Takashi Okagaki

Clinical-pathologic study of stage IIB, III, and IVA carcinoma of the cervix : extended diagnostic evaluation for paraaortic node metastasis : a gynecologic oncology group study*

Three hundred twenty patients were entered into GOG Protocol 63, a clinical-pathologic study of stage IIB, III, and IVA cervical carcinoma. Following the completion of FIGO staging prerequisites, patients had computerized tomography (CT), a lymph-angiogram (LAG), and an ultrasound (US) of the aortic area. If any study was positive, a cytologic or histologic evaluation by fine-needle aspiration or selective paraaortic lymphadenectomy was performed. Paraaortic node dissection was mandated for patients with negative extended staging studies. Results of extended staging evaluations were compared with histologic or cytologic results. Two hundred sixty-four patients were eligible and evaluable. One hundred sixty-seven patients (63%) were stage IIB, 89 (34%) were stage III, and 8 (3%) were stage IVA. Positive paraaortic nodes occurred in 21% of stage IIB, 31% of stage III, and 13% of stage IVA. LAG sensitivity was 79% with a specificity of 73%. Sensitivity of CT and US was 34 and 19%, respectively, with specificities of 96 and 99%, respectively. The frequency of false-negative results with LAG for patients with stage IIB disease was 6%. This decrease is consistent with a stable sensitivity and specificity. These findings suggest that a negative LAG may be adequate to eliminate surgical staging in subgroups with low risk of metastasis to the aortic nodes. Until new noninvasive testing methods are developed, LAG appears to be the most reliable noninvasive examination to evaluate spread of cervical cancer to aortic nodes.

Trophoblastic pseudotumor—Evidence of malignant disease potential

Abstract Trophoblastic pseudotumor, the histopathologic entity described by Kurman and associates (R. J. Kurman, R. E. Scully, and H. J. Norris, Cancer 38 , 1214–1226 (1976)), has been considered in the scheme of gestational trophoblastic neoplasia as an exaggerated form of syncytial endometritis and, therefore, associated with a benign outcome. The manifestation of malignant sequalae and ultimate demise of a patient in a recognized case of trophoblastic pseudotumor is presented. Light and electron microscopic studies and autopsy findings are discussed. Therapies, both surgical and chemotherapeutic, and serum assay of the β subunit of human chorionic gonadotropin are correlated to the clinical course.

Human genital papilloma infections: An evaluation of immunologic competence in the genital neoplasia-papilloma syndrome

Immunologic evaluations of women with genital neoplasia-papilloma syndrome demonstrated the presence of subclinical immunodeficiency when compared with results in 20 control women. All patients with genital neoplasia-papilloma syndrome were previously found to have human papillomavirus deoxyribonucleic acid in genital neoplasias or papillomas occurring either synchronously (in at least two genital organs at the same time) or metachronously (at different times during a period of months to years). Immunologic tests included blastogenic responses of lymphocytes to mitogens (phytohemagglutinin, concanavalin A, pokeweed mitogen, and tetanus antigen) and lymphocyte phenotyping with the use of monoclonal antibodies (OKT3, OKT4, OKT8, and OKT11). As compared with those of control subjects, the responses of the lymphocytes of patients with genital neoplasia-papilloma syndrome to mitogens were significantly decreased. The group with genital neoplasia-papilloma syndrome had a significantly higher percentage of suppressor-cytotoxic T cells (OKT8-positive cells) when compared with that of control subjects (mean 33% versus 18%) and a lower proportion of helper T cells (OKT4-positive cells) when compared with that of control subjects (35% versus 50%). The mean helper-to-suppressor/cytotoxic T-cell ratio (mean OKT4/OKT8 ratio) in the human papillomavirus-infected women was 1.72 +/- 0.29 (SE) as compared with 3.21 +/- 0.33 (SE) in the control group, demonstrating a significant reduction of the ratio in the patients with genital neoplasia-papilloma syndrome. These findings suggest that patients with genital neoplasia-papilloma syndrome have a reduced suppressor/cytotoxic T-cell ratio (mean OKT4/OKT8 ratio; that in the human papillomavirus-infected women was 1.72 +/- 0.29 (SE) as compared with 3.21 +/- 0.33 (SE) in the control group, demonstrating a significant reduction of the ratio in patients with genital neoplasia-papilloma syndrome. These findings suggest that patients with genital neoplasia-papilloma syndrome have reduced immunocompetence of unknown etiology.

