Arlan F. Fuller

Intensive Surgical and Chemotherapeutic Management of Advanced Ovarian Cancer

We have presented the background and rationale for initiating a program of intensive surgical and chemotherapeutic management of advanced ovarian cancer. Our goal of excising all tumor masses larger than 1.5 cm in diameter has been explained and our operative approach described. The necessity for nutritional support has been emphasized. Preliminary results among patients with Stage III disease treated by optimal operation and Adriamycin-cyclophosphamide chemotherapy are encouraging. Aggressive operations have been unsuccessful when employed as secondary treatment. The single most important contraindication to extensive operation is the inability to initiate effective chemotherapy in the postoperative period.

Borderline tumors of the ovary: correlation of frozen and permanent histopathologic diagnosis

Objective To evaluate the correlation between the diagnosis of borderline tumor of the ovary by frozen and permanent pathology. Methods All pathology reports with diagnoses of borderline tumor of the ovary between 1980 and 1998 at Massachusetts General Hospital were reviewed. Univariate and multivariable logistic regression models were constructed for patient age, tumor size, histology, presence of bilateral or extraovarian disease, and concurrent diagnosis of endometriosis or endosalpingiosis. Results We reviewed 140 cases. The average age of patients was 52.3 years. Eighty tumors were serous, 47 mucinous, 11 mixed, and two endometrioid. The mean diameter overall was 13.7 cm (range 1–70 cm), 10.2 cm for serous, and 20.1 cm for mucinous. Diagnoses of borderline tumors by frozen and permanent pathology were consistent in 60% of cases. Frozen section interpreted a benign lesion as malignant (overdiagnosed) in 10.7% of cases, and interpreted a malignant lesion as benign (underdiagnosed) in 29.3%. No variable was a significant predicator of overdiagnosis. In univariate analysis, underdiagnosis was more likely for other types of tumors than serous (P < .001), tumors larger than 20 cm (P = .039), and tumors confined to the ovaries (P = .009). When all variables were included in a multiple regression model, only histology was a significant predictor of underdiagnosis (P = .039). Conclusion Frozen or permanent pathology reports of diagnoses of borderline tumor were consistent 60% of the time, whereas the positive predictive value of borderline by frozen section was 89.3%. Tumors other than serous are more likely to be misinterpreted.

Stage IE primary malignant lymphomas of the uterine cervix.

The experience of the authors with primary non‐Hodgkins lymphoma of the uterine cervix from 1980 to 1986 included five Ann Arbor Stage IE cases successfully managed by meticulous staging and radiation therapy. The clincopathologic features of the patients are described and compared with 38 previously reported Stage IE cases. When all 43 patients were evaluated, the median age was 40 years of age (range, 20 to 80 years of age) and 77% were premenopausal. Most patients (74%) reported abnormal vaginal bleeding, although approximately 20% were asymptomatic. The primary cervical tumors were typically of large size, with half exceeding 4 cm in diameter. Using the International Federation of Gynecology and Obstetrics (FIGO) system for staging cervical cancer, stage distribution was 44% Stage I, 42% Stage II, 12% Stage III, and 2% Stage IV. Histologically, approximately 70% were of the diffuse, large cell type (Working Formulation). External beam radiation therapy supplemented by brachytherapy or hysterectomy was used for 76% of the patients reviewed. There was only one treatment failure among the 28 patients whose treatment included radiation and whose cases were followed for at least 2 years. This experience and a review of the literature indicate that most cases of primary lymphoma of the uterine cervix are Ann Arbor Stage IE, and can be cured with traditional combinations of surgery and radiation therapy after careful evaluation.

Mullerian inhibiting substance inhibits growth of a human ovarian cancer in nude mice.

