Angiogenesis in endometrial carcinoma.

BACKGROUND: Tumor angiogenesis is essential for tumor growth and metastases. Recently, microvessel density (MVD), a measure of tumor angiogenesis, has been found to have prognostic significance for predicting metastasis and survival in many tumor types. This study was conducted to determine how MVD was related to several clinicopathologic parameters and correlated with metastasis and survival in patients with endometrial carcinoma. METHODS: From 1979 through 1989, 85 cases of clinical Stage I and II endometrial carcinomas treated initially by hysterectomy with pelvic lymph node dissection were reviewed histologically. All hysterectomy specimens were stained immunohistologically for factor VIII-related antigen. MVD was counted in a x200 field (x20 objective lens and x10 ocular lens, 0.785 mm2 per field) in the most active area of neovascularization. Results were expressed as the highest number of microvessels identified within any single x200 field. Statistical analysis included the Mann-Whitney U test, Kruskal-Wallis test of variance, and the Spearman rank correlation test. Survival was calculated using the Kaplan-Meier method and differences in survival were analyzed using the log rank test. MVD and several other prognostic parameters were examined for their correlation with progression free survival (PFS) and overall survival (OS) by a multivariate analysis according to the Cox proportional hazards model. RESULTS: MVD was significantly correlated with tumor grade (P = 0.0281), myometrial invasion (P = 0.0282), and lymph-vascular space invasion (P = 0.0073). There was no correlation between microvessel count and lymph node status and stage. Patients with a high MVD (> or =60) had significantly worse PFS and OS than those with a low MVD (<60) (log rank test, P = 0.0116 and P = 0.0096, respectively). Multivariate analysis showed that MVD correlated significantly and independently with PFS and OS. CONCLUSIONS: In this study, MVD was found to be an independent prognostic factor for PFS and OS in patients with endometrial carcinoma.

The significance of peritoneal cytology in uterine cervix and endometrial cancer.

OBJECTIVE: The purpose of this study was to determine the incidence of positive peritoneal cytology and to elucidate the prognostic value of peritoneal cytology in patients with uterine cervix and endometrial cancer. MATERIALS AND METHODS: The incidence of positive peritoneal cytology was investigated in 642 patients including 339 uterine cervix and 303 endometrial cancers. Survival was estimated by the Kaplan-Meier method in a subgroup of 116 stage II cervix and 199 stage I endometrial cancers, and multivariate analysis using Cox's proportional hazards model was used to identify an independent prognostic factor. RESULTS: The incidence of positive peritoneal cytology was found to be 9% in uterine cervix cancer and 15% in endometrial cancer. The incidence was higher in patients with some clinicopathologic status such as advanced stage, lymph node metastasis, ovarian metastasis, and deeper myometrial invasion. The 5-year survival rate for patients with positive or negative peritoneal cytology was 44 or 80% in stage II cervix cancers and 80 or 92% in clinical stage I endometrial cancers, respectively. Multivariate analysis revealed that independent prognostic determinants were pelvic and paraaortic lymph node metastasis and peritoneal cytology in stage II cervix cancer and peritoneal cytology in stage I endometrial cancer. Proper treatment protocol should be scheduled for patients with positive peritoneal cytology.

Childhood acute lymphoblastic leukemia relapse in the uterine cervix.

PURPOSE: Extramedullary relapse outside the testes and CNS is rare in children with acute lymphoblastic leukemia (ALL). We describe a case of a recurrence of ALL in the uterine cervix during hematopoietic remission. RESULTS: Primary recurrence in the uterine cervix was diagnosed by cytology with immunochemistry 43 months after initial diagnosis. She was successfully treated with systemic chemotherapy, without hysterectomy or irradiation. She remains in second complete remission 54 months after relapse. CONCLUSIONS: Immunocytochemistry using monoclonal antibodies against cell surface antigens made the cytologic diagnosis of leukemic relapse in the uterine cervix possible. Systemic chemotherapy is the first treatment of choice for ALL recurrence in the genital tract in a patient without poor prognostic factors in order to spare gonadal function and reproductive potential.

Endometrial carcinoma in women 65 years of age or older: a clinicopathologic study.

