Giorgio Giorda

Long-term follow-up is crucial after treatment for granulosa cell tumours of the ovary

Objective:The aim of this study is to evaluate the long-term outcome of granulosa cell tumour (GCT) of the ovary in a large series of patients treated in MITO centres (Multicentre Italian Trials in Ovarian Cancer) and to define prognostic parameters for relapse and survival.Methods:A retrospective multi-institutional review of patients with GCTs of the ovary treated or referred to MITO centres was conducted. Surgical outcome, intraoperative and pathological findings and follow-up data were analysed. Kaplan–Meier and Cox proportional hazards analyses were used to determine the predictors for survival and recurrence.Results:A total of 97 patients with primary GCT of the ovary were identified. The median follow-up period was 88 months (range 6–498). Of these, 33 patients had at least one episode of disease recurrence, with a median time to recurrence of 53 months (range 9–332). Also, 47% of recurrences occurred after 5 years from initial diagnosis. At multivariate analysis, age and stage were independent poor prognostic indicators for survival; surgical treatment outside MITO centres and incomplete surgical staging retained significant predictive value for recurrence in both univariate and multivariate analyses.Conclusions:This study confirms the generally favourable prognosis of GCTs of the ovary, with 5-year overall survival approaching 97%. Nevertheless, prognosis after 20 years was significantly poorer, with 20-year survival rate of 66.8% and a global mortality of 30–35. These findings support the need for lifelong follow-up even in early-stage GCT.

Recurrent granulosa cell tumors (GCTs) of the ovary: A MITO-9 retrospective study

OBJECTIVE Optimal treatment of recurrent GCTs is unknown. The aim of this study was to evaluate the characteristics of recurrent GCTs. METHODS Data on 35 recurrent GCTs were reviewed. RESULTS Initial FIGO stages were: 11 IA, 11 IC, 6 Ix, 1 IIB, 5 IIIC and 1 IV. All patients had undergone primary surgical treatment, and in 8 cases adjuvant chemotherapy was given. The median RFS was 53.2 months with differences between patients receiving (72.5 months) and not receiving (48 months) adjuvant chemotherapy and between patients optimally staged (64.5 months) or not staged (47 months). Recurrence sites were: pelvic, 13; abdominal, 6; lymph-nodal, 2; pelvic+abdominal, 7; abdominal+lymph-nodal, 4; and pelvic+lymph-nodal, 3. Twenty-five patients underwent debulking surgery+chemotherapy, 6 surgery, 2 surgery+radiotherapy, 1 chemotherapy and 1 palliation. 69% completed the chemotherapy. No difference was found in OS among patients receiving or not receiving chemotherapy after secondary surgery at recurrence and among the different relapse sites. Eleven patients developed a second relapse after a median time of 38 months. 81.8% had received adjuvant therapy at first recurrence. Four patients underwent surgery, 4 surgery+chemotherapy, 1 surgery+radiotherapy and 2 palliation. Four patients developed a third recurrence after a median time of 41 months. Two patients received chemotherapy and 2 hepatic resection. Nine patients (25.7%) died of disease. 5y-OS from the first recurrence was 55.6% and 87.4% for patients with or without residual tumor at subsequent debulking surgery, respectively. CONCLUSIONS In GCTs surgery remains the cornerstone treatment at relapse. RFS was higher in patients who received adjuvant therapy after initial diagnosis, with no difference in OS.

Comparison of repeat smear, colposcopy, and colposcopically directed biopsy in the evaluation of the mildly abnormal smear

