microscopically, the tumor is composed of tubular structures that characteristically show intraluminal non-villous papillary projections and a peripheral myoepithelial cell layer. A tumor that is histologically and immunohistochemically identical to tubulopapillary hidradenoma occurred in the mandible of a 73-year-old man and resulted in considerable diagnostic difficulty. The neoplasm developed in a mandibular cyst and recurred 5 years after initial enucleation. This is the first report of a central (intraosseous) sweat gland adenoma of the mandible. The differential diagnosis and possible histogenesis are discussed.

Clinical correlations with allelotype in supraglottic squamous cancer.

Frequent allelic loss at a genetically polymorphic locus in tumors is an established marker for the presence of a tumor suppressor gene in the neighboring chromosomal region. This technique can be used to identify novel tumor suppressor genes and to monitor their status before the cloning of the gene itself. We have used the polymerase chain reaction and microsatellite loci on all 39 nonacrocentric autosomal chromosomal arms to identify sites of frequent allelic loss in squamous cell carcinomas of the supraglottic larynx. Our allelotype identified seven chromosomal arms (3p, 5q, 8p, 9p, 9q, 13q, and 17p) likely to contain tumor suppressor genes frequently inactivated during squamous tumorigenesis in the larynx. We tested for associations between allelic losses on these chromosomal arms and the clinical and histopathologic features of these tumors. There were no correlations with either T or N classifications. Allelic loss on chromosomal arm 13q is significantly associated with a number of histopathologic features characteristic of poorly differentiated or histologically aggressive tumors. Allelic loss on this arm also exhibits statistical trends toward association with early tumor recurrence and poor survival. The association with survival was substantiated by a multivariate Cox proportional hazards model.

Chromosome 8 allelic loss and the outcome of patients with squamous cell carcinoma of the supraglottic larynx.

BACKGROUND: Loss of genetic heterogeneity (allelic loss or loss of heterozygosity) on chromosome arm 8p is frequent in squamous cell carcinomas of the head and neck and has been associated with poor prognosis. We have previously demonstrated that there are three minimal regions of allelic loss on this chromosome arm. The location of each region is marked by a microsatellite locus: D8S264 (8p23), D8S552 (8p23-p22), and D8S133 (8p21). These findings imply the existence of at least three putative tumor suppressor genes on this chromosome arm that may become inactivated during the progression of squamous cell carcinoma. PURPOSE: We used allelic loss data from these three loci to determine if inactivation of these putative suppressors is associated with poor prognosis for patients with squamous cell carcinoma of the supraglottic larynx. We also used multivariate statistics to compare the prognostic power of allelic loss at these genetic markers with that of demographic, clinical, and histopathologic parameters. METHODS: We examined the D8S264, D8S552, and D8S133 microsatellites in tumors from a retrospective population of 59 patients. All patients had histologically confirmed squamous cell carcinoma of the supraglottic larynx and had been treated surgically. DNA was extracted from matched sets of normal and microdissected tumor tissue and used for polymerase chain reaction amplification of the microsatellite markers. Reaction products were separated by denaturing gel electrophoresis and visualized by autoradiography. Patient data were obtained from the original pathology report and from the tumor registry of the Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO. Histopathologic data were obtained by reviewing the portion of the resection specimen used for DNA extraction. Parameters whose association with reduced disease-free interval and reduced disease-specific survival was statistically significant were identified by use of the Kaplan-Meier method and the logrank statistic. Multivariate Cox proportional hazards models were used to identify independent predictors of poor prognosis. All statistical tests were two-sided. RESULTS: In this patient population, allelic loss at the D8S264 locus was associated with both shorter disease-free interval (logrank P = .028) and reduced disease-specific survival (logrank P = .004). Allelic loss at the next most centromeric locus, D8S552, had a statistically significant association with only reduced disease-specific survival (logrank P = .034), whereas allelic loss at the most centromeric region, D8S133, showed no statistically significant association with reductions in either interval. Multivariate Cox models suggested that D8S264 was the only 8p marker of the three microsatellites with a statistically significant and independent association with shortened disease-free interval (relative risk [RR] = 3.38; P = .0107) and reduced disease-specific survival (RR = 3.41; P = .0105). CONCLUSIONS: Allelic loss in the p23 region of chromosome 8 appears to be a statistically significant, independent predictor of poor prognosis in patients with supraglottic squamous cell carcinoma.

