HIV-associated oral Kaposi sarcoma and HHV-8: a review

Kaposi sarcoma is the most common malignant tumour associated with HIV infection. In the majority of cases oral tissues are involved and in 22% the initial presentation is in the oral cavity. The oral lesions are either single or multifocal, and the palate, gingiva and tongue are the sites most frequently involved. The pathogenesis of Kaposi sarcoma in HIV-seropositive subjects is complex. It involves interaction between human herpesvirus-8 (HHV-8) and HIV, altered cellular signal transduction pathways, and increased production of cytokines and growth factors. The multifactorial nature and clinical stages in the growth of oral Kaposi sarcoma are discussed.     

Conceptual emergence of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) as an oral herpesvirus

Recognition of the various clinico-epidemiologic forms of Kaposi's sarcoma, a disease putatively caused by an infectious agent, did not provide ready clues as to how that agent might be transmitted, although fecal and sexual routes were implicated. Application of serologic and genome-detection assays, and cell-culture studies following the identification of human herpesvirus 8 as the causative agent now implicate that virus as one that is orally shed. While oral transmission of the virus might account for the viral endemicity in Africa and Mediterranean countries, why it is particularly prevalent among male homosexuals in the West remains more difficult to explain. Such explanation may be sought from behavioral studies into the role saliva plays in sexual interactions.     

Ultrastructural findings in oral Kaposi's sarcoma (AIDS)

Ten biopsies of oral Kaposi's sarcoma were examined histologically and ultrastructurally. Histologically, early and late tumor stages could be differentiated. On the ultrastructural level, endothelial-like and spindle-shaped tumor cells were revealed. Tumor cells associated with vessel-like spaces showed partly interrupted basal membranes, Weibel-Palade bodies, desmosomes and tight-junctions, while spindle-shaped cells lacked these ultrastructural features of endothelial cells. Within the cytoplasm of endothelial-like cells, aggregates of tubular structures were observed. Histological and ultrastructural findings in oral Kaposi sarcoma are comparable to those of such other organs as skin and intestines. The ultrastructural findings indicate an endothelial origin, at least of endothelial-like tumor cells.     

Ultrastructural findings in oral Kaposi's sarcoma (AIDS)

Ten biopsies of oral Kaposi's sarcoma were examined histologically and ultrastructurally. Histologically, early and late tumor stages could be differentiated. On the Ultrastructural level, endothelial-like and spindle-shaped tumor cells were revealed. Tumor cells associated with vessel-like spaces showed partly interrupted basal membranes, Weibel-Palade bodies, desmosomes and tight-junctions, while spindle-shaped cells lacked these Ultrastructural features of endothelial cells. Within the cytoplasm of endothelial-like cells, aggregates of tubular structures were observed. Histological and Ultrastructural findings in oral Kaposi sarcoma are comparable to those of such other organs as skin and intestines. The Ultrastructural findings indicate an endothelial origin, at least of endothelial-like tumor cells.     

Distribution of immunocompetent cells in oral Kaposi's sarcoma (AIDS)

Fifteen biopsy specimens of oral AIDS-associated Kaposi's sarcoma (KS), 19 biopsy specimens of uninvolved oral mucosa of HIV-seropositive patients (HIV⁺) and 22 biopsy specimens of oral mucosa of HIV-seronegative persons (HIV⁻) were analysed for the distribution of CD4⁺ and CD8⁺ lymphocytes and HLA-DR⁺ cells. The results were statistically evaluated. According to their clinical appearance KS were classified as flat lesions (n = 10) or exophytic tumours (n = 5). KS lesions of both clinical groups as well as uninvolved mucosa of HIV⁺ patients revealed infiltration with CD4⁺ cells. In flat, patch-like KS there was a marked increase of CD8⁺ cells compared to HIV⁻ mucosa, while their numbers decreased in later tumour stages. In both, flat and exophytic KS the number of HLA-DR⁺ cells was significantly higher than in uninvolved mucosa of HIV⁺ and HIV⁻ persons. These findings may reflect the local influence of KS growth factors on the inflammatory reaction in the setting of systemic immunosuppression.     

