Bovine papillomavirus E5 oncoprotein upregulates parkin-dependent mitophagy in urothelial cells of cattle with spontaneous papillomavirus infection: A mechanistic study.

This study aimed to provide mechanistic insights into mitophagy pathway associated with papillomavirus infection in urothelial cells of cattle. The elimination of mitochondria via autophagy, termed mitophagy, is an evolutionarily conserved mechanism for mitochondrial quality control and homeostasis. PINK1/parkin-mediated mitophagy, a ubiquitin-dependent selective autophagy of dysfunctional mitochondria, has been described here, for the first time, in urothelial cells from 25 bladder cancers in cattle infected by bovine papillomavirus (BPV). The expression of BPV-2 and BPV-13 E5 oncoprotein was detected by RT-PCR. Abnormal mitochondria delimited by expanding phagophores, were peculiar ultrastructural features of neoplastic urothelial cells. High levels of mitochondrial phosphorylated PINK1/parkin were observed in neoplastic urothelial cells infected by BPVs. Phosphoparkin interacted with mitofusin 2 (Mfn2) and ubiquitin (Ub), which confirmed that Mfn2 is a parkin receptor at the mitochondrial level, where parkin interacted also with Ub. Furthermore, parkin established a complex that was comprised of optineurin, p62, LC3, laforin, and embryonic stem cell-expressed Ras (ERAS), that interacted with BPV E5 oncoprotein, and Bag3, which, in turn, regulated the formation of a complex composed of Hpc70/Hsp70, CHIP, an HSC70-interacting E3 ubiquitin ligase. It is conceivable that ERAS is involved in mitophagosome maturation via phosphatidylinositol 3-kinase (PI3K) pathway. Bag3, in association with Hsc70/Hsp70, may contribute to the transport and degradation of CHIP-ubiquitinated cargo as this complex recognises ubiquitinated cargos and transports them to aggresomes to be degraded. Furthermore, Bag3 may be involved in mitophagosome formation as it interacted with synaptopodin 2, which is known to play a role in mitophagosome biogenesis.

Cervical carcinomas with a micropapillary component: a clinicopathological study of eight cases.

AIMS: Micropapillary carcinomas, or carcinomas with a micropapillary component, are well recognised in the breast and other anatomical sites. However, they have seldom been described in the cervix. In this article, we present a clinicopathological analysis of eight cervical tumours that showed at least a focal (≥5%) component of micropapillary carcinoma. METHODS AND RESULTS: The study group comprised eight cervical carcinomas (four adenocarcinomas and four adenosquamous carcinomas) with a micropapillary component. The median patient age was 41.5 years (range 27-65 years). At presentation, five patients were stage IB, two were stage IIB, and one was stage IV. The micropapillary component accounted for ≤25% of the tumour on initial biopsy or resection specimens in all but one case. Immunohistochemistry showed 'inside-out' (reverse polarity) mucin 1 staining along the cell membrane abutting the stroma. Four patients developed metastasis, all of whom showed a pure micropapillary pattern; this led to a misdiagnosis of an apparently independent peritoneal serous carcinoma in one case. All tumours showed diffuse p16 expression, and all three cases that were tested were positive for human papillomavirus (HPV) 18. Three of the six patients with at least 12 months of follow-up died of disease, and one is alive with distant metastasis. CONCLUSIONS: Usual-type (HPV-related) cervical carcinomas may show micropapillary differentiation, usually as a focal finding, and the cells show reverse polarity like similar tumours arising in other sites. Micropapillary cervical carcinoma appears to be a clinically aggressive malignancy, although this needs to be confirmed in larger studies.

Evaluation of the presence of Epstein-Barr virus (EBV) in Iranian patients with thyroid papillary carcinoma.