Prognostic significance of clinical factors and p53 expression in patients with glottic carcinoma treated with radiation therapy.

BACKGROUND: Numerous clinical parameters have been suggested as predictors of outcome for patients with head and neck carcinoma treated with radiation therapy, but their applicability remains controversial. Inactivation of the p53 tumor suppressor results in radioresistance in experimental systems and might predict treatment failure in human patients. We have tested this hypothesis by comparing the predictive power of nuclear accumulation of p53 protein with that of clinical and histopathologic markers in patients with glottic carcinoma treated with primary radiotherapy. METHODS: Clinical charts were reviewed for 165 patients with glottic squamous cell carcinoma treated with radiation therapy. One hundred and twenty-one patients with T1 or T2 classified tumors were determined to have received adequate treatment and to have adequate follow-up data for further study. Archival pretreatment tumor biopsies from a subpopulation of patients were examined for p53 protein by immunohistochemistry. The influence of clinical and histopathologic variables and p53 nuclear protein on tumor recurrence was studied by bivariate and multivariate analysis. RESULTS: The recurrence rate was lowest for patients with moderately to poorly differentiated tumors (P < 0.05). This was the only significant predictor of outcome in this patient population. The presence of immunohistochemically detectable p53 antigen was not predictive of tumor recurrence in 70 patients for whom there was both p53 and sufficient follow-up data. CONCLUSIONS: Histologic differentiation was prognostic for tumor recurrence in this population of patients with glottic carcinoma treated with radiation therapy. In contrast, nuclear accumulation of p53 protein was not predictive of tumor response or recurrence in this population.

Allelic loss in squamous cell carcinomas of the larynx: discordance between primary and metastatic tumors.

The mutational inactivation of suppressor genes, a process required for cancer progression, generates new genetic subclones within a tumor. The allelic losses that frequently unmask these mutations serve not only as markers of the chromosomal locations of these genes but also as clonal fingerprints of the shifting relationships between these genetically heterogeneous cell populations. The rise of the metastasis-competent subclone to dominance within the primary tumor should be reflected in the similarity of the genetic fingerprints of the primary tumor and its resultant metastases. We have tested this hypothesis by comparing the patterns of allelic loss of individual primary laryngeal squamous cell carcinomas and their resultant cervical lymph node metastases at 16 different genetically polymorphic loci on 15 chromosome arms. Although primary tumors and metastases both frequently lose heterozygosity on the same chromosome arms (3p, 9p, 9q, 13q, and 17p), five of the 12 metastases differed from their primary tumors at one or two of the loci examined. Discordance between the two tumor cell populations from the same patient is suggestive of either subclone heterogeneity within the primary tumor at the time of establishment of the metastasis or further clonal evolution of both tumors after metastasis.

Frequent loss of heterozygosity for Rb, TP53, and chromosome arm 3p, but not NME1 in squamous cell carcinomas of the supraglottic larynx.

BACKGROUND: The inactivation of some tumor suppressor genes classically manifests itself through the loss of heterozygosity at nearby genetic mapping markers. Inactivation of these genes appears to have diagnostic/prognostic significance in some types of tumors. Molecular genetic tools based on suppressor inactivation might, therefore, have great utility in treatment planning. METHODS: The polymerase chain reaction and highly informative microsatellite markers were used to compare DNA derived from matched sets of tumor and normal tissue samples from 37 supraglottic laryngeal squamous cell carcinomas. Tumor samples were microdissected free of contaminating normal tissue to maximize the detection of allelic loss. Polymerase chain reaction products were fractionated by denaturing gel electrophoresis and were visualized by autoradiography. RESULTS: Allelic losses were frequent at TP53 (56% of the tumors), the retinoblastoma gene (Rb, 59%), and the p13-14 region of chromosome 3 (64%). In contrast, the putative metastasis suppressor, NME1 (also known as NM23), was lost infrequently (7%). NME1 allelic loss did not correlate with the presence of lymph node metastases in these patients. CONCLUSIONS: The high frequencies of allelic loss at TP53, Rb, and 3p13-14 suggest that these suppressors play a major role in laryngeal carcinogenesis. In sharp contrast, the low frequency of loss at NME1 and its equal distribution in nodal metastasis-positive and -negative patients suggests that inactivation of this gene by allelic loss probably does not play a role in the development of regional metastases from these tumors. Allelic loss in 3p13-14 was found in tumors of all histopathologic grades.