Prognostic significance of the presence of human papillomavirus DNA in patients with invasive carcinoma of the cervix

Cases of invasive carcinoma of the uterine cervix were analyzed to determine whether the presence or absence of human papillomavirus (HPV) DNA in the neoplasms was a contributing factor to their outcome. The presence of HPV DNA was evaluated using in situ hybridization on formalin‐fixed, paraffin‐embedded tissue sections. Eighty‐five patients with cervical carcinoma who had been surgically evaluated were included in the study. Data from these patients was analyzed retrospectively to determine survival, recurrence, presence of nodal metastases, tumor grade, mode of therapy, peritoneal fluid cytologic results, and age in relation to presence or absence of HPV DNA. No significant statistical differences were found between the HPV‐16‐positive, HPV‐18‐positive, and HPV DNA‐negative patients.

Human papillomavirus DNA in adenocarcinoma in situ, microinvasive adenocarcinoma of the uterine cervix, and coexisting cervical squamous intraepithelial neoplasia.

Previously, human papillomavirus (HPV) DNA, mainly HPV-18 DNA, was detected in more than 40% (17/40 cases) of invasive adenocarcinoma of the uterine cervix in our laboratory. In order to identify HPV DNA in the precursor lesions of adenocarcinoma of the cervix, 11 cases of adenocarcinoma in situ containing microinvasive adenocarcinoma and 10 cases of adenocarcinoma in situ were studied for the presence of HPV DNA by in situ hybridization using highly sensitive 3H-labeled HPV-16 and HPV-18 DNA probes. HPV types present in cervical squamous intraepithelial neoplasia (CIN) coexisting with adenocarcinoma in situ and microinvasive adenocarcinoma were also studied. Apart from the coexisting CIN II-III with glandular neoplasms, 48 cases of CIN III (severe dysplasia and squamous carcinoma in situ) removed by conization or hysterectomy and known to be free of adenocarcinoma were used for comparison. HPV DNA was detected in 64% of microinvasive adenocarcinoma, 70% of adenocarcinoma in situ, and 63% of the control CIN III. HPV-18 DNA was the preponderant type of HPV DNA found in adenocarcinoma in situ and microinvasive adenocarcinoma. All cases of HPV DNA-positive microinvasive adenocarcinoma contained the same type of HPV DNA as the lesions of coexisting adenocarcinoma in situ. CIN coexisting with microinvasive adenocarcinoma or adenocarcinoma in situ contained the same type of HPV as identified in the glandular lesions, whereas all of the HPV DNA-positive control CIN III cases contained HPV-16 DNA. These results suggest that adenocarcinoma in situ is a precursor lesion of adenocarcinoma of the cervix that contains HPV DNA, and that CIN coexisting with adenocarcinoma may be a result of a metaplastic process of adenocarcinoma or of bidirectional differentiation of the affected reserve cells.

Primary carcinoid tumor of the testis: case report, ultrastructure and review of the literature.

A case of primary pure carcinoid tumor of the testis which occurred in a 71‐year‐old male is reported. The patient was treated by radical orchiectomy and remains well and symptom free 10 months after operation. Histologically as well as ultrastructurally the tumor showed typical appearances of carcinoid tumor of midgut derivation. 23 cases of carcinoid tumors of the testis were discovered in the literature. Of these 17 were primary testicular carcinoids, and 6 were metastatic to the testis. Of the 17 cases of primary carcinoid tumors, 14 were pure carcinoids and only 3 were associated with teratoma. None of the primary testicular carcinoids were associated with metastases and the prognosis after orchiectomy was excellent, thus indicating that no further therapy is necessary. The prognosis of patients with carcinoid metastatic to the testis is poor. In view of this it is very important to determine whether the tumor is primary or metastatic. Cancer 42:2696–2706, 1978.