BACKGROUND AND PURPOSE: Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. EBV is one of the most important viruses related to different types of malignancies. This study investigated the relationship between EBV and papillary thyroid carcinoma. MATERIAL AND METHODS: In this study the presence of Epstein-Barr Nuclear Antigen 1 (EBNA1) gene in papillary thyroid carcinoma tissues were examined by nested-PCR method. Paraffin-embedded tissues (N=41) blocks of thyroid cancer were used. DNA was extracted from all samples and then samples were evaluated for the presence of EBV gene. RESULTS: In 41 samples, EBNA1 was detected in 65.8% of patients with papillary thyroid carcinoma which was significantly higher in younger ages. CONCLUSION: The significant presence of EBV genome in papillary thyroid carcinoma suggests that this virus may play a role in this cancer especially in younger ages. As a result, monitoring of patients with EBV latent infection for PTC can be very important.

Human papillomavirus-related squamous cell carcinoma of the anal canal with papillary features.

Human papillomavirus (HPV) related squamous cell carcinoma (SCC) involving the anal canal is a well-known carcinoma associated with high-risk types of HPV. HPV-related SCC with papillary morphology (papillary SCC) has been described in the oropharynx. We describe, for the first time, a case of anal HPV-related squamous carcinoma with papillary morphology. The tumor arose from the anal mucosa. The biopsies revealed a superficially invasive SCC with prominent papillary features and associated in situ carcinoma. The tumor cells were positive for p16 and were also positive for high-risk types of HPV using chromogenic in situ hybridization. The findings are consistent with a HPV-related SCC of the anal canal with papillary features. This tumor shows histologic features similar to a papillary HPV-related SCC of the oropharynx. Additional studies are needed to characterize these lesions.

No evidence of association between human cytomegalovirus infection and papillary thyroid cancer.

BACKGROUND: Human cytomegalovirus (CMV) has been detected in the thyroid gland and thyroid tumors. CMV infection may activate the mitogen-activated protein kinase pathway, of which aberrant activation is frequently associated with BRAF mutation in papillary thyroid cancer. METHODS: A total of 45 paired tumorous and adjacent non-neoplastic tissue samples, including 5 follicular adenoma and 40 papillary thyroid cancer, were obtained during thyroidectomy. BRAF mutational status was determined using direct sequencing. The presence of CMV DNA was determined using conventional PCR and quantitative real-time PCR. CMV protein in the tissue samples were evaluated with Western blot analysis. RESULTS: BRAF mutation was identified in the cancerous part of 31 (78%) papillary thyroid cancers. Papillary cancer with BRAF mutation was significantly associated with a larger tumor size (P = 0.045), extrathyroidal invasion (P = 0.012), lymph node metastasis (P = 0.008), and a higher TNM stage (P = 0.044). CMV DNA and protein were not detected in any studied samples. CONCLUSIONS: Our results suggest no association between CMV infection and papillary thyroid cancer.

Infection and persistence of erythrovirus B19 in benign and cancerous thyroid tissues.

Human erythrovirus B19 (EVB19) is a small, pathogenic DNA virus that has been associated with a wide range of illnesses. The primary site of replication is in bone marrow-derived erythroid progenitor cells, but EVB19 DNA has been detected in a wide range of organs. Recently, studies have linked EVB19 to thyroid cancers and other thyroid diseases. Previous studies from multiple laboratories have detected EVB19 capsid proteins in Graves' disease, Hashimoto's thyroiditis, and thyroid cancer tissues. Data on viral gene expression and mechanism of infection in the thyroid are lacking. To investigate EVB19 infection and persistence in the thyroid, previously archived adult and pediatric tissue sections were examined for EVB19 DNA, RNA, and capsid proteins, as well as EVB19 receptor P-antigen and co-receptor α5ß1 integrin. EVB19 DNA and protein were detected in a majority of tissues examined (87% and 68%, respectively). Detection was similar in adult and pediatric samples. Quantification of viral genomes revealed no significant difference in the amount of viral DNA in benign, cancerous, or metastatic thyroid tissues. EVB19 capsid RNA was detected in 67% of the tissues examined, confirming at least low-level viral gene expression. Immunohistochemical staining for P-antigen and α5ß1 detected the receptor and co-receptor most frequently on normal thyroid epithelial cells. EVB19 capsid staining could be detected in tumors lacking viral receptors. These results suggest that normal thyroid epithelial cells are the initial target for EVB19 infection in the thyroid and allow for continued persistence in both normal and cancerous thyroid tissues.