Eosinophilic ulcer of the oral mucosa. Report of 38 new cases with immunohistochemical observations.

Eosinophilic ulcer of the oral mucosa (traumatic eosinophilic granuloma) mimics oral cancer clinically and is occasionally misdiagnosed as lymphoma on microscopic examination. Trauma is believed to play a role in its development, but its exact pathogenesis is not known. The demographic, clinical, and histologic features of 38 previously unreported cases of eosinophilic ulcer of the oral mucosa are reviewed. Nine representative cases were studied immunohistochemically. Microscopically, the lesions contained a polymorphic inflammatory infiltrate extending deep into the submucosa, underlying muscle, and salivary glands. Numerous eosinophils and large mononuclear cells with pale nuclei and frequent mitoses were seen in all lesions. Lymphocytes, histiocytes, plasma cells, granulocytes, and mast cells were also present. Immunohistochemical stains showed that the lymphocytic infiltrate was composed predominantly of T cells. T-cell-specific antigen-presenting cells were more numerous than the non-antigen-presenting cell type. The large cells with pale nuclei stained positively only for vimentin; the possible myofibroblastic nature of these cells is discussed. Although trauma might have an etiologic role, the pathogenesis of eosinophilic ulcer of the oral mucosa is probably T cell mediated.

Mucosal calcified nodule. The oral counterpart of the subepidermal calcified nodule.

The subepidermal calcified nodule, also known as cutaneous calculi, is a form of idiopathic calcinosis that affects children and is occasionally present at birth. It occurs usually in the facial skin and has no relationship to connective tissue disease or to any abnormality in calcium or phosphorus metabolism. The oral cavity is very rarely affected by calcinosis cutis of any type, and idiopathic calcinosis has not been previously reported in the oral mucosa. This is a report of two cases of calcified nodules that occurred in the gingiva of a 1-year-old girl and the tongue of a 5-year-old boy. The lesions showed clinical, histologic, and histochemical similarities to the subepidermal calcified nodule. The name oral mucosal calcified nodule is proposed for this form of calcinosis.

Peripheral ameloblastoma: a clinical and histologic study of 11 cases.

Peripheral ameloblastoma (PA) is a rare odontogenic tumor. Previously, only 39 cases of PA had been reported in the English literature. In this article 11 additional cases of PA are presented. Concordance with previous cases was evident with regard to race, clinical appearance, and site of predilection. However, differences were observed with regard to age, sex distribution, and predominant histologic pattern. The average age in the current cases is younger, there is no male bias, and the most common histologic pattern is plexiform rather than follicular or acanthomatous. Recurrence following simple excision is rare, but has been reported. Long-term postoperative follow-up is recommended.

Lymph node metastasis in spindle cell carcinoma arising in odontogenic cyst. Report of a case.

The majority of primary intraosseous carcinomas of the jaws develop in preexisting odontogenic cysts. These tumors are usually well-differentiated keratinizing carcinomas with relatively good prognosis. Only two of 41 previously reported acceptable cases of primary intraosseous carcinomas from ex-odontogenic cysts were associated with cervical lymph node metastasis. Spindle cell carcinoma is an anaplastic dimorphic neoplasm with poor prognosis. It has a special predilection for the upper aerodigestive tract. This is to our knowledge the first report of spindle cell carcinoma developing in an odontogenic cyst. Cervical lymph node metastasis showing typical histologic features of spindle cell carcinoma was detected 8 months postoperatively. The prognostic implications of this finding are discussed in light of previously reported cases of intraosseous carcinoma arising in odontogenic cysts and of spindle cell carcinoma of the oral cavity.