Repeat smear, colposcopy, and colposcopically directed biopsy were performed in 161 patients referred to our department because of a Pap smear showing mild dysplasia (CIN 1). Colposcopically directed biopsies revealed the presence of CIN of different grades in 61 cases (37.5%). In 33 (20.4%) the CIN grade found at biopsy was higher than 1. Repeat smear confirmed the presence of CIN 1 in 67 women (47.2%). In this group of patients colposcopically directed biopsies showed a CIN grade greater than 1 in 12 cases (17.9%). The repeat smear was negative in 59 patients (41.5%). In this group, biopsy showed varying grades of neoplasia in 12 cases. Colposcopic examination indicated no dysplasia but the presence of minor cervical abnormalities in 76 women (47.2%): at biopsy a CIN grade higher than 1 was found in 9 cases (11.5%). These data suggest that the mildly atypical smear identifies a group of patients at increased risk of CIN but gives little or no information on the disease severity. Repeat smear and colposcopic examination alone appear inadequate to demonstrate the severity of the cervical lesion. Due to the high proportion of CIN 2 and 3 in patients with a mildly abnormal smear, the systematic biopsy of any colposcopically abnormal area seems essential to proper management of the patient.

Laparoscopic versus abdominal approach to endometrial cancer: A 10-year retrospective multicenter analysis

Objective The objective of this study was to give a reality-based picture of the use of laparoscopic surgery for staging endometrial cancer patients out of the experimental setting. Methods Consecutive data of patients with endometrial cancer who underwent laparoscopic or abdominal surgical staging in 6 Italian centers were recorded. Baseline patients and tumors characteristics, surgery performed, and safety data were collected and analyzed. Results A total of 1012 subjects (403 and 609 treated by laparoscopy and laparotomy, respectively) who received surgical stadiation for endometrial cancer were included in the final analysis. The laparoscopic approach to endometrial cancer was more commonly performed in younger and nonobese patients who had received less previous surgeries, whereas the abdominal approach was preferred for the advanced stages and rare histotypes. Irrespectively to stage, the operative time was higher for the laparoscopy than laparotomy, whereas blood loss and postoperative complications were lower in the laparoscopy group than in the laparotomy group. No difference between surgical approaches was observed in complication rates in stage I endometrial cancers, whereas they were worst in higher stages. The site, but not the incidence, of recurrences differed only for advanced stage endometrial cancers. No differences in overall, disease-free, and cancer-related survival rates were also observed. Conclusions In the clinical practice, heterogeneous criteria are adopted to recur to laparoscopy for staging endometrial cancer. The safety and the feasibility of the laparoscopy are confirmed for stage I endometrial cancers, whereas they appear suboptimal for the advanced stages.

Weekly topotecan and cisplatin (TOPOCIS) as neo-adjuvant chemotherapy for locally-advanced squamous cervical carcinoma: Results of a phase II multicentric study.

OBJECTIVES The aim of this phase II multicentric study was to evaluate the efficacy and toxicity of neo-adjuvant chemotherapy with weekly topotecan and cisplatin in locally-advanced squamous cervical cancer. PATIENTS AND METHODS From November 2008 to January 2011, 92 patients met the inclusion criteria and were enrolled. Eligibility criteria were: squamous or adenosquamous cervical cancer; clinical stages IB2, IIA, IIB; Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)≤ 2; neutrophils ≥1500/μL; platelets ≥100,000/μL, normal renal and liver function. Treatment consisted of six courses of weekly topotecan (2mg/m(2)) and cisplatin (40 mg/m(2)). All responsive and stable patients were submitted to radical surgery, while progressed cases underwent definitive radiotherapy±chemotherapy. Primary end-point was evaluation of efficacy and toxicity. All patients are evaluable for toxicity and efficacy. RESULTS Ninety-six percent of patients completed the six planned courses of chemotherapy, and 95% of courses were administered at a full dose and without interruption or delay. Mean age was 49 years (35-64 years). FIGO Stage distribution was 30 IB2, 13 IIA and 49 IIB. Treatment was well tolerated and no death occurred. G3-G4 haematological toxicity was observed in 28% of patients (5% out of cycles). Support therapies (blood transfusions and/or erythropoietin and/or Granocyte-Colony Stimulating Factor) were given to 24% of patients. Clinical response rate was 77%. The nine progressed cases were irradiated, while the remaining 83 patients were submitted to radical surgery. An overall pathologic response was observed in 67% of patients, with an optimal response rate of 32% and a disease downstage in 57% of patients. Nodal metastases occurred in 36% of patients. Adjuvant therapy (radiotherapy and or chemotherapy) was prescribed in 55% of patients, because of lymph node metastases, parametrial or vaginal involvement or cut-through margins. Median follow-up was 18 months: 76% of patients are alive and free from recurrence, 24% of patients relapsed and 13% died. CONCLUSIONS Weekly topotecan and cisplatin showed an acceptable toxicity profile; the promising response rate warrants further investigation.

