Stacey E. Mills

Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive “grungy” calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.

Mucoepidermoid carcinoma: A clinicopathologic study of 80 patients with special reference to histological grading

We sought to review our experience with salivary mucoepidermoid carcinoma (MEC) over two decades to confirm the validity and reproducibility of histologic grading and to investigate MIB-1 index as a prognosticator. Diagnosis was confirmed on 80 cases, and chart review or patient contact was achieved for 48 patients, with follow-up from 5 to 240 months (median 36 months). Immunohistochemistry with citrate antigen retrieval for MIB-1 was performed on a subset of cases. Kaplan-Meier survival curves were generated for each stage, site, and grade according to our proposed grading system. To address the issue of grading reproducibility, 20 slides were circulated among five observers, without prior discussion; slides were categorized as low-, intermediate-, or high-grade according to ones “own” criteria, and then according to the AFIP criteria proposed by Goode et al. 10 Weighted kappa (&kgr;) estimates were obtained to describe the extent of agreement between pairs of rating. The Wilcoxon signed rank test or the Friedman test as appropriate tested variation across ratings. There was no gender predominance and a wide age range (15–86 years, median 49 years). The two most common sites were parotid and palate. All grade 1 MECs presented as Stage I tumors, and no failures were seen for this category. The local disease failure rates at 75 months for grades 2 and 3 MEC were 30% and 70%, respectively. Tumor grade, stage, and negative margin status all correlated with disease-free survival (DFS) (p = 0.0091, 0.0002, and 0.048, respectively). The MIB index was not found to be predictive of grade. Regarding the reproducibility of grading, the interobserver variation for pathologists using their “own” grading, as expressed by the &kgr; value, ranged from good agreement (&kgr; = 0.79) to poor (&kgr; = 0.27) (average &kgr; = 0.49). A somewhat better interobserver reproducibility was achieved when the pathologists utilized the standardized AFIP criteria (average &kgr; = 0.61, range 0.38–0.77). This greater agreement was also reflected in the Friedman test (statistical testing of intraobserver equality), which indicated significant differences in using ones own grading systems (p = 0.0001) but not in applying the AFIP “standardized” grading (p = 0.33). When ones own grading was compared with the AFIP grading, there were 100 pairs of grading “events,” with 46 disagreements/100 pairs. For 98% of disagreements, the AFIP grading “downgraded” tumors. This led us to reanalyze a subset of 31 patients for DFS versus grade, for our grading schema compared with the AFIP grading. Although statistical significance was not achieved for this subset, the log rank value revealed a trend for our grading (p = 0.0993) compared with the Goode schema (p = 0.2493). This clinicopathologic analysis confirms the predictive value of tumor staging and three-tiered histologic grading. Our grading exercise confirms that there is significant grading disparity for MEC, even among experienced ENT/oral pathologists. The improved reproducibility obtained when the weighted AFIP criteria were used speaks to the need for an accepted and easily reproducible system. However, these proposed criteria have a tendency to downgrade MEC. Therefore, the addition of other criteria (such as vascular invasion, pattern of tumor infiltration [i.e., small islands and individual cells vs cohesive islands]) is necessary. We propose a modified grading schema, which enhances predictability and provides much needed reproducibility.

Basaloid squamous cell carcinoma of the head and neck. A clinicopathologic and immunohistochemical study of 40 cases.

In this study of 40 cases of basaloid squamous cell carcinoma, 83% arose in the pyriform sinus, base of tongue, tonsil, and larynx. The 35 men and five women ranged in age from 27 to 88 years (median 62). In patients for whom social habits were recorded, 24 of 26 patients were smokers and 22 of 25 drank ethanol. Most presented with stage III or IV disease. Twenty-seven patients had regional metastases at the time of presentation and 15 developed distant metastases. Seventeen patients died with disease (median survival 18 months). The tumors were composed of moderately pleomorphic basaloid cells forming nests, cords, and frequent cribriform patterns. Squamous dysplasia of surface mucosa, focal squamous differentiation within invasive basaloid squamous cell carcinoma, or foci of conventional squamous cell carcinoma were present, alone or in combination. All studied neoplasms were immunohistochemically positive for keratins with the 34(3E12 antibody. Approximately 80% were immunoreactive using AE1/AE3 or CAM 5.2. Epithelial membrane antigen, carcinoembryonic antigen, and SI00 protein were found in 83%, 53%, and 39%, respectively, of the cases. Diffuse, weak immunoreactivity for neuronspecific enolase was seen in 75% of tumors. Synaptophysin, chromogranin, muscle-specific actin, and glial fibrillary acidic protein were absent. Basaloid squamous cell carcinoma has been confused with adenoid cystic carcinoma and small cell undifferentiated carcinoma, but is usually distinguishable in routine hematoxylin and eosin- stained sections, or, in rare problematic cases, with the aid of immunohistochemical studies. Distinction is warranted because the biologic behavior of basaloid squamous cell carcinoma differs from that of both of these lesions.