The purpose of this study is to clarify the clinical and pathologic features of endometrial carcinomas in women 65 years of age or older in Japan where the incidence of endometrial carcinoma is still low. Between 1979 and 1990, 24 of 164 patients with endometrial carcinoma were 65 years old or over. In addition, 41 patients 50 years of age or younger were also analyzed, comparing clinicopathologic features with those of older age group. Seventeen of 24 (71%) showed deep myometrial invasion (more than a half of the myometrium). Endometrial carcinomas in older age groups have deeper myometrial invasion, and higher histologic grade than those of younger age groups. The adjacent endometrium is usually atrophic and the presence of hyperplasia and/or metaplasia was significantly less frequent in the older group as compared with that in the younger group. Nine of these 24 patients died of disease in a relatively short follow-up period. The prognosis for the older group (expected 5-year survival 69.2%) is significantly worse than for the younger group (expected 5-year survival 94.3%) (P = 0.006). Endometrial carcinomas in patients over 65 years of age are usually of high histologic grade, and have deep myometrial invasion and an unfavorable prognosis.

Endometrial carcinoma associated with hyperplasia.

The aim of this study was to clarify the relationship of endometrial hyperplasia to endometrial carcinoma. From 1979 through 1990, 115 cases of stage I-IV endometrial carcinomas treated initially by hysterectomy were reviewed histologically. Forty-two of 115 (36.3%) patients had hyperplasia in the endometrium adjacent to the carcinoma. Women with both endometrial carcinoma and hyperplasia were significantly younger than those with carcinoma without hyperplasia (P < 0.05). In a comparison of patients with carcinoma without hyperplasia, those with hyperplasia were better differentiated (P = 0.0072), and lacked deep myometrial invasion (P < 0.0001), cervical involvement (P = 0.0192), lymph-vascular space invasion (P = 0.0102), and para-aortic lymph node metastases (P = 0.0434). The presence of endometrial metaplasia (P = 0.0001). The estimated 5-year survival rates for patients with carcinoma with hyperplasia and those with carcinoma without hyperplasia were 96.55 and 73.33%, respectively (P = 0.0016). In endometrial carcinomas, the presence of endometrial hyperplasia may demonstrate a more favorable prognosis.

Primary jejunal adenocarcinoma masquerading as a primary ovarian malignancy.

Primary adenocarcinoma of the jejunum which accounts for only approximately 3% of all gastrointestinal tract malignancies, is distinctly unusual. Ovarian metastasis from a jejunal cancer is extremely rare. It has significant therapeutic and prognostic implications to differentiate primary ovarian carcinoma from metastatic disease to the ovary. A 49-year-old Japanese woman presented with intermittent nausea, vomiting, and palpable abdominal mass. Pelvic examination and imaging studies revealed a huge ovarian tumor, suspicious for malignancy. Upper GI series and barium enema were unremarkable. Exploratory laparotomy was done for presumed primary ovarian malignancy. Mucinous adenocarcinoma of the right ovary, measuring 25 x 18 x 12 cm, without other intraabdominal dissemination was found. Exploration of the upper abdomen revealed an annular constriction of the jejunum 30 cm distal to the ligament of Treitz. Partial jejunectomy with end-to-end anastomosis was done. Metastatic ovarian cancer from the primary jejunal adenocarcinoma was confirmed microscopically. Although small bowel malignancy is uncommon, small bowel follow-through examination or enteroclysis may be indicated in patients with positive stool for occult blood who have no abnormality in the upper gastrointestinal series and barium enema. In addition to the imaging studies, thorough exploration of the entire abdominal cavity is necessary at ceiliotomy in patients with ovarian malignancy to distinguish primary ovarian cancer from metastatic disease to the ovary.

The prognostic significance of lymphovascular space invasion in endometrial cancer when conventional hemotoxylin and eosin staining is compared to immunohistochemical staining.

The current study was undertaken to compare the usefulness of hemotoxylin and eosin (H&E) staining and immunohistochemical staining to identify lymphovascular space invasion (LVSI) in endometrial cancer and to evaluate the presence of LVSI detected by either technique as an independent prognostic factor. Histologic sections from 92 patients with clinical stage I-II endometrial cancer were reviewed, and representative sections were stained immunohistochemically with antibodies for von Willebrand factor and blood group isoantigens. To compare the prognostic significance of LVSI detected by H&E staining with that detected by immunohistochemical staining, univariate and multivariate analyses were performed. Thirty (32.6%) of the 92 cases showed LVSI in H&E staining. In 8 of the 30 cases, LVSI was negative by immunohistochemical staining, while LVSI was positive by immunohistochemical stainings in 2 of 62 cases showing negative LVSI in H&E staining. In univariate analysis, LVSI detected by H&E and immunohistochemical staining was proved to be significant as a prognostic factor. In multivariate analysis by Cox's proportional hazards model, LVSI identified by H&E staining was selected as one of significant prognostic factors, but LVSI identified by immunohistochemical staining not selected. The results of this study indicate that LVSI is one of the independent prognostic factors in endometrial cancer, and that LVSI as detected by H&E is more prognostic of survival than immunohistochemical detection.