Papillary squamous cell carcinoma of the trachea associated with human papillomavirus-18 infection.

A 75-year-old man presented with the chief complaints of coughing and dyspnea. Chest computed tomography revealed narrowing of the trachea. A tumor measuring 40×33×15 mm in size that caused -90% reduction in the cross-sectional area of the trachea 4 cm above the carina was cauterized with high-frequency electrocautery via a rigid bronchoscope. A pathological examination revealed papillary squamous cell carcinoma with immunohistochemical p16 overexpression. Multiplex polymerase chain reaction confirmed human papillomavirus type 18 DNA in the tumor. At the 12-month follow-up visit following the administration of radiotherapy, the patient exhibited no local recurrence or distant metastasis.

Papillary squamous cell carcinoma of the head and neck: clinicopathologic and molecular features with special reference to human papillomavirus.

A relationship between human papillomavirus (HPV) infection and papillary squamous cell carcinoma (PSCC) has been suggested. However, to date, no studies have thoroughly and directly evaluated for transcriptional activity of the virus or the clinicopathologic significance of HPV-positive PSCC. Forty-eight cases of PSCC were retrieved from our surgical pathology database and were reviewed by 4 study pathologists, with tumors defined as SCC with a significant component of papillary growth in the tumor. Immunohistochemical analysis for p16 and p53 was performed. Overexpression of p16 was used as a surrogate marker of transcriptionally active HPV. Transcriptional activity was also directly evaluated using RNA in situ hybridization to detect high-risk HPV E6/E7 mRNA. Clinical follow-up data were obtained by chart review. Seven cases were located in the oral cavity, 19 in the oropharynx, and 22 in the larynx. Two morphologic types of PSCC were identified: keratinizing type, in which the epithelial cells showed a maturation trend with minimal surface parakeratin, and nonkeratinizing type, in which the papillae were completely covered by immature basaloid cells. Transcriptionally active HPV was present in 23 of 43 (53.4%) tumors. The majority of tumors harboring transcriptionally active HPV arose in the oropharynx, showed nonkeratinizing morphology, were p16 positive, and p53 negative. Transcriptionally active HPV was also present in many laryngeal and oral cavity PSCCs. Overall survival, disease-specific survival, and disease-free survival were favorable and did not significantly differ by anatomic subsite. However, HPV-related tumors showed a trend toward better survival.

Human papillomavirus infection and papillary squamous cell carcinoma in the head and neck region.

Papillary squamous cell carcinoma (PSCC) is a rare variant of SCC in the head and neck region. The role of human papillomavirus (HPV) infection in PSCC is still unclear. We retrospectively reviewed 11 PSCCs in our institute over a 21-year period and compared the HPV status of PSCCs with 26 squamous cell papillomas (SCPs). Polymerase chain reaction (PCR) amplification to detect HPV DNA and in situ hybridization (ISH) were performed to analyze the relationship between the papillary lesions and HPV infection. Immunohistochemical (IHC) staining for p16 protein expression was used to analyze the PSCC specimens. Nine of 11 (82 %), eight of 11 (73 %), and eight of 11 (73 %) PSCC samples were found to be HPV positive by PCR, ISH, and IHC staining for p16 protein expression, respectively. PSCC had a significantly higher rate of HPV infection than SCP by PCR (p = 0.002) and ISH (p = 0.001) analysis. This study presents different HPV status in two papillary neoplasms and may help to clarify the unique morphological and biological characteristics of head and neck PSCC.

Productive infection of bovine papillomavirus type 2 in the placenta of pregnant cows affected with urinary bladder tumors.