Intraoral manifestation of thromboangiitis obliterans (Buerger's disease).

A case of thromboangiitis obliterans (Buerger's disease) showing vascular lesions in the oral cavity is presented. To our knowledge, this is the first report of involvement of branches of the external carotid artery with this disease. The clinical, radiographic, plethysmographic, and histologic features of Buerger's disease are presented. Etiologic factors, pathogenesis, and treatment modalities are discussed.

Tumors of the intraoral minor salivary glands: a demographic and histologic study of 426 cases.

In a demographic and histologic study of 426 oral minor salivary gland tumors, 57.5% were classified as benign and 42.5% were classified as malignant or potentially malignant. There was an overall female preponderance (1.59/1). The mean age for females was 53.1 years and for males was 50.6 years. The mean age for patients with malignant tumors was 5.4 years greater than for patients with benign tumors and was statistically significant. The palate was the most common site for oral minor salivary gland tumors followed by the upper lip and the buccal mucosa. These three sites accounted for 76.1% of all cases. Pleomorphic adenoma was the most common benign tumor (41% of all cases and 71% of benign tumors) followed by monomorphic adenoma of the canalicular and basal cell subtypes (10% of all tumors and 18.9% of benign lesions). Mucoepidermoid carcinoma was the most commonly encountered malignant tumor, accounting for 15.2% of all tumors and 35.9% of malignant lesions. Low-grade (terminal duct, lobular, polymorphous) adenocarcinoma was the most second most common type, making up 11% of all tumors and 26.4% of all malignant tumors. The results of this study are compared with other recent studies.

A histopathologic study of 116 ameloblastomas with special reference to the desmoplastic variant.

The histopathologic features of 116 ameloblastomas were reviewed with special reference to the incidence of the recently described desmoplastic variant. The series included 110 intraosseous lesions and 6 extraosseous ameloblastomas. Ninety-six (88%) of the intraosseous tumors were found in the mandible, and 61% involved the molar-ascending ramus area. Fourteen examples of the desmoplastic variant were identified, representing 13% of the intraosseous tumors. The lesions showed distinctive histologic features characterized by an extensive collagenized stroma containing small islands of tumor epithelium with scant tendency to form cystic structures. This histologic variant has a marked tendency to involve the anterior portions of the jaws with 7 of the 14 examples being located in the maxilla. These desmoplastic lesions also showed unusual radiographic findings, often more suggestive of a benign fibro-osseous lesion than of ameloblastoma.

Growth behavior and lineage of isolated and cultured cells derived from giant cell granuloma of the mandible.

A central giant cell granuloma of the mandible was fractionated into its mononuclear and multinuclear cellular constituents. The cells were subsequently grown in tissue culture. Sections from the original lesion and the cultured cells were analysed histochemically and immunocytochemically. Acid phosphatase, non-specific esterase, Lysozyme and alpha-1-antitrypsin were employed as markers for cells of histiocytic origin and Factor VIII-related antigen served as an endothelial cell marker. The mononuclear cells were of 2 types; a spindle-shaped cell and a round macrophage-like cell. The giant cells and the macrophage-like cells had a limited life span in culture and survived for up to 2 and 5 weeks respectively. However, the spindle-shaped cells continued to proliferate with a doubling time of 48 h. The giant cells and the macrophage-like cells were identical in their staining characteristics and showed positive staining for all the histiocytic markers tested. In contrast, the spindle-shaped cells were negative for those markers. None of the 3 cell types stained positively for Factor VIII-related antigen. These findings suggest that the giant cells in giant cell granuloma of the jaw are reactive, fully differentiated end-cells that are probably derived from stromal macrophages. The histogenesis of the spindle-shaped cell is not yet known. It is also shown in this study that the histochemical and in vitro growth characteristics of the cells of central giant cell granuloma of the mandible are analogous to those of giant cell tumors of long bones.