: Mullerian inhibiting substance (MIS) was investigated for its ability to inhibit growth of a human ovarian cancer in nude mice. Biologically active preparations from newborn calf testes, obtained after sequential ion exchange chromatography, delayed or prevented growth of a human ovarian cancer (HOC-21) when 2 X 10(6) cells were preincubated with them prior to subcutaneous injection of the tumor cells into Balb/C homozygous nude mice. Preincubation of a human colon carcinoma cells (SW-48) with similar preparations of MIS failed to inhibit growth of the tumor cells in nude mice. Human serous carcinomas are thought to arise from the ovarian surface epithelium, a derivative of the coelomic epithelium of the urogenital ridge, which invaginates to form the mullerian duct early in embryonic life. The neoplastic cells of serous tumors simulate morphologically the lining cells of the fallopian tube, which are derivatives of mullerian duct epithelium. This study provides physiologic confirmation of the mullerian nature of this type of tumor and suggests that MIS may ultimately prove to be effective in its therapy.

Prognostic implication of endometriosis in clear cell carcinoma of the ovary

OBJECTIVE The aim of this study is to investigate whether the presence of endometriosis is a prognostic factor in patients diagnosed with clear cell carcinoma (CCC) of the ovary. METHODS Retrospective chart review was performed to all patients diagnosed with CCC and endometriosis between 1975 and 2002. All pathology reports were reviewed and slides were reviewed when available. Cox regression analysis and Kaplan-Meier test were used to calculate survival prognostic factors. The level of significance was set at 0.05. RESULTS Eighty-four patients with CCC were identified with a 49% rate of coexisting endometriosis. Patients with tumors arising in endometriosis (n=15), with endometriosis found elsewhere in the specimen (n=26), and those without endometriosis (n=43) were analyzed comparatively. Patients with CCCs arising in endometriosis were 10 years younger (95% C.I. 0.6-18 years) than those with CCC not arising in endometriosis (P<0.05). Patients with endometriosis anywhere in the surgical specimen presented at early stage 66% of the times versus 42% for patients without endometriosis (P<0.05). Median overall survival (OS) for patients with endometriosis was 196 months (95% C.I. 28-363) versus 34 months (95% C.I. 13-55) for patients without endometriosis (P=0.01). Advanced tumor stage at diagnosis (HR 13, 95% C.I. 5-29, P=0.001) and absence of endometriosis (HR 2, 95% C.I. 1-3.9, P=0.03) were the only significant prognostic factors associated with poor survival. Disease recurrence or death among optimally and completely cytoreduced patients was 31% and 59% for those with and without endometriosis respectively (P>0.05). CONCLUSIONS Our study suggests that the presence of endometriosis in patients with CCC of the ovary is associated with progression free and OS advantages with no difference in initial resectability.

Müllerian-Inhibiting Substance: An Update

The decades long study of Mullerian Inhibiting Substance by numerous laboratories around the world has been driven, in large part, by pediatric surgeons and pediatric endocrinologists who have a keen interest in the molecular pathophysiology of genital tract defects that are visited upon their patients. A better understanding of the genes involved in the development of the normal reproductive tract in males and females should lead to a more rational analysis of the diseases caused by their abnormal function. Furthermore, a translation of this knowledge from the bench to the bedside may lead to clinically useful advances in the diagnosis and management of intersex patients. The molecular analyses of MIS and MIS receptor gene mutations and persistent Mullerian duct syndrome and the development of MIS ELISAs to evaluate testicular function as well as to follow the progress of gonadal tumors are several clear examples of successes over the years. It will be interesting to see what lies ahead.

Uterine Smooth-Muscle Tumors with Unusual Growth Patterns: Imaging with Pathologic Correlation

OBJECTIVE This essay illustrates the salient features of variant smooth-muscle tumors on multiple imaging techniques with correlative pathology. We describe how recognition of these features allows the radiologist to distinguish a uterine leiomyoma variant from the classic fibroid or a leiomyosarcoma. Finally, we highlight the role of the radiologist in triaging these patients to surgical versus medical management and in surgical planning. CONCLUSION Parasitic leiomyoma, intravenous leiomyomatosis, disseminated peritoneal leiomyomatosis, and benign metastasizing leiomyoma show key features on multiple imaging techniques that correlate with pathology findings. In the appropriate clinical setting, the radiologist should include these unusual lesions in the broader differential diagnosis of smooth-muscle tumors and, in certain cases, aid in surgical planning.