Lobular capillary hemangioma: The underlying lesion of pyogenic granuloma

Pyogenic granuloma (PG) has a diagnostic, lobular arrangement of capillaries at its base. The lobules consist of discrete clusters of endothelial cells, and the lumina vary from indistinct to prominent. The superficial portions of the lesion may undergo secondary, nonspecific changes including stromal edema, capillary dilation, inflammation, and a granulation tissue reaction. PG has often been equated with these inflammatory changes but objective diagnostic criteria have not been presented. To avoid confusion and focus on the intrinsic nature of PG we suggest the accurate, descriptive term, lobular capillary hemangioma (LCH). A review of 639 vascular lesions of the oral cavity and upper respiratory tract yielded 73 cases with the characteristic features of LCH. The lip was the most common site (38%), followed by the nose (29%), oral mucosa (18%), and tongue (15%). LCH usually presents as a spontaneous, painless, bleeding mass. There is a predilection for males less than 18 years old, females in the reproductive years, and an equal sex distribution beyond 40 years of age. No examples of LCH were found in 68 vascular lesions from the larynx or trachea.

Reassessment of malignant "angioendotheliomatosis". Evidence in favor of its reclassification as "intravascular lymphomatosis".

Malignant angioendotheliomatosis (MAE) is a lethal intravascular proliferation which has been thought to be of endothelial origin. In order to characterize its cellular nature, we studied 15 cases of MAE immunocytochemically, using antisera for factor VIII-related antigen, cytokeratin, epithelial membrane antigen, vimentin, blood group isoantigens, thoracic duct lining cell antigens (TDLCA), common leukocyte antigen, and Ulex europaeus I lectin. In 14 of 15 cases, common leukocyte antigen was observed in malignant intravascular cells. Similar reactivity for factor VIII-related antigen was present in 14 cases, but was largely restricted to cells enmeshed in fibrin-platelet thrombi, and probably represents adsorption of platelet-derived factor VIII by tumor cells. All cases failed to bind Ulex europaeus lectin and lacked immunoreactivity for TDLCA, cytokeratin, epithelial membrane antigen, and blood group isoantigens; two manifested positivity for vimentin. Immunofluorescent microscopy of frozen tissue in one case showed monoclonal IgM-kappa immunoglobulin on the surfaces of tumor cells. Electron-microscopic study of three cases disclosed a predominant cell type lacking features of epithelial or endothelial differentiation; a minor cell population displayed endothelial characteristics and was thought to be reactive. Four patients with typical MAE also had extravascular large-cell lymphoma in lymph nodes, spleen, adrenal glands, stomach, or soft tissues. Six patients showed clinical evidence of autoimmune disease. These results suggest that MAE displays lymphoid rather than endothelial differentiation.

Sinonasal undifferentiated carcinoma. An aggressive neoplasm derived from schneiderian epithelium and distinct from olfactory neuroblastoma.

Eight cases of a highly aggressive undifferentiated carcinoma of the nasal cavity and paranasal sinuses are described. The patients, who ranged in age from 30-77 years, had multiple sinonasal symptoms, and each had involvement of the nasal cavity, maxillary antrum, and ethmoid sinus. Six tumors extended into the orbital bones, and five penetrated the cranial cavity. Five patients died of disease from 1 to 41 months after diagnosis (median: 4 months), and three are alive with tumor less than 1 year following diagnosis. Microscopically, the neoplasms formed nests, trabeculae, and sheets containing medium-sized cells with small to moderate amounts of eosinophilic cytoplasm. A high mitotic rate, tumor necrosis, and prominent vascular permeation were characteristic. Seven neoplasms were immunoreactive for cytokeratin, five for epithelial membrane antigen, and four for neuron-specific enolase. Ultrastructurally, occasional small desmosomes and rare membrane-bound, dense-core granules were observed. Sinonasal undifferentiated carcinoma is a distinctive clinicopathologic entity that must be distinguished from other, less aggressive sinonasal neoplasms.

