A 39-Year-Old Woman With Synchronous Endobronchial and Adrenal Tumors.

CASE PRESENTATION: A 39-year-old woman with systemic lupus erythematosus that was complicated by end-stage renal disease that had required a deceased donor renal transplant 16 years ago was referred for evaluation of chronic, nonproductive cough for 2 years. She was a lifetime nonsmoker whose condition was maintained on prednisone 5 mg daily, tacrolimus 3 mg twice day, mycophenolate mofetil 500 mg twice a day for her immunosuppression regimen, valacyclovir 500 mg twice a day for prophylaxis, and clonidine 0.1 mg daily and metoprolol succinate 100 mg twice daily for hypertension.

Mycobacterium avium-intracellulare presenting as an endobronchial tumour due to immune reconstitution inflammatory syndrome.

Mycobacterium avium-intracellulare (MAI) infection in an HIV-positive patient can present shortly after starting antiretroviral therapy, as a result of immune reconstitution inflammatory syndrome (IRIS). We report a case of a 33-year-old woman where MAI presented as an endobronchial tumour due to IRIS. She responded well to standard anti-MAI treatment (rifamycins, macrolide and ethambutol).

Detection of human papillomavirus genotypes in bronchial cancer using sensitive multimetrix assay.

BACKGROUND: Since first suggested in 1979, evidence on the involvement of human papillomavirus (HPV) in bronchial carcinogenesis has been accumulated through several lines of research. The causal role of HPV in lung cancer still remains controversial, however, and more data are needed particularly on genotype distribution and cofactors of HPV regarding this disease. MATERIALS AND METHODS: The present series consists of 77 patients diagnosed and treated for lung cancer at the Department of Respiratory Medicine, Turku University Hospital, (Finland) during 2008-2010. All available histological samples (n=77) were subjected to HPV genotyping with the Luminex-based Multimetrix kit, detecting 24 low-risk (LR) and high-risk (HR) HPV types. Pertinent clinical data were collected and subjected to univariate and multivariate regression analysis to disclose the covariates associated with HPV detection in lung cancer. RESULTS: Out of 77 histological samples analyzed, four (5.2%) (three squamous cell and one adenocarcinoma) were found to be HPV-positive, out of which three were HPV16 infections and one a double-infection with HPV6 and HPV16. All four patients were males, and all but one reported no asbestos exposure. Three of them had refrained from smoking for a period >22 years. Disease-specific survival was twice as long for individuals with HPV+ than those with HPV- tumors (25.5 vs. 12.8 months), but confounding by treatment cannot be excluded. In univariate analysis, four covariates were significantly associated with HPV detection: i) older age (p=0.003) ii) older age at smoking initiation (p=0.027), iii) fewer years of active smoking (p=0.036), and iv) fewer total pack years (p=0.002). In a multivariate regression model adjusted to all significant covariates, only absolute age was significantly associated with testing as HPV-positive (odds ratio=1.16, 95% confidence interval 1.04-1.39, p=0.008). CONCLUSION: Given the fact that initiation of smoking at an older age, fewer pack years and long smoking abstinence were associated with HPV, it is tempting to speculate that oncogenic HPV can substitute smoking as a risk factor, leading to lung cancer in these patients despite >22 years elapsing since their smoking cessation. In the era of prophylactic HPV vaccination, there is an urgent need to provide more data on the global HPV burden and covariates of the virus associated to lung cancer.

Spectrum of cancer risk late after AIDS onset in the United States.

BACKGROUND: Persons living with AIDS today remain at elevated cancer risk. Highly active antiretroviral therapy (HAART), widely available since 1996, prolongs life, but immune function is not fully restored. We conducted this study to assess long-term cancer risk among persons with AIDS relative to the general population and the impact of HAART on cancer incidence. METHODS: Records of 263 254 adults and adolescents with AIDS (1980-2004) from 15 US regions were matched to cancer registries to capture incident cancers during years 3 through 5 and 6 through 10 after AIDS onset. Standardized incidence ratios (SIRs) were used to assess risks relative to the general population. Rate ratios (RRs) were used to compare cancer incidence before and after 1996 to assess the impact of availability of HAART. RESULTS: Risk was elevated for the 2 major AIDS-defining cancers: Kaposi sarcoma (SIRs, 5321 and 1347 in years 3-5 and 6-10, respectively) and non-Hodgkin lymphoma (SIRs, 32 and 15). Incidence of both malignancies declined in the HAART era (1996-2006). Risk was elevated for all non-AIDS-defining cancers combined (SIRs, 1.7 and 1.6 in years 3-5 and 6-10, respectively) and for the following specific non-AIDS-defining cancers: Hodgkin lymphoma and cancers of the oral cavity and/or pharynx, tongue, anus, liver, larynx, lung and/or bronchus, and penis. Anal cancer incidence increased between 1990-1995 and 1996-2006 (RR, 2.9; 95% confidence interval [CI], 2.1-4.0), as did that of Hodgkin lymphoma (RR, 2.0; 95% CI, 1.3-2.9). CONCLUSION: Among people who survived for several years or more after an AIDS diagnosis, we observed high risks of AIDS-defining cancers and increasing incidence of anal cancer and Hodgkin lymphoma.