Papillomaviruses (PVs) are believed to be highly epitheliotropic as they usually establish productive infections within stratified epithelia. In vitro, various PVs appear to complete their entire life-cycle in different trophoblastic cell lines. In this study, infection by and protein expression of bovine papillomavirus type 2 (BPV-2) in the uterine and chorionic epithelium of the placenta has been described in four cows suffering from naturally occurring papillomavirus-associated urothelial bladder tumors. E5 oncoprotein was detected both by Western blot analysis and immunohistochemically. It appears to be complexed and perfectly co-localized with the activated platelet-derived growth factor ß receptor (PDGFßR) by laser scanning confocal microscopy. The activated PDGFßR might be involved in organogenesis and neo-angiogenesis rather than in cell transformation during pregnancy. The major capsid protein, L1, believed to be only expressed in productive papillomavirus infection has been detected by Western blot analysis. Immunohistochemical investigations confirmed the presence of L1 protein both in the cytoplasm and nuclei of cells of the uterine and chorionic epithelium. Trophoblastic cells appear to be the major target for L1 protein expression. Finally, the early protein E2, required for viral DNA replication and known to be expressed during a productive infection, has been detected by Western blot and immunohistochemically. Electron microscopic investigations detected viral particles in nuclei of uterine and chorionic epithelium. This study shows that both active and productive infections by BPV-2 in the placenta of pregnant cows can occur in vivo.

High-risk human papillomavirus in mammary gland carcinomas and non-neoplastic tissues of Mexican women: no evidence supporting a cause and effect relationship.

Human papillomavirus (HPV) has been implicated in breast carcinogenesis. Consecutive and non-selected mastectomy specimens from Mexican patients harboring breast carcinomas were sampled in order to look for the presence of HPV DNA. HPV-16 was detected in 6 (10%) of 60 breast carcinomas. Two of these also had HPV genome in adjacent non-neoplastic mammary-tissues. Seven cases had HPV DNA only in non-neoplastic tissue specimens. HPV DNA was also detected in 4 (25%) of 10 tumor-bed specimens without residual neoplastic lesions that were obtained from patients who underwent neoadjuvant chemotherapy or neoadjuvant chemotherapy/radiotherapy. HPV-positive tumors tended to be smaller in size, than HPV-negative tumors (p=0.047). Histological distributions of HPV-positive and -negative cases showed no significant difference. Although all the HPV-16 DNA were found integrated, its low viral load rendered it difficult to incriminate this virus in breast carcinogenesis. However, the possibility that HPV infection occurred during carcinoma development cannot be ruled out.

Detection of human papillomavirus in a urothelial carcinoma mimicking urethral caruncle.

Primary carcinoma of the female urethra is an uncommon diagnosis, accounting for less than 0.02% of all carcinomas in women. Urothelial carcinomas occupying the distal urethra in young females are considered to be extremely rare. Here we report what we believe to be the sixth case of primary urothelial carcinoma in the published English-language literature. The patient, a 26-year-old woman, presented with a distal urethral lesion that resembled a caruncle, but which was proved to be a urothelial carcinoma on histopathological examination of the resected specimen. Human papillomavirus type 51 DNA was detected in the tumor by polymerase chain reaction and in situ hybridization. These findings suggest that human papillomavirus might be involved in a subset of urothelial carcinomas of the urethra.

A male patient with malignant lymphoma and thyroid papillary carcinoma after pediatric renal transplantation.

A 6-year-old boy received renal transplantation and was treated with methylprednisolone, cyclosporine A and mizoribine. He developed Epstein-Barr virus-associated malignant lymphoma at 10 years and thyroid papillary carcinoma at 20 years of age. Chemotherapy for the malignant lymphoma was done after withdrawal of cyclosporine A and mizoribine, and thyroidectomy was performed for thyroid carcinoma. He was well and his serum creatinine was 1.0 mg/dl at 22 years of age. To our knowledge, no pediatric renal transplant recipient who had thyroid carcinoma or two different types of tumor has been reported in Japan.