Mullerian inhibiting substance reduction of colony growth of human gynecologic cancers in a stem cell assay

Mullerian Inhibiting Substance (MIS), a fetal testicular product that causes regression of the Mullerian duct in the male mammalian embryo, was evaluated for its antitumor effect on the premise that a substance active against this genital precursor in the fetus might also be active against tumors derived from these tissues. Increasingly pure fractions of biologically active MIS, prepared from newborn calf testes, were tested in the soft agar colony inhibition assay against single cell suspensions of fresh tumors derived in ascitic or solid form from patients with gynecologic malignancies. Twenty-eight tumor specimens placed in soft agar culture have provided sufficient growth to assess an MIS effect. Twenty-five of these 28 tumors showed significant colony inhibition after incubation with MIS. Increased antitumor response correlated with increased purification of MIS when the same tumor was treated with preparations of different purity. Samples obtained from the same patient at different times, from both ascites and solid tumor sources, produced nearly identical responses to MIS. MIS preparations, previously shown to be active in microcytotoxicity and colony inhibition assays against established human ovarian and endometrial carcinoma lines demonstrate consistent antitumor activity against fresh human gynecologic cancers removed at surgery.

Prognostic variables in the treatment of squamous cell carcinoma of the vulva

Abstract Records of 98 patients undergoing surgery for squamous cell carcinoma of the vulva between 1960 and 1982 were analyzed to evaluate and develop treatment policy. There were 32, 34, 26, and 6 patients in FIGO stages I–IV, respectively. Eighty-six patients underwent radical vulvectomy, 8 patients underwent less extensive procedures, and 4 underwent more extensive procedures. Eighty-seven patients underwent inguinal node dissection, and 40 underwent pelvic node dissection as well. Eight patients received external beam irradiation. Actuarial 5-year survival was 57%. Age, tumor size, FIGO (clinical) stage, surgically determined T and N stages, tumor differentiation, lymph vessel invasion, extent of surgical procedure, and adjuvant irradiation were analyzed to determine their effects on local control, freedom from distant metastases, and survival, using single variable and multivariate analysis. Local control was significantly related to FIGO stage; freedom from distant metastasis was significantly related to surgical N stage, tumor size, and surgical T stage; survival was significantly related to surgical N stage, tumor size, surgical T stage, age, and lymph vessel invasion. Metastatic involvement of inguinal lymph nodes was significantly correlated with tumor size and differentiation. Of 87 evaluable patients, 33 had inguinal node involvement, and of these, 17 developed recurrent disease. All 7 patients with pelvic node metastases had positive inguinal nodes, and all died; the cause of death could be determined in 5, of whom 4 manifested distant metastases. Pelvic lymphadenectomy conferred no survival benefit in this series, even in the presence of positive inguinal nodes. Local vulvar recurrence is a significant problem in patients with positive inguinal nodes, and postoperative irradiation should be directed to this area in these patients. Patients with vulvar recurrences, esepcially those occurring at least 2 years after surgery, can be successfully salvaged, and should therefore be treated aggressively.

Müllerian Inhibiting Substance: Gene Structure and Mechanism of Action of a Fetal Regressor

Publisher Summary A lifelong interest in fetal inducers and inhibitors was awakened by the work of Grobstein (1967) and renewed by the elegant experiments of Alfred Jost (1946a,b, 1947) describing the function of a fetal inhibitor, Mullerian Inhibiting Substance (MIS), which caused the regression of the Mullerian duct, the anlagen of the uterus, fallopian tube, and vagina in mammalian males. The influence of this substance explained, at least partially, the clinical complex of the testicular feminization syndrome. Since Picon (1969) had developed an organ culture assay to identify this substance, MIS could be studied in vitro and potentially analyzed to shed some light on a potentially new class of compounds, fetal inhibitors. This chapter discusses the role of MIS in reproductive biology and meiosis inhibition as a function of MIS. The chapter also discusses the mechanisms of action of MIS including its role as an inhibitor of tyrosine kinase. It reviews the techniques used to isolate both the bovine and human gene and the strategies to achieve expression of biologically active human recombinant MIS.