Is the endometrial evaluation routinely required in patients with adult granulosa cell tumors of the ovary

OBJECTIVE Granulosa cell tumors (GCTs) are the most common estrogen-secreting ovarian tumors; perhaps due to the persistent hyperestrogenism, a wide spectrum of associated endometrial pathologies ranging from endometrial hyperplasia to carcinoma has been documented in patients with GCTs. The aim of this study is to evaluate the incidence of endometrial pathologies in a large series of GCT patients treated in MITO centers. METHODS A retrospective multi-institutional review of patients with granulosa cell tumors of the ovary treated or referred to MITO centers was conducted. Descriptive statistics were used to characterize the patient population and to assess the association of GCT and endometrial abnormalities at the time of diagnosis; multivariate regression analysis was also performed to identify independent predictors of endometrial abnormalities. RESULTS A total of 150 patients with primary adult GCT was identified. During the preoperative assessment, endometrial pathology was found in 35.9% of symptomatic patients and in 90.9% of asymptomatic women with endometrial thickening at transvaginal ultrasound. At the time of surgery, hyperplasia was documented in 29.2% of patients, whereas endometrial cancer occurred in 7.5% of patients. Almost all of the patients (97.6%) with endometrial hyperplasia were older than 40years. All patients with endometrial cancer were older than 40years and postmenopausal. CONCLUSIONS Endometrial carcinoma/atypical hyperplasia were commonly observed in GCT patients >40years; based on these data, endometrial sampling should be performed in symptomatic women at least 40years of age. In asymptomatic women <40years, endometrial sampling is of low yield.

Adjuvant chemotherapy does not improve disease-free survival in FIGO stage IC ovarian granulosa cell tumors: The MITO-9 study

OBJECTIVE Evidence-based management of granulosa cell tumors of the ovary (GCT) has been not yet standardized: surgery, including fertility-sparing procedures for young women, has been traditionally the standard treatment; on the other hand, chemotherapy has been used for treatment of advanced and/or recurrent disease. However, very limited experience, has been selectively focused on the role of adjuvant chemotherapy in stage IC patients. The objective of this retrospective study was to assess the efficacy of first line postoperative chemotherapy in patients with stage IC treated at the Italian Centers involved in the MITO (Multicenter Italian Trials in Ovarian cancer) Group. PATIENTS AND METHODS A retrospective multi-institutional review of patients with GCT of the ovary at FIGO stage IC treated or referred to MITO centers was conducted. Surgical outcome, pathological findings and follow-up data were analysed. Kaplan-Meier and Cox proportional hazards analyses were used to determine the predictors factors for disease free survival. RESULTS A total of 40 patients with primary GCT of the ovary at FIGO stage IC were identified. The median follow-up period was 96months (range 7-300). At multivariate analysis, surgical treatment outside MITO centers and incomplete surgical staging were independent poor prognostic indicators for recurrence; adjuvant chemotherapy did not retain significant predictive value for recurrence. CONCLUSIONS This study raises the question about the value of adjuvant chemotherapy in stage IC GCT: a comprehensive evaluation of a larger series is urgently needed in order to characterize stage IC substages who can be spared treatment toxicity.

Conservative treatment of microinvasive adenocarcinoma of uterine cervix: long-term follow-up.

