Human papillomavirus-related diseases of the female lower genital tract: oncogenic aspects and molecular interaction.

The causal role of human papillomavirus (HPV) in all cancers of the uterine cervix has been firmly established biologically and epidemiologically. Most cancers of both the vulva and the vagina are also induced by HPV. Papillomaviruses are perfectly adapted to their natural host tissue, the differentiating epithelial cell of skin or mucosae, and exploit the cellular machinery for their own purposes. The infectious cycle is initiated once the infectious particles reach the basal layer of the epithelium, where they bind to and enter the cells. The critical molecules in the process of virus replication are the viral proteins E6 and E7, which interact with a number of cellular proteins. In experimental system these interactions have been shown to induce proliferation and eventually immortalization and malignant transformation of cells. Binding of E7 to pRb activates the E2F transcription factor, which then triggers the expression of proteins necessary for DNA replication. Unscheduled S-phase would normally lead to apoptosis by the action of p53. However, in HPV-infected cells, this process is counteracted by the viral E6 protein, which targets p53 for proteolytic degradation. Besides blocking p53 function in regulation of apoptosis, high-risk HPV proteins interact with both extrinsic and intrinsic apoptotic pathways. As an aberration of virus infection, constant activity of the viral proteins E6 and E7 leads to increasing genomic instability, accumulation of oncogene mutations, further loss of cell-growth control and ultimately cancer. The immune system uses innate and adaptive immunity to recognize and combat foreign agents that invade the body, but these methods are sometimes ineffective against human papillomavirus. HPV has several mechanisms for avoiding the immune system. Furthermore, HPV infections disrupt cytokine expression with the E6 and E7 oncoproteins, particularly targeting the expression of interferon genes. Approximately 10% of individuals develop a persistent infection, and it is this cohort who is at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma.

Extraskeletal myxoid chondrosarcoma of the vulva with PLAG1 gene activation: molecular genetic characterization of 2 cases.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare mesenchymal neoplasm, rarely reported in the genitourinary tract with only 5 cases reported in the vulva. We investigated 2 cases of vulvar sarcomas whose morphologic appearance and immunohistochemical profiles were consistent with EMC using fluorescence in situ hybridization (FISH), reverse-transcription polymerase chain reaction, and a whole genome expression array. FISH and reverse-transcription polymerase chain reaction assays showed no EWSR1 and NR4A3 loci rearrangements. Microarray-based analysis also revealed no changes in NR4A3 and EWSR1 gene transcription levels. Microarray data showed a significant downregulation of the muscle-related genes (eg, myosin heavy chain family, actins, myoglobin, desmin, creatine kinase, troponins) and cytokeratins (KRT6A, 6B, 13, 14, and 78), upregulation of several neuron-specific genes [neural cell adhesion molecule 1 (NCAM-1/CD56), neurofilament (NEFH)], along with some well-characterized tumor biomarkers [carbonic anhydrase IX (CA-9), topoisomerase IIα (TOP2A), matrix metalloproteinases (MMP-7, MMP-9), CDKN2 gene (p16-INK4a), checkpoint homolog 2 (CHEK2)]. Notably, both tumors showed upregulation of the pleomorphic adenoma gene 1 (PLAG1), and in 1 case PLAG1 gene rearrangement was detected by break-apart FISH. Some vulvar tumors with morphologic and immunohistochemical characteristics of EMC may represent a molecular genetic entity separate from EMCs arising in other locations. PLAG1 gene activation appears to be involved in the development of these neoplasms.

[Clinical recommendations for diagnosing, treatment and monitoring of patients with ovarian cancer -- Croatian Oncology Society and Croatian Society for Gynecology and Obstetrics as Croatian Medical Association units and Croatian Society of Gynecological Oncology]. / Klinicke upute za dijagnostiku, lijecenje i pracenje bolesnica oboljelih od raka jajnika hrvatskoga onkoloskog drustva i hrvatskog drustva za ginekologiju i opstetriciju hrvatskoga lijetnickog zbora te hrvatskoga ginekoloskoonkoloskog drustva.