Early invasive and in situ warty carcinoma of the valva: Clinical, histologic, and electron microscopic study with particular reference to viral association

Cases of carcinoma of the vulva with a warty appearance were reviewed. Altogether, 27 cases of warty carcinoma of the vulva were treated at the University of Minnesota Hospitals between 1976 and 1980, which accounted for 22.4% of all vulvar epithelial malignancies. As compared to the previous experience between 1951 and 1970, this relative frequency increased fourfold. Clinical history indicated that warty carcinoma of the vulva was not necessarily preceded by long lead periods of in situ lesions. The lesions seemed to occur in all ages after adolescence, were multifocal in one third of the cases, were frequently locally recurring, and were relatively benign despite their often large size. Many of them were originally diagnosed as condyloma acuminatum. Virus-like particles were seen in eight of the 12 cases (67%) examined with transmission electron microscopy, which included six cases of invasive lesions. These observations suggest that human papillomavirus (HPV) may be the important etiologic agent of this group of tumors. Warty carcinoma of the vulva must be clearly separated from conventional invasive squamous cell carcinoma of the vulva, as its clinical behavior and a possible etiology appear unique.

Adenosquamous carcinoma of skin appendages (adenoid squamous cell carcinoma, pseudoglandular squamous cell carcinoma, adenoacanthoma of sweat gland of lever) of the vulva. A clinical and ultrastructural study

History and clinical findings of 18 cases of adenosquamous carcinoma of the skin appendages found among 135 cases of primary carcinoma of the vulva seen at the University of Minnesota Hospitals between 1951 and 1970 were analyzed. In addition, two recent cases of this tumor were studied with conventional transmission electron microscopy. Adenosquamous carcinoma of the vulva showed poorer survival and a higher rate of lymph node metastases than squamous cell carcinoma of the corresponding stages (carcinoma in situ excluded). In four out of thirteen cases, the metastatic lesions in the lymph nodes retained glandular pattern. The ultrastructure showed mucin‐producing columnar cells lining glandular lumina, and poorly differentiated squamous cells elsewhere; further, cells of the intermediate type between the two were present. This study indicates that adenosquamous carcinoma of the vulva is a distinctively separate entity from squamous cell carcinoma of the vulva, and possibly arises from mucin‐producing cells of the skin appendages as suggested by Johnson and Helwig. Cancer 42:1851‐1858, 1978.

Adenocarcinoma of the endometrium with trophoblastic differentiation and metastases as choriocarcinoma: a case report

Nongestational choriocarcinoma is seldom observed outside of gonads or teratomas. No case of choriocarcinoma arising in endometrium is reported in the literature. Here we present a 70-year-old female with endometrial adenocarcinoma focally differentiating to choriocarcinoma, and metastasizing to liver, kidney, brain, and lung as pure choriocarcinoma. Foci of trophoblastic differentiation in the primary endometrial lesion and metastatic lesions are positive for hCG by immunocytochemical stain. This case is similar to gastrointestinal and lung carcinomas that contain trophoblastic change. Possible histogenesis of this tumor is discussed.

Therapeutic implications of the natural history of advanced cervical cancer as defined by pretreatment surgical staging

From 1978 to 1983, 112 women with advanced cervical carcinomas received radiotherapy after pretreatment surgical staging. Five‐year actuarial relapse‐free survival rates were a strong function of lymphatic spread: 40% with periaortic node metastases, 50% with pelvic node metastases, and 84% without node metastases. Primary treatment failure had a distant component in 75% of recurrences (50% of recurrences with negative nodes and 85% of recurrences with positive nodes). It was concluded that adjuvant systemic therapy is necessary to substantially raise the probability of cure.