Obstructive endo-bronchial pseudotumour due to herpes simplex type 2 infection in an HIV-infected man.

We report a 31-year-old man with an obstructive bronchial lesion due to herpes simplex type 2 infection, who responded promptly to endoscopic resection and oral treatment with acyclovir. Exophytic lesions of the respiratory tract are rare, potentially life-threatening, but readily treated complication of herpes simplex virus infection in HIV-infected individuals.

Envelope proteins of Jaagsiekte sheep retrovirus and enzootic nasal tumor virus induce similar bronchioalveolar tumors in lungs of mice.

Jaagsiekte sheep retrovirus (JSRV) induces bronchioalveolar tumors in sheep and goats. Expression of the JSRV envelope (Env) protein in mouse airway epithelial cells induces similar tumors, indicating that Env expression is sufficient for tissue-specific tumor formation. Enzootic nasal tumor virus (ENTV) is related to JSRV but induces tumors in the nasal epithelium of sheep and goats. Here we found that ENTV Env can also induce tumors in mice but, unexpectedly, with a phenotype identical to that of tumors induced by the JSRV Env, indicating that factors other than Env mediate the tissue specificity of tumor induction by ENTV.

Epstein-Barr virus-associated bronchial leiomyoma in a boy with cellular immunodeficiency.

Bronchial leiomyoma is a rare disease in children. Recently, the association of leiomyoma and HIV infection was reported. We describe a boy with a cellular immunodeficiency, who had endobronchial leiomyoma. The tumor cells were positive for Epstein-Barr virus-encoded RNA-1 (EBER-1) and Epstein-Barr virus-determined nuclear antigen-2, suggesting a role of Epstein-Barr virus in the pathogenesis of leiomyoma.

Integration of human papillomavirus type 11 in recurrent respiratory papilloma-associated cancer.

OBJECTIVES/HYPOTHESIS: The main objective was to demonstrate that human papillomavirus (HPV) type 11 is an aggressive virus that plays a significant role in the development of laryngeal cancer in patients with a history of recurrent respiratory papillomatosis (RRP). We have done so by preliminary investigation into the molecular mechanism underlying the malignant transformation of RRP to invasive squamous cell carcinoma. STUDY DESIGN: An experimental, nonrandomized, retrospective study using tissue specimens from nine patients with a history of RRP that progressed to laryngeal or bronchogenic cancer was performed. METHODS: DNA and RNA were extracted from 20 formalin-fixed, paraffin-embedded specimens from six patients with a history of early onset RRP and laryngeal cancer and from three patients with early onset RRP and bronchogenic cancer. Polymerase chain reaction (PCR) was performed on DNA to determine the HPV type in each specimen. Reverse-transcriptase PCR specific for virus transcripts was performed on RNA to determine whether the viral genome was integrated into the host genome. RESULTS: HPV-11 but not HPV-6, 16, or 18 was found in all of the laryngeal and bronchogenic cancers in patients with a history of early onset RRP in this study. RNA, sufficiently intact for examination, was obtained from seven patients. Analysis of HPV 11 transcripts revealed integration of the viral genome in three of seven patients. CONCLUSIONS: HPV type 6 and 11 are considered "low-risk" viruses and are not associated with genital cancers, as are HPV types 16 and 18. However, our data suggests that HPV type 11 is an aggressive virus in laryngeal papilloma that should be monitored in patients with RRP.

Interferon treatment of multiple pulmonary malignancies associated with papilloma virus.

Over a period of four years, beginning in spring 1988, a previously healthy man developed a primary squamous cell carcinoma of the tonsil, treated with radiotherapy, followed by 10 distinct, primary bronchial squamous cell carcinomas. Four of the cancers were surgically resected, all of which were positive by hybridization for human papilloma virus (type 16). Following the institution of alpha interferon, three smaller lesions disappeared and a larger one shrank in size, facilitating surgical resection. Over the following seven years no new ones have appeared. The finding of papilloma virus in malignancies should prompt consideration of antiviral therapy.

PCR-screening of human esophageal and bronchial cancers reveals absence of adenoviral DNA sequences.

