Potential for Mitochondrial DNA Sequencing in the Differential Diagnosis of Gynaecological Malignancies.

In the event of multiple synchronous gynecological lesions, a fundamental piece of information to determine patient management, prognosis, and therapeutic regimen choice is whether the simultaneous malignancies arise independently or as a result of metastatic dissemination. An example of synchronous primary tumors of the female genital tract most frequently described are ovarian and endometrial cancers. Surgical findings and histopathological examination aimed at resolving this conundrum may be aided by molecular analyses, although they are too often inconclusive. High mitochondrial DNA (mtDNA) variability and its propensity to accumulate mutations has been proposed by our group as a tool to define clonality. We showed mtDNA sequencing to be informative in synchronous primary ovarian and endometrial cancer, detecting tumor-specific mutations in both lesions, ruling out independence of the two neoplasms, and indicating clonality. Furthermore, we tested this method in another frequent simultaneously detected gynecological lesion type, borderline ovarian cancer and their peritoneal implants, which may be monoclonal extra-ovarian metastases or polyclonal independent masses. The purpose of this review is to provide an update on the potential use of mtDNA sequencing in distinguishing independent and metastatic lesions in gynecological cancers, and to compare the efficiency of molecular analyses currently in use with this novel method.

Mitochondrial DNA sequencing demonstrates clonality of peritoneal implants of borderline ovarian tumors.

Borderline ovarian tumors are rare low malignant potential neoplasms characterized by the absence of stromal invasion, whose main prognostic factors are stage and type of peritoneal implants. The latter are defined as invasive when cell proliferation invades the underlying tissue (peritoneal surface, omentum and intestinal wall), or noninvasive. It is still unknown if these implants are metastatic spread from the primary ovarian mass or a neoplastic transformation de novo of the peritoneal surface. Mitochondrial DNA sequencing was performed to assess clonality in eight patients presenting both borderline ovarian tumors and implants. In 37.5% of the cases, the same mitochondrial DNA mutation was present in both borderline ovarian tumors and the peritoneal implant, being this evidence that implants may arise as a consequence of a spread from a single ovarian site.

Mitochondrial DNA genotyping efficiently reveals clonality of synchronous endometrial and ovarian cancers.

Simultaneous independent primary tumors of the female genital tract occur in 1-2% of gynecological cancer patients, 50-70% of which are synchronous tumors of the endometrium and ovary. Recognition of synchrony upon multiple tumors is crucial for correct prognosis, therapeutic choice, and patient management. Current guidelines for determining synchrony, based on surgical and histopathological findings, are often ambiguous and may require further molecular analyses. However, because of the uniqueness of each tumor and of its intrinsic heterogeneity, these analyses may sometimes be inconclusive. A role for mitochondrial DNA genotyping was previously demonstrated in the diagnosis of synchronous endometrial and ovarian carcinoma. We have analyzed 11 sample pairs of simultaneously revealed endometrial and ovarian cancers and have thereby applied conventional histopathological criteria, current molecular analyses (microsatellite instability, ß-catenin immunohistochemical staining/CTNNB1 mutation screening), and mitochondrial DNA sequencing to distinguish separate independent tumors from metastases, comparing the performance and the informative potential of such methods. We have demonstrated that in ambiguous interpretations where histopathological criteria and canonical molecular methods fail to be conclusive, mitochondrial DNA analysis may act as a needle of balance and allow to formulate a diagnosis in 45.5% of our cases. Additional advantages of mitochondrial DNA genotyping, besides the high level of information we demonstrated here, are the easy implementation and the need for small amounts of starting material. Our results show that mitochondrial DNA genotyping may provide a substantial contribution to indisputably recognize the metastatic nature of simultaneously detected endometrial and ovarian cancers and may change the final staging and clinical management of these patients.

Single or repeated gonadotropin-releasing hormone agonist treatment avoids hysterectomy in premenopausal women with large symptomatic fibroids with no effects on sexual function.

AIM: The aim of our study was to explore the effects on symptoms and female sexual function of the medical management with gonadotropin-releasing hormone agonist (GnRHa) in women of more than 45 years old compared to surgical management. METHODS: Women with symptomatic uterine fibroids were enrolled to participate to the present open-label study. We offered two different treatment options: medical with GnRHa for 6 months (group A) or hysterectomy (group B). The patients were reviewed in follow-up for 24 months. The impact of medical or surgical therapy on sexual life was evaluated. RESULTS: No significant differences were found in population characteristics between the two groups. GnRHa treatment was efficient in reducing symptoms in 88% of patients but 22% of patients needed adjunctive cycles of medical therapy. After 24 months, 16% of the patients did not complete the study. The failure percentage of the medical treatment was 12%. No severe side-effects were recorded, and eight patients had reached menopause. No significant differences were observed in the Female Sexual Function Index score in each domain between the medical and surgical groups, with total scores of 18.94 ± 10.16 and 22.00 ± 8.86, respectively (mean ± standard deviation), and the prevalence of dysfunction was 12% and 22%, respectively, similar to the general population of the same age. CONCLUSION: We found that medical therapy with GnRHa is a satisfactory alternative to surgery for fibroids in women of more than 45 years old.

Electrochemotherapy can be used as palliative treatment in patients with repeated loco-regional recurrence of squamous vulvar cancer: a preliminary study.

OBJECTIVE: Electrochemotherapy (ECT) is an attractive treatment for solid cutaneous tumours with a good response rate (55-92%). No studies have evaluated ECT performed in vulvar cancer. The aim of our study was to evaluate the safety, local tumour efficacy and relief of symptoms of ECT treatment in patients affected by recurrence of squamocellular vulvar cancer (V-SCC) unsuitable for standard treatments. METHODS: We enrolled nine patients with histological diagnosis of recurrence of V-SCC. Intravenous bleomycin was injected under general sedation after an accurate mapping of all lesions and ECT was performed. Patients were reviewed after one, three and six months. Response to therapy was evaluated using RECIST criteria and quality of life (QoL) was evaluated via questionnaires. RESULTS: The median age was 84 years (range 80-90 years). The main location of recurrences was the vulva (87.5%). Multiple lesions were present in 25% of cases. No peri-operative complications were observed. Response to therapy was complete in 62.5% of patients, partial in 12.5%, no change was observed in 12.5% and progression of disease in 12.5% of patients respectively. Evaluation of symptoms showed a significant reduction of pain, bleeding, odour (p < 0.04) and urinary discomfort (p < 0.04). We observed two relapses at four and seven months after treatment. After nine months fifty percent of patients were alive. CONCLUSIONS: Our preliminary study showed that ECT is a suitable procedure in elderly patients with loco-regional vulvar cancer relapses. ECT can be used as palliative therapy and the treatment relieves symptoms and improves QoL.