Reassessment of myometrial invasion in endometrial carcinoma.

OBJECTIVE: To assess different methods of measuring the depth of myometrial invasion in endometrial carcinoma as a prognostic factor. METHODS: Eighty-eight cases of stage I or II endometrial carcinoma treated initially by hysterectomy between 1979-1989 were reviewed histologically. Three methods of measuring myometrial invasion were evaluated: 1) percentage of invaded tumor thickness to whole thickness of myometrium, 2) percentage of whole tumor thickness to total thickness of tumor and myometrium, and 3) distance from the tumor-myometrial junction to the uterine serosa. We evaluated the effect of several factors on prognosis by multivariate analysis using Cox regression models. RESULTS: Myometrial invasion determined by these three measurement methods was associated significantly with survival in a univariate analysis. When myometrial invasion assessed by each method and other prognostic factors were entered into a multivariate model, the distance from the tumor-myometrial junction to the uterine serosa, lymph-vascular space invasion, and cervical stromal involvement were identified as independently significant prognostic factors. CONCLUSION: This method of evaluating myometrial invasion by measuring the distance from the tumor-myometrial junction to the uterine serosa was most useful as a correlate with survival.

Adenoma malignum of the uterine cervix detected by imaging methods in a patient with Peutz-Jeghers syndrome.

Adenoma malignum of the uterine cervix in a 25-year-old Japanese woman with Peutz-Jeghers syndrome (PJS) is described. A cervical multicystic mass was detected by CT scan, sonography, and MR imaging. These imaging findings strongly suggested the presence of adenoma malignum in spite of normal Pap smear, colposcopy, and cervical biopsy reports. Radical hysterectomy, bilateral salpingo-oophorectomy, pelvic lymphadenectomy, and para-aortic lymph node biopsy were performed after confirmation of adenoma malignum by conization. Both ovaries showed multicentric sex cord tumor with annular tubules. She is alive and well with no evidence of disease 23 months after surgery. Imaging methods including sonography, CT scan, and MR imaging may be useful aids in detecting the presence of adenoma malignum, especially in patients with PJS.

Association of endometrial epithelial metaplasias with endometrial carcinoma and hyperplasia in Japanese and American women.

We reviewed endometrial tissue from 166 cases of endometrial adenocarcinoma and hyperplasia--91 seen at Kyushu University, Fukuoka, Japan, and 75 at George Washington University, Washington, D.C., U.S.A.--to compare the prevalence of epithelial metaplastic changes in the two populations. Metaplasias were more common in the benign endometrium associated with carcinoma at George Washington University (78%) than at Kyushu University (54%). They were associated with carcinomas of lower grade and accompanied by hyperplasia at both institutions. These results indicate that endometrial metaplasias, like endometrial hyperplasias, tend to be associated with less virulent endometrial carcinomas and to be more common in American women (who represent a high-risk population for endometrial carcinoma) than in Japanese women (in whom the risk is low but rising.

Ovarian mucinous cystadenocarcinoma with sarcoma-appearing mural nodule of anaplastic carcinoma.

An ovarian mucinous cystadenocarcinoma with sarcoma-appearing solid mural nodules in an 18-year-old Japanese woman is reported. Right ovarian cyst had two poorly circumscribed, solid nodules and several tiny studs. Microscopically, the epithelial elements consisted of benign, low malignant potential and malignant mucinous tumors. The mural nodules were made up of highly malignant anaplastic cells simulating sarcoma. In one of the mural nodules, continuity between the malignant mucinous cells and sarcoma-appearing cells was identified. Immunohistochemically, the sarcoma-appearing nodule was uniformly positive for vimentin and focally positive for epithelial markers such as EMA, CAM5.2, and AE1/AE3. This case demonstrated an orderly transformation and dedifferentiation of epithelial cells to undifferentiated mesenchymal cells. Although she had stage IIb disease, she lived disease free for 3 years and 5 months after surgery followed by 10 courses of chemotherapy containing cisplatin and Adriamycin.

Histopathologic prognostic factors in stage IIb cervical carcinoma treated with radical hysterectomy and pelvic-node dissection - an analysis with mathematical statistics.