Treatment of oral Kaposi's sarcoma with a sclerosing agent in AIDS patients: A preliminary study

Presently oral Kaposi's sarcoma is primarily treated with systemic and intralesional chemotherapy, immunotherapy, radiation, and occasionally lasers. Each of these modalities achieves varying degrees of success. In patients with acquired immunodeficiency syndrome, the traditional treatments are frequently accompanied by local and generalized side effects that are detrimental to an already compromised immune system. Experience using sclerosing agents to treat other oral vascular lesions in healthy patients is known to produce excellent results. To evaluate the use of this treatment method in patients with acquired immunodeficiency syndrome, 15 oral lesions in 12 patients were injected with 3% sodium tetradecyl sulfate (Sotradecol). Thirteen lesions were located on hard palate; nine were nodular, three papular, and three macular. One week after treatment, some degree of ulceration occurred in all lesions with healing beginning by the middle of the second week. Six lesions required a second treatment to completely resolve. In one patient, healing was delayed, and the patient encountered a period of discomfort as a result of superficial bone sequestration. All other lesions healed uneventfully without the major side effects encountered with the other commonly used methods. Patients were followed for recurrence until they died or moved away. No recurrences were noted, with many followed for 18 months or longer. It is suggested that for lesions 2.6 cm or less in size, a sclerosing agent may be a better treatment modality than those now commonly used for oral Kaposi's sarcoma.     

Human herpesvirus-6 (HHV-6) DNA and virus-encoded antigen in oral lesions

Archival oral tissues comprising 51 squamous cell carcinomas, 18 non-malignant lesions and 7 normal mucosa samples were investigated for human herpesvirus-6 (HHV-6)-encoded antigens and HHV-6 DNA. The virus-specific antigens were detected by an immunohistochemical method using monoclonal antibodies. Two further techniques used for HHV-6 DNA detection included the polymerase chain reaction (PCR) with virus-specific primers and in situ hybridization using digoxigenin-labelled oligonucleotides specific for HHV-6A and HHV-6B genotypes. A high proportion (79-80%) of the squamous cell carcinomas were positive for HHV-6 with the various detection methods. In cases of lichen planus and leukoplakia a high prevalence rate (67-100%) was noted with in situ hybridization and immunohistochemical techniques but a lower proportion (22–33%) was detected with the PCR method. All 7 normal tissues tested were negative for HHV-6. The HHV-6 variant B was found in 60% of the oral carcinoma tissues analysed. The study demonstrates the frequent presence of HHV-6 in neoplastic and non-malignant lesions of the oral cavity. While the role of HHV-6 in oral mucosal tissues remains to be determined, the in vitro tumorigenic potential of the virus suggests a possible role in the etiopathogenesis of oral lesions.     

Oral Kaposi's sarcoma: a clinicopathologic study of 23 homosexual and bisexual men from the New York metropolitan area

A total of 3970 cases of Kaposi's sarcoma (KS) associated with the acquired immunodeficiency syndrome had been reported to the Centers for Disease Control by the end of 1986. The prevalence of oral KS in patients with KS of the skin varies, reaching a maximum of 44% in one published study. We present a retrospective clinicopathologic analysis of 23 previously unreported cases of oral KS in male homosexual and bisexual patients from the New York metropolitan area. Our data reveal that 21 of the patients had KS confined to the oral cavity and that, in 16 cases, the oral KS was the first presenting sign of the acquired immunodeficiency syndrome. Sixteen of the 23 patients had solitary oral lesions. Nineteen of the tumors showed prominent endothelium-lined capillaries resembling lymphatics, 16 exhibited a prominent spindle cell component, and 17 demonstrated areas of fibrosis. Of the 13 patients for whom there was adequate follow-up information, five were dead within 6 to 15 months. All five deaths were due to Pneumocystis pneumonia.     

Pathogenesis of oral Kaposi's sarcoma in HIV-infection: Relevance of endogenous glucocorticoid excess in blood and saliva

Endogenous glucocorticoid excess with concomitant hypercortisolaemia and increased saliva level of the free active hormone, is a common feature of HIV-infected/AIDS patients. Exposure of the oral tissues to virtually uninterrupted high burden of glucocorticoids through saliva may contribute to the high frequency of oral Kaposi's sacoma (KS) in these patients. AIDS-KS cells contain unusually high levels of glucocorticoid receptor protein and recent studies indicate that growth of these cells in culture is significantly stimulated by glucocorticoids, particularly in the presence of growth factors, such as oncostatin-M. The suggestion that glucocorticoid excess may be important in the pathogenesis of KS in AIDS is not in conflict with the suspected aetiological role of newly reported KS-associated herpesviruses (KSHV), since steroid hormones may upregulate the expression of the viral gene. The latter is consistent with the observation that infection by specific oncogenic viruses does not necessarily result in cancers in the human, and does require the presence of other cellular factors or events.     