A number of human esophageal (3) and bronchial (10) cancers have been characterized clinically and by their histopathology. These tumors have been investigated for the persistence of human adenoviral DNA sequences. The polymerase chain reaction (PCR) and Southern transfer hybridization (SBH) techniques have been applied. All analyses have consistently yielded negative results. These findings are discussed in the light of comparisons to the Ad12 hamster tumor system in which tumor cell or transformed cell revertants can lose the integrated Ad12 DNA sequences, but retain the oncogenic phenotype, when reinjected into hamsters. Ad12-transformed cells and Ad12-induced tumor cells have previously been shown to exhibit altered cellular methylation and transcription patterns. In one of the revertants, which has lost all Ad12 DNA sequences, changes in cellular DNA methylation patterns are also maintained. Since in the hamster tumor system the loss of Ad12 DNA sequences is still compatible with the oncogenic phenotype, the possibility exists that human tumors, though themselves devoid of viral DNA sequences, could have had cells as precursors which originally carried integrated adenoviral DNA sequences.

Molecular transformation of recurrent respiratory papillomatosis: viral typing and p53 overexpression.

Recurrent respiratory papillomatosis (RRP) is a histologically benign disease of the larynx, trachea, and bronchi. Here we report on the histologic and molecular characteristics of 7 cases of malignant transformation of RRP to squamous cell carcinoma (SCCA). The clinical histories of 7 patients with RRP who developed SCCA were carefully reviewed. Sequential biopsies were available from 5 of the 7 cases of spontaneous transformation of RRP to SCCA and were reviewed. In addition, p53 protein overexpression and human papillomavirus (HPV) typing for all cases was examined. The average age of patients with juvenile-onset RRP was 3 years, and that of patients with adult-onset RRP was 31 years. The average age of onset of transformation to SCCA was 28 years. All patients had laryngeal involvement with RRP, and 3 of the 7 patients had tracheal extension of disease. Five patients were tracheotomy-dependent. Four of the 7 patients developed SCCA of the lung, while 3 patients developed laryngeal SCCA. There was no consistent histologic progression from squamous papilloma to papilloma with dysplasia, and all but 1 of the SCCAs were well differentiated. The overexpression of p53 protein was variable in each of the 5 patients. We detected HPV types 6/11 in papillomas from 3 patients, and HPV types 6/11, 16/18, and 31/33/51 in a papilloma of a fourth patient. No HPV DNA was detected in papillomas of 2 patients. We found HPV 6/11 in 4 of the carcinomas. We conclude that the spontaneous transformation of RRP to SCCA is not characterized by a histologic progression through dysplasia over time. Transformation can result in the loss of HPV expression. It does not appear that p53 is a molecular marker for monitoring the transformation process. Thus, these cancers may be very difficult to diagnose histologically and clinically early in the course of the transformation of the disease.

Detection of human papillomavirus DNA in bronchopulmonary carcinomas by hybrid capture II: a study of 185 tumors.

BACKGROUND: Some human papillomaviruses (HPVs) are oncogenic in the cervix and are also associated with benign and malignant proliferations in other organs. Currently, the association of HPV with tumors of the lower respiratory tract is not so clearly defined because the studies are difficult to compare; series of cases reported from different geographic regions have used frozen or formalin fixed samples and a variety of techniques of HPV detection. METHODS: The authors studied the prevalence of HPV in a large series of 185 frozen bronchopulmonary tumor samples with a new solution hybridization technique, Hybrid Capture II assay. This test is largely applied in cervical pathology. Its sensitivity is very close to the sensitivity of PCR. It allows the detection of 18 mucosal HPV types, divided into 1 oncogenic and 1 nononcogenic group. RESULTS: Oncogenic HPV DNA was detected by the Hybrid Capture II assay in 5 cases (2.7%) of 185 (3 males and 2 females). In the rare positive cases detected, the authors could not find any consistent morphologic changes classically associated with HPV infection in anogenital lesions, such as koilocytosis. CONCLUSIONS: Oncogenic HPV DNA is detected in a small proportion of cases of bronchopulmonary carcinoma, and thus HPV infection appears to play a limited role in the tumorigenesis of most lung carcinomas.

Solitary squamous papilloma of the bronchus associated with human papilloma virus type 11.

A 79-year-old female presented with persistent dry cough, and a chest radiograph showed a mass shadow in the right upper lung. Bronchoscopic examination revealed that the right main bronchus was severely obstructed by a polypoid tumor, which was diagnosed pathologically as squamous papilloma. After the failure of the attempted endobronchial snare to remove the tumor, right upper lobectomy was performed. The polymerase chain reaction (PCR) examination showed the presence of human papilloma virus type 11 DNA in the resected tumor, suggesting that this virus was the cause of this solitary squamous papilloma of the lung.