Of 107 patients with stage IIb cervical cancer who underwent laparotomy, 82 (77%) could be treated with radical hysterectomy (RAH) and pelvic-node dissection (PND). The remaining 25 patients were unsuitable for radical surgery because of para-aortic lymph node metastases, direct cancer invasion into the bladder muscle, and/or fixed enlarged pelvic lymph nodes (PLN): Such patients were treated with radiation therapy after laparotomy. Fifty-nine of RAH patients were given postoperative pelvic radiation because they had PLN metastases, parametrial invasion, and/or full thickness cervical stromal invasion. The overall 5-year survival of the patients undergoing RAH was significantly better than that of those who could not be treated with RAH (P < 0.001). In the RAH patients, parametrial invasion, which clinically defines stage IIb, was found only in 45%. Univariate analysis of histopathologic prognostic factors revealed that PLN metastasis, parametrial invasion, adenocarcinoma, and lymph-vascular space invasion significantly affected survival of the RAH patients (P < 0.05). Multivariate analysis using Cox's proportional hazards regression model, however, selected only PLN metastasis as a strong prognostic factor (P < 0.001). Concerning PLN metastasis patients with two or more positive nodal groups vs. 49%, P < 0.0001). The logistic regression analysis revealed that tumor diameter, parametrial invasion and lymph-vascular space invasion were independently correlated with PLN metastases in two or more nodal groups. The present data suggest that (i) the patients with massive pelvic extension of cancer cannot be cured by radiation therapy alone, (ii) the strong determinant of the prognosis of the patients undergoing RAH and PND is PLN metastasis. Therefore, for these patients with poor prognosic factors, other treatment modalities should be considered. From the present study it seems that planning RAH and PND for patients with stage IIb disease might make it possible to select poor prognostic subgroups, who have extra cervical extension or PLN metastases in two or more groups, and be useful in individualizing treatment.

Endometrial carcinoma in women aged 40 years or younger: a Japanese experience.

We report on the clinical and pathologic findings in 17 cases of endometrial carcinoma in Japanese women aged 40 years or younger. Age of the patients ranged from 16 to 40 years, with a median of 35 years. Nine of 17 tumors (52.9%) were stage I or II (FIGO 1988) but 8 (47.1%) were stage III. Four of the 8 patients with stage III disease had pelvic lymph node metastases and one also had para-aortic lymph node metastasis. One patient had metastasis to the ovary and peritoneal cytology was positive in 4 patients. Histologically, 13 of these 17 patients had endometrioid adenocarcinoma, 3 had adenoacanthoma and 1 had an undifferentiated carcinoma. Ten were well differentiated tumors (G1), 3 were moderately differentiated tumors (G2), and 4 were poorly differentiated tumors (G3). Nine of 17 (52.9%) showed deep myometrial invasion (more than a half of the myometrium) and 5 of 17 (29.4%) demonstrated lymphatic/vascular space invasion. Pelvic and para-aortic lymph node metastases were seen in 4 of 15 (26.7%) and 1 of 15 (6.7%), respectively. Two of these 17 patients died of disease in a relatively short follow-up period. In our experience there is no difference in the survival rates between patients aged 40 years or younger and those over 40 years.

Relationship between paraaortic lymph node involvement and intraperitoneal spread in patients with ovarian cancer--a multivariate analysis.

In 125 patients with epithelial ovarian cancer (FIGO stages I-IV), 32 (26%) had paraaortic lymph node (PAN) metastases. The estimated 5-year survival rate of PAN-negative patients was 71%, while that of PAN-positive patients was 17% (P < 0.0001). Positive rates of PAN metastasis at each stage level, based only on intraperitoneal spread of the disease, were 2% for stage I, 9% for stage II, 43% for stage III, and 87% for stage IV. According to univariate analysis, histological grade, and all disease site parameters examined, such as subdiaphragmatic surface, liver and spleen capsule, intestines and mesentery, omentum, pelvic peritoneum, sigmoid colon and rectum, uterus and tubes, and peritoneal cytology, showed a statistically significant correlation to the presence of PAN metastasis. Multivariate analysis using the logistic regression model revealed that the omental involvement, uterine and tubal involvement, and histological grade were independently correlated with PAN metastasis. The relative risk of PAN metastasis in the patients with these three factors is 18.5 times higher than that in patients without these factors. The present data suggested that, for the disease with omental and/or uterine and tubal involvement, surgical evaluation of PAN is mandatory in order to perform correct FIGO staging.

Expression of alpha-smooth muscle actin in benign or malignant ovarian tumors.