Clinical, histological and immunohistochemical findings in oral Kaposi's sarcoma in a series of Mexican AIDS patients. Comparative study

Background:  The origin of spindle cells (SC) in oral Kaposi's sarcoma (OKS) is still an intriguing aspect. Thus the aim of the present study was to compare the clinical, histological and immunohistochemical characteristics of OKS and oral pyogenic granuloma (OPG), in order to contribute to the knowledge of the cells involved in Kaposi's sarcoma pathogenesis.
Methods:  In this retrospective, observational and comparative study, 39 OKS and 30 OPG cases were included. Immunohistochemical studies were performed for vimentin, αSMA, desmin, C-kit, CD34, D2-40 and LANA-1 [human herpesvirus-8(HHV-8)]. Statistical comparisons were done using the chi-square and Wilcoxon–Mann–Whitney rank sum tests.
Results:  Fourteen (35.9%) OKS cases also affected the skin, and 83.8% involved the palate. All OKS and OPG were positive for vimentin and CD34. OKS samples were positive for αSMA, and 25.6% expressed C-kit. All OKS cases were positive for HHV-8, and the number of positive cells increased significantly from early / intermediate to late histological stage. D2-40 was expressed in the cellular component and vascular walls of all OKS cases, but it was negative in OPG. HHV-8 expression was increased in late histological stages of OKS lesions.
Conclusions:  The expression of D2-40 marker in the vascular walls and SC supports the view of a lymphatic differentiation in neoplastic cells of OKS. Desmin, αSMA , D2-40, C-kit and HHV-8 were the main markers differently expressed in OKS and OPG.     

Plasmacytoma of the oral cavity and jaws: A clinicopathologic study of 13 cases

Plasmacytoma of the jaw bones and oral cavity, as in other anatomic sites, comprises three distinct entities: multiple myeloma, solitary plasmacytoma of bone, and extramedullary plasmacytoma. This article is a retrospective study of 13 cases; 9 occurred in the mandible and 4 in the maxilla. The most common radiographic finding was a radiolucency that many times was superimposed on the roots or apices of nearby teeth. The most common symptom was localized pain, and the most frequent clinical sign was a raised red lesion on the alveolar ridge. The disease affects older persons, and the posterior mandible is the most frequently reported location. The degree of dysplasia of tumor cells was evaluated as there is a reported correlation with survival rates.     

A clinicopathologic study on basaloid squamous cell carcinoma in the oral and maxillofacial region

Basaloid squamous cell carcinoma (BSCC) is a rare distinct variant of squamous cell carcinoma (SCC). To investigate its clinical behavior and prognosis, 15 patients with BSCC in the oral and maxillofacial region were clinically analyzed and compared with 15 patients with conventional SCC matched for site, stage, gender and age. To understand its immunohistochemical features, sections for cytokeratin AE1/AE3, CK 13. CK 7, CK 8, proliferating cell nuclear antigen (PCNA) and p53 were reviewed from 12 patients with BSCC. The rate of cervical lymph node metastasis of BSCC was as high as 67% and that of distant metastasis 13%. The tumor recurrence rate was 33% and the 3-year and 5-year survival rates were 53% and 32%, respectively. For conventional SCC, the cervical lymph node metastasis rate was 27%, that of distant metastasis 7%, tumor recurrence rate was 33%, and 3-year and 5-year survival rates were 80% and 70%, respectively. In most BSCC patients (10/12) the PCNA index was over 50%. Twelve BSCC patients were diagnosed with grade II or III conventional SCC when the original records of the primary diagnosis for the 15 patients with BSCC were reviewed. The biological behavior and prognosis of BSCC are similar to those of poorly differentiated SCC.     

口腔颌面部Ewing肉瘤/原始神经外胚层瘤的临床病理学研究

目的提高对口腔颌面部Ewing肉瘤／原始神经外胚层瘤（Ewing肉瘤／PNET）的临床病理特征的认识，减少误诊。方法收集四川大学华西口腔医学院病理科1970年1月至2004年12月临床病理诊断符合Ewing肉瘤／PNET的病例共15例，年龄1～49岁，平均14．5岁，主要表现为肿胀，影像学可见骨质破坏。结合文献对其组织学特征进行分析，并行免疫组化LSAB法染色，抗体为CD99（12E7）、波形蛋白、神经冗特异性烯醇化酶（NSE）、S-100、突触素（Syn）、CD45（LCA）及结蛋白。结果①组织学特征：肿瘤主要由密集的小细胞组成，弥漫分布，纤维性条索将其分隔成不规则片块状，可见菊形团样结构，部分细胞含糖原。②免疫组化标记：所选7例CD99及波形蛋白均阳性，CD45、结蛋白均阴性；S-100阳性4例，NSE阳性3例，Syn阳性1例，2例对NSE、S-100、Syn均为阴性。结论口腔颌面部Ewing肉瘤／PNET极为少见，多为青少年，免疫组化可辅助诊断，p30／32^MIC2高水平表达对确诊有价值。     

Human papillomavirus (HPV) DNA sequences in oral precancerous lesions and squamous cell carcinoma demonstrated by in situ hybridization