Analysis of lymphoepithelioma and lymphoepithelioma-like carcinomas for Epstein-Barr viral genomes by in situ hybridization.

Lymphoepithelioma of the nasopharynx has a strong association with Epstein-Barr virus (EBV). To test the hypothesis that lymphoepithelioma-like carcinomas occurring at other sites are also associated with EBV virus, we used in situ hybridization to analyze 20 cases of lymphoepithelioma and histologically similar lesions and five basaloid squamous cell carcinomas for evidence of EBV genomes. EBV genomes were demonstrated in six of six lymphoepitheliomas of the nasopharynx but in none of five basaloid squamous cell carcinomas. Only one of 14 lymphoepithelioma-like carcinomas was found to contain EBV genomes. The single positive lymphoepithelioma-like carcinoma occurred in the lung of an Asian patient, suggesting that ethnic or geographic influences may be important in determining whether EBV is associated with these nonnasopharyngeal neoplasms. Despite their histologic similarity, most lymphoepithelioma-like carcinomas probably have a different pathogenesis from nasopharyngeal lymphoepithelioma.

Neuroectodermal Neoplasms of the Head and Neck with Emphasis on Neuroendocrine Carcinomas

Tumors exhibiting neuroectodermal differentiation occur throughout the body, and the diverse tissues of the head and neck give rise to a wide assortment of these neoplasms. Neuroectodermal neoplasms may be divided into lesions showing primarily epithelial differentiation (Group I, neuroendocrine carcinomas) and a more diverse group (Group II) of nonepithelial neoplasms. This article reviews these neuroectodermal tumors of the head and neck with emphasis on the neuroendocrine carcinomas and their nomenclature. The author believes that with regard to Group I tumors, the older terminology of carcinoid, atypical carcinoid, and small cell carcinoma should be replaced by subclassifications of well-differentiated, moderately differentiated, and poorly differentiated neuroendocrine carcinoma. The latter category should be further subdivided into small cell and large cell variants. Neuroendocrine carcinomas, particularly the moderately differentiated subtype, are often underdiagnosed in the head and neck region. In the larynx, these tumors are the most common form of nonsquamous carcinoma. Poorly differentiated neuroendocrine carcinoma of small cell type is most common in the salivary glands but can occur elsewhere in the region. The large cell subtype of poorly differentiated neuroendocrine carcinoma has not been well documented in this region. However, the most likely candidate for this tumor category is the so-called sinonasal undifferentiated carcinoma. Group II tumors discussed include olfactory neuroblastoma, malignant melanoma, and Ewing’s sarcoma. In addition, differential diagnostic problems related to Group I and II tumors are reviewed in detail. This article reviews and updates our understanding of neuroectodermal neoplasms arising in the head and neck. The focus is on tumors that exclusively involve this region or show a strong predilection to occur here.

Small-cell neuroendocrine carcinoma of the cervix : a human papillomavirus type 18-associated cancer

Small-cell undifferentiated carcinomas comprise a rare but aggressive subset of uterine cervical neoplasms. Analogous to small-cell anaplastic carcinoma of the lung, these tumors frequently exhibit neuroendocrine differentiation. Although human papillomaviruses (HPV) types 16 and 18 are strongly associated with the development of cervical squamous carcinoma, there is as yet little information describing the relationship of these viruses to small-cell carcinomas. To address this question, we analyzed 20 cases of small-cell carcinoma of the cervix using in situ hybridization to detect HPV gene expression. In addition, immunohistochemistry was used to evaluate three markers of neuroendocrine differentiation. Eighteen of 20 tumors (90%) demonstrated some evidence of neuroendocrine differentiation; 17 of 20 (85%) expressed HPV type 16 or 18 messenger RNA. Of the neuroendocrine-positive cases, 14 of 18 expressed HPV 18 messenger RNA. In contrast, both of the cases with squamous differentiation were HPV 16 positive. These findings broaden the spectrum of HPV-associated cervical neoplasia and strongly suggest that HPV 18 is a viral type specifically associated with cervical small-cell neuroendocrine carcinomas.

Sinonasal undifferentiated carcinoma: a distinctive and highly aggressive neoplasm

Eleven cases of sinonasal undifferentiated carcinoma were treated between 1975 and 1986. This distinctive neoplasm involved the orbital cavity in 6 of 11 patients (55%) and the cranial cavity in 7 of 11 patients (64%) at the time of presentation. Of the eight patients (73%) who died of disease, six died within 13 months after the diagnosis. One patient has no evidence of disease 10 months after therapy, and two are alive with disease after 15 and 22 months.