Ovarian cancer together with fallopian tube represents the fifth most common female cancer in the Republic of Croatia. Epithelial ovarian cancer, serous subtype, encompasses most of malignant ovarian neoplasms. Less common are various non-epithelial ovarian malignancies. A special group consists of epithelial carcinomas of low malignant potential with clinically indolent flow, good prognosis and no invasion, and primary cancer of the peritoneum and fallopian tube cancer. Clinically, these malignant tumors are generally asymptomatic in early stages, and usually diagnosed in advanced stages. The diagnosis is confirmed by pathological examination, and occasionally, cytological findings after completing diagnostic procedures. Multidisciplinary team makes treatment decisions, taking into account age, general condition and comorbidities of the patient and characteristics of the tumor itself, including disease stage, histological type and grade of the tumor. The principles of treatment of primary peritoneal and fallopian tube cancer are based on the principles of treatment of epithelial ovarian cancer involving surgery, chemotherapy, immune and hormone therapy, and symptomatic-supportive care throughout the treatment. Less common histological types have a different treatment approach being more frequently diagnosed in the early stages of the disease, have more indolent flow, so in these patients conservative surgeries with the goal of preserving fertility are more often employed. The following text presents the clinical guidelines in order to standardize the procedures and criteria for the diagnosis, management, treatment and monitoring of patients with ovarian carcinoma, fallopian tube and primary peritoneal cancer in the Republic of Croatia.

A surgical approach to giant condyloma (Buschke-Löwenstein tumour) with underlying superficial vulvar carcinoma: A case report.

Anogenital warts (condyloma acuminatum or venereal warts) are a common sexually transmitted disease in males and females. Common clinical treatment of anogenital warts is conservative, however, in extreme cases conservative therapy is insufficient and surgical excision is required. Giant condyloma acuminata (Buschke-Löwenstein tumour) is an extremely rare clinical type of genital wart, characterised by aggressive down growth into underlying dermal structures. A 55-year-old female presented with cauliflower-like growth over the anogenital and sacral region, earlier diagnosed as condyloma acuminatum which was resistant to conservative therapy. During the period between 2005 and 2008 the patient underwent five surgical procedures. Due to the size and location of the tumour, gynaecological and plastic surgeons were involved in the procedures. In addition, definitive histology examination identified a superficial vulvar carcinoma.

Reliability of sentinel node assay in vulvar cancer: the first Croatian validation trial.

OBJECTIVE: To evaluate the reliability of sentinel node assay in early stage vulvar cancer patients by using preoperative lymphoscintigraphy. METHODS: Technetium-99m colloid albumin was injected intradermally around the tumor for lymphoscintigraphic mapping and intraoperative hand-held gamma probe detection of sentinel nodes. For all patients, sentinel node biopsy was followed by inguinofemoral lymphadenectomy, regardless of the sentinel lymph node status. RESULTS: From December 2008 until May 2011, 25 consecutive patients with T1 or T2 stage of vulvar squamous cell cancer were enrolled. The median age of patients was 69 years (range, 48-79). The detection of sentinel lymph node was successful in all 25 patients. A total of 36 sentinel lymph nodes were harvested and metastatic carcinoma was identified in 12 sentinel nodes from 8 patients. There was 1 patient with metastatic non-sentinel lymph node despite the negative sentinel node. Two patients with negative sentinel nodes proven by routine histopathological examination were positive by immunohistochemical staining. The sensitivity, specificity and negative predictive value of sentinel node assay with immunohistochemistry included were 89%, 100%, and 94%, respectively. CONCLUSIONS: Lymphoscintigraphy and sentinel lymph node biopsy under gamma-detecting probe guidance proved to be an easy and reliable method for the detection of sentinel node in early vulvar cancer. Immunohistochemical analysis improves the sensitivity for the detection of regional micrometastases. The sentinel node assay is highly accurate in predicting the status of the remaining inguinofemoral lymph nodes. Our results indicate that patients best suited to SLN assay have had a simple punch biopsy to confirm the diagnosis rather than a previous tumor excision. This technique represents a true advance in the selection of patients for less radical surgery.