A series of routinely processed, paraffin-embedded biopsies from 73 surgically treated oral precancerous lesions (OPL) (22 cases), and oral squamous cell carcinomas (SCC) (51 cases), was first screened using an in situ DNA hybridization technique with a human papillomavirus (HPV) DNA probe cocktail containing the 35S-labelled DNA of HPV types 6, 11, 13, 16, 18 and 30. The specific HPV types in lesions shown to contain HPV DNA in this procedure were further analysed by using in situ hybridization and the 6 HPV DNA probes separately. A total of 12/73 (16.4%) of the lesions proved to contain HPV DNA; 6/51 (11.8%) carcinomas and 6/21 (28.6%) dysplasias. The most frequent sites of HPV DNA-positive lesions were palate (4/7; 57%), followed by the floor of the mouth (2/8; 25%), the tongue and gingiva (11.8%). HPV 13 or HPV 30 were not found in any of the lesions studied. HPV 11 DNA was demonstrated in 2 mild dysplasia lesions, but not in carcinomas. One additional mild dysplasia proved to contain HPV 6 DNA. HPV 16 DNA was present in 5 biopsies; 3 carcinomas and 2 dysplasias. In one of the HPV 16-positive carcinomas, HPV 18 DNA was simultaneously present. HPV 18 alone was found in 3 additional carcinomas and in one moderate dysplasia lesion. The results confirm the recently reported evidence on HPV involvement in OPL and oral cancer. The implications of these findings are discussed in terms of the possible HPV etiology of oral SCC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human papillomavirus (HPV) DNA sequences in oral precancerous lesions and squamous cell carcinoma demonstrated by in situ hybridization

A series of routinely processed, paraffin-embedded biopsies from 73 surgically treated oral precancerous lesions (OPL) (22 cases), and oral squamous cell carcinomas (SCC) (51 cases), was first screened using an in situ DNA hybridization technique with a human papillomavirus (HPV) DNA probe cocktail containing the 35S-labelled DNA of HPV types 6, 11, 13, 16, 18 and 30. The specific HPV types in lesions shown to contain HPV DNA in this procedure were further analysed by using in situ hybridization and the 6 HPV DNA probes separately. A total of 12/73 (16.4%) of the lesions proved to contain HPV DNA; 6/51 (11.8%) carcinomas and 6/21 (28.6%) dysplasias. The most frequent sites of HPV DNA-positive lesions were palate (4/7; 57%), followed by the floor of the mouth (2/8; 25%), the tongue and gingiva (11.8%). HPV 13 or HPV 30 were not found in any of the lesions studied. HPV 11 DNA was demonstrated in 2 mild dysplasia lesions, but not in carcinomas. One additional mild dysplasia proved to contain HPV 6 DNA. HPV 16 DNA was present in 5 biopsies; 3 carcinomas and 2 dysplasias. In one of the HPV 16-positive carcinomas, HPV 18 DNA was simultaneously present. HPV 18 alone was found in 3 additional carcinomas and in one moderate dysplasia lesion. The results confirm the recently reported evidence on HPV involvement in OPL and oral cancer. The implications of these findings are discussed in terms of the possible HPV etiology of oral SCC. The use of the in situ DNA hybridization as a powerful tool (enabling the localization of specific HPV DNA sequences and the proper classification of the lesion at the same site) in the study of routinely processed oral biopsies is strongly advocated.     

Thymidylate synthase and dihydropyrimidine dehydrogenase expression in oral squamous cell carcinoma: an immunohistochemical and clinicopathologic study

OBJECTIVE: Thymidylate synthase (TS) is the target enzyme for 5-fluorouracil (5-FU), and dihydropyrimidine dehydrogenase (DPD) is the first enzyme that metabolizes 5-fluorouracil. Until now, only the enzyme activities of TS and DPD have been investigated; however, there are few reports about the immunohistochemistry of TS and DPD and none regarding oral carcinoma. The purpose of this article was to investigate the expression of TS and DPD in oral squamous cell carcinoma. STUDY DESIGN: In this study, 109 oral squamous cell carcinomas were investigated for the immunohistochemical expression of TS and DPD proteins. RESULTS: The expressions of TS in carcinoma cases was significantly higher than in controls (P <.05, t test). DPD was expressed both in carcinomas and in areas adjacent to the carcinomas. There was no correlation between the clinical factors and the TS labeling index or between the clinical factors and the DPD labeling index (DPD-LI). Pathologically, DPD-LI was significantly different in both the World Health Organization classification and Anneroth's classification. The TS labeling index was significantly correlated with the Ki-67 LI (P <.05, Pearson's correlation coefficient). Although TS showed no correlation between tegafur-uracil response and TS labeling index, there was a significant correlation between the tegafur-uracil response and DPD-LI. CONCLUSIONS: TS may reveal tumor cell proliferation, but DPD-LI may correlate with a response to anticancer drug treatment.