Papillary squamous cell carcinoma of the head and neck: frequent association with human papillomavirus infection and invasive carcinoma.

Papillary squamous cell carcinoma (SCC) is an uncommon variant of SCC in the upper aerodigestive tract. It is most frequently located in the larynx, oropharynx, and sinonasal tract, and is more common in older men. Because of its complex exophytic papillary architecture, histologic assessment of underlying invasion can be challenging. Risk factors and pathogenesis are unclear. We reviewed 31 papillary SCCs of the upper aerodigestive tract seen at our institution over a 17-year period with respect to p16 immunoreactivity and human papillomavirus (HPV) status. Twelve papillary SCCs were associated with invasive SCC in their disease course. In our study, more than two-thirds of papillary SCCs in the upper aerodigestive tract were immunoreactive with antibody to p16 and 68% of those lesions had identifiable high-risk HPV by in situ hybridization. As with other HPV-associated SCCs of the upper aerodigestive tract, the majority of HPV-associated papillary SCCs are oropharyngeal (base of tongue and palatine tonsils), although both sinonasal and laryngeal tumors were also associated with infection (67% and 33% of cases, respectively). Given the better prognosis of HPV-associated SCCs of the upper aerodigestive tract, it may be prudent to report the p16 and HPV status of these tumors when they are encountered.

Detection of human papillomavirus type 11 in a case of Buschke-Löwenstein tumor.

We here report a 31-year-old male affected by a papillary tumor in his pubic region. At 26 years of age, he consulted a nearby clinic and was prescribed a topical cream. Although the condition was not relieved, he left the disease untreated. The gradually growing tumor adversely affected his quality of life, and he consulted another clinic, where he was referred to our hospital for surgery. The tumor had infiltrated the tissue at the base of the penis, but not the glans. After careful examination, we performed local excision of the tumor and a split-thickness skin graft. On pathological examination, elongation of the epidermis and koilocytes in the uppermost portion of the spinous layer were observed. Moreover, PCR examination confirmed the presence of human papillomavirus (HPV) type 11 in the tumor tissue. These findings supported a diagnosis of Buschke-Löwenstein tumor (BLT).

Review article: relationship of human papillomavirus with papillary squamous cell carcinoma of the upper aerodigestive tract: a review.

The purpose of this review is to evaluate case reports of papillary squamous cell carcinoma (PSCC) of the upper aerodigestive tract (UADT) to assess its relationship with human papillomavirus (HPV). The medical literature was searched for case reports of this condition. A total of 115 cases of PSCC were found that described the condition in sufficient detail. HPV detection was performed in only 22 of the 115 cases of PSCC (19%), and 11 of the 22 cases (50%) are related to this virus. The majority of cases related to HPV are produced by low-risk HPV type 6 followed by high-risk HPV type 16. Today, the association of HPV with PSCCs seems unclear because in the majority of patients tests were not performed for the detection of the HPV. This association should be clearly established to make a correct diagnosis and propose the best therapeutic strategies, such as new vaccines.

Detection of human parvovirus B19 in papillary thyroid carcinoma.

To evaluate whether parvovirus B19, a common human pathogen, was also involved in papillary thyroid carcinoma (PTC), 112 paraffin-embedded thyroid specimens of benign nodules, papillary, medullary and follicular carcinomas, and normal controls were examined for B19 DNA and capsid protein by nested PCR, in situ hybridisation (ISH) and immunohistochemistry (IHC). The expression of the nuclear factor-kappaB (NF-kappaB) was investigated by IHC. The results showed B19 DNA commonly exists in human thyroid tissues; however, there were significant differences between PTC group and normal controls, and between PTC and nonneoplastic adjacent tissues (P<0.001). The presence of viral DNA in PTC neoplastic epithelium was confirmed by laser-capture microdissection and sequencing of nested PCR products. B19 capsid protein in PTC group was significantly higher than that of all the control groups and nonneoplastic adjacent tissues (P