Solitary pulmonary papillomas in adults: a clinicopathologic and in situ hybridization study of 14 cases combined with 27 cases in the literature.

Solitary endobronchial papillomas in adults are rare neoplasms. Only sporadic cases have been documented. The histologic classification of these tumors remains problematic, and little is known about their clinical behavior. The clinical and pathologic features of 13 endobronchial papillomas and a single endobronchiolar papilloma were reviewed. In situ hybridization for human papillomavirus (HPV) types 6/11, 16/18, and 31/33/51 was performed on seven cases. Twenty-seven additional well-documented cases were identified in a literature review. Human papillomavirus studies were performed in four of the previously reported cases. The 41 neoplasms combined from the Armed Forces Institute of Pathology and literature review were divided into three groups according to their histologic features. Thirty-one of 41 (76%) patients were men. The ages of the patients ranged from 26 to 74 years (median, 57 years). Three morphologically distinct histologic types were recognized; 27 squamous cell papillomas, 7 glandular papillomas, and 7 mixed squamous and glandular papillomas. Squamous papillomas: 23 of 27 (85%) patients were men, and the median age was 54 years. Six of eleven (55%) of these patients smoked. Twenty-six lesions were exophytic and a single lesion had an inverted pattern. Seven of 24 (29%) lesions featured cytologic atypia and 5 of 24 (14%) had viral cytopathic effect. Five of seven (71%) cases examined for HPV DNA were positive. Three of 18 (17%) recurred. Glandular papillomas: Four of seven (57%) patients were women. The mean age was 67 years. One of five (20%) patients smoked. Five lesions were central, and two were peripheral. Four lesions had columnar epithelium, and three had ciliated epithelium. One of six (17%) lesions recurred. Mixed papillomas: five of seven (71%) patients were men. The median age was 64 years. Three of five (60%) patients smoked. Three of seven (43%) lesions featured cytologic atypia. Four of five lesions were examined for HPV DNA and all were negative. No lesions recurred. This study demonstrates that solitary endobronchial papillomas can be separated into three distinct morphologic categories. Squamous cell and mixed papillomas are predominantly lesions of male smokers in their 6th decade. Although cytologic atypia is observed in many cases, the rarity of these tumors and difficulty in separating papillomas from endobronchial papillary squamous carcinomas make generalizations regarding the risk of progression to carcinoma tenuous at best. Human papillomavirus appears to play a pathogenetic role in some squamous cell papillomas, but not in mixed papillomas, yet its presence in the squamous lesions does not correlate with recurrence or malignancy. The first report of an inverted squamous cell papilloma indicates clinical features similar to the more common exophytic squamous cell papillomas. Glandular papillomas, the rarest of all endobronchial papillomas, are found in an older age group than squamous and mixed papillomas, and most-patients are nonsmokers. Based on these findings, all endobronchial papillomas should be completely excised.

Association of Kaposi's sarcoma associated herpesvirus (KSHV) DNA in bronchoalveolar lavage fluid of HIV infected individuals with bronchoscopically diagnosed tracheobronchial Kaposi's sarcoma.

OBJECTIVES: To determine the frequency of detection of Kaposi's sarcoma associated herpesvirus (KSHV), also known as human herpesvirus (HHV) type 8, DNA in bronchoalveolar lavage (BAL) fluid from HIV infected individuals with and without KS and to compare this with the detection rate in peripheral blood. Also to identify whether KSHV was associated with specific cell types in lavage fluid. METHODS: Nested PCR was used to detect KSHV DNA in BAL fluid from 41 consecutive individuals with Kaposi's sarcoma (KS) and in 41 controls with similar CD4 lymphocyte counts. Semiquantification of viral DNA was by end point titration. A positive cell sorting selection procedure was used to isolate specific BAL fluid cell types. RESULTS: KSHV DNA was detected in BAL fluid from 24 of 29 (83%) individuals with a bronchoscopic diagnosis of tracheobronchial KS. None was detected in 12 individuals with only cutaneous KS, or in 41 matched controls without KS. In five, KSHV DNA was detected in the cell depleted and cellular fractions of BAL fluid and in 1/5 in the CD14 (macrophage) fractions. None was detected in the CD19 (B lymphocyte) or CD4/CD8 (T lymphocyte) fractions. CONCLUSIONS: There was a clear association between the diagnosis of tracheobronchial KS and detection of KSHV DNA in BAL fluid. The cell type supporting KSHV in the respiratory tract is not CD 19 positive and has yet to be conclusively identified.