Obiective This study aimed to evaluate the safety of conservative treatment in women desiring preservation of fertility with stage IA adenocarcinoma of the cervix. Materials and Methods Clinical report of all women with stage IA adenocarcinoma of the cervix, endocervical subtype, with clear margins on cone biopsy, diagnosed in our cancer center inclusive between January 1995 and December 2007, were evaluated, after either conservative therapy or hysterectomy. All diagnoses were reviewed by a pathologist expert in gynecologic oncology. Follow-up methods include at least cervical cytology, colposcopy with direct biopsy if indicated, and cervical curettage. Results Of 783 laser cone biopsy specimens, 7 were diagnostic for microinvasive adenocarcinoma, endocervical subtype (6 stage IA1 lesions and 1 stage IA2 lesion) with clear margins. No lymphovascular space invasion was seen. No residual invasive disease was observed in the specimens of 2 patients treated with hysterectomy after conization. Five women treated with laser cone biopsy only are free of invasive disease at 44, 66, 72, 86 and 100 months; 1 patient was found to have persistent adenocarcinoma in situ on endocervical cytology. Conclusions Cone biopsy as definitive therapy is safe in women with stage IA1 adenocarcinoma of the cervix, endocervical subtype, with clear margins and no lymphovascular space invasion. Because of the low reliability of follow-up techniques (cytology, colposcopy, and endocervical curettage), conservative treatment should be reserved only for women strongly desiring to preserve fertility and accepting the risk of recurrent disease.

Surgical Treatment of Paget Disease of the Vulva: Prognostic Significance of Stromal Invasion and Surgical Margin Status.

ObjectiveThe aim of the study was to evaluate the risk of recurrence according to the surgical margin status and the presence of invasion or of superficially invasive carcinoma in patients with extramammary Paget disease (EMPD) of the vulva, who underwent elective surgical treatment. Materials and MethodsWe performed a retrospective analysis of 27 patients with first diagnosis of extramammary Paget disease of the vulva, who underwent primary and elective surgical treatment from January 1989 to December 2014. A p value of less than .05 was considered statistically significant. Multivariable logistic regression was performed to adjust for confounding factors. ResultsWe observed invasive disease in 11 cases, with microinvasion in 8 of them. A positive surgical margin was found in 10 patients. During a median follow-up period of 79.5 months, 8 patients (29.6%) showed a first recurrence after a median (range) time of 4.9 (2.3–7.1) years. No significant differences were observed between patients with recurrence and patients without recurrence with respect to age, number of vulvar sectors involved, bilaterality and multifocality, presence of invasion or microinvasion, and surgical margin status. However, during the follow-up period, the presence of invasion was higher (67% vs 41%) in patients with recurrence compared with patients without recurrence. ConclusionsThe rate of recurrence of the disease after therapy is high. Patients should be subjected to a close and long-term follow-up to identify those who must undergo further treatment, especially if they presented with an invasive or even microinvasive disease. A free margin of no greater than 1 to 2 cm might be the most appropriate surgical choice.

Polymorphic thymidylate synthase gene impacts on overall survival of patients with epithelial ovarian cancer after platinum-based chemotherapy

AIM High levels of TS have been associated with a worse clinical outcome in several cancers including epithelial ovarian cancer (EOC). The TS gene (TYMS) is highly polymorphic and has an effect on mRNA/protein expression. MATERIALS & METHODS Six TYMS polymorphisms were investigated for overall survival (OS) in 216 EOC patients: TYMS 1494ins/del, TSER (variable number of tandem repeats of 28 bp), TSER G>C, TYMS 1053C>T, TYMS IVS6-68C>T and TYMS 1122A>G. RESULTS In a multivariate analysis, TYMS 1494 del/del genotype was associated with a significant increased OS compared with the ins/ins genotype (hazard ratio: 0.36; 95% CI: 0.16-0.82, p = 0.01). Similar results were obtained for the mutant genotypes TYMS 1053TT and TYMS IVS6-68TT. The event-free survival was significantly higher in TYMS 1053TT patients compared with wild-type patients (p = 0.05). CONCLUSION TYMS 1494ins/del, 1053C>T and IVS6-68C>T polymorphisms can be prognostic markers for OS in patients with EOC, independently from stage at diagnosis, median age and tumor histotype.