We compared the expression of alpha-smooth muscle actin (alpha-SMA) between benign and malignant human ovarian tissues by immunohistochemical staining and Western blot analysis using the monoclonal antibody specific to alpha-SMA. In normal human ovaries, alpha-SMA was found in the blood vessel walls, muscle fibers, and stromal cells surrounding the follicles. The main source of alpha-SMA in the benign ovarian tumors was the blood vessel walls which highly expressed the alpha-SMA throughout the tumor. In malignant tumor tissues, however, the vessels located in or close to the cluster of cancer cells did not express alpha-SMA. It corresponded to the results of the Western blot analysis, showing that the amount of alpha-SMA in malignant ovarian tumor tissues was much smaller than that in benign tumor tissues. Thus, the alteration in alpha-SMA expression seems to reflect the qualitative difference in vessels between benign and malignant ovarian tissues, and therefore alpha-SMA is considered to potentially be a histopathologically useful marker for indicating the malignant potential of ovarian tumors.

Uterine leiomyoma: correlation between signal intensity on magnetic resonance imaging and pathologic characteristics.

To correlate the signal intensity of uterine leiomyoma with its pathologic characteristics, with particular emphasis on the fibrous component, 33 magnetic resonance (MR) examinations that revealed 93 leiomyomas were prospectively studied. All patients were imaged in axial and sagittal planes with different spin-echo pulse sequences to obtain T1-, T2-weighted, and proton density images. Nondegenerative leiomyomas (n = 62) showing a homogeneous signal of low intensity, and degenerative leiomyomas (n = 31) with a heterogeneous signal of variable intensity on T2-weighted images could be correlated. Histopathological assessment of fiber constitution and degeneration, and MR intensity were interpreted by independent observers. There was excellent accord between the averages for MR intensity, T2 relaxation time and fiber content, although the intensity values in each fiber grade showed a wide range. The greater the fiber content the lower the MR intensity on T2-weighted images, and the shorter the T2 relaxation time (p < 0.0001). In addition, the manner in which fiber distribution affected MR appearance was also elucidated. These data contribute guidelines for precise tissue differentiation of myogenic tumors on MR images, and for MR imaging tissue diagnosis of any lesion with a considerable fibrous element.

Endometrial metaplasia associated with endometrial carcinoma.

OBJECTIVE: To clarify the relationship of metaplasia to endometrial carcinoma. METHODS: Between 1984-1990, 73 cases of stage I-II endometrial carcinoma treated initially by hysterectomy were reviewed histologically. The metaplasias were classified as squamous, syncytial papillary, ciliated-cell, eosinophilic, mucinous, clear-cell, or hobnail. We assessed the histologic type and grade of the carcinoma, depth of myometrial invasion, presence or absence of lymph-vascular space invasion, and presence or absence of lymph node metastases. RESULTS: Forty of 73 patients (55%) had one or more areas of metaplasia in the endometrium adjacent to the carcinoma. Ciliated-cell metaplasia (28 of 73; 38%) was the most common type encountered. Women with both endometrial carcinoma and metaplasia were significantly younger than those with carcinoma without metaplasia (P < .05). Compared with carcinomas without metaplasia, those with metaplasia were well differentiated (P < .01) and lacked myometrial invasion (P < .01) and pelvic lymph node metastases (P < .05). The presence of metaplasia was also significantly correlated with the presence of endometrial hyperplasia (P < .01). CONCLUSION: In endometrial carcinomas, the presence of endometrial metaplasia suggests a favorable prognosis.

Multivariate analysis of the histopathologic prognostic factors of cervical cancer in patients undergoing radical hysterectomy.

Three hundred forty-five patients with invasive carcinoma of the uterine cervix, Stages Ib (211 patients) and II (134 patients), underwent radical hysterectomy and pelvic lymphadenectomy. The influence of histologic factors including histologic subtype, maximum depth of cervical stromal invasion, degree of stromal invasion, longitudinal tumor diameter, lymph-vascular space invasion, corpus invasion, parametrial invasion, vaginal invasion, and pelvic lymph node (PLN) metastases on survival were examined by multivariate analysis. Univariate analysis revealed that all the variables except corpus invasion and vaginal invasion were significant in survival (P less than 0.05). Among these variables, however, PLN metastases, histologic subtype, and longitudinal tumor diameter were identified as independent and significant prognostic factors by multivariate analysis using Cox regression models. The prognostic index (PI), defined by the model (an indicator of the patient's place in the prognostic spectrum), was able to divide the patients into three prognostic groups. The key factors in the definition of these groups were (1) squamous cell carcinoma, small tumor diameter, and no PLN metastases for the good prognostic group and (2) PLN metastasis in two or more node groups, adenocarcinoma with one positive PLN group, or squamous cell carcinoma with one PLN group and large diameter for the poor prognostic group. These prognostic findings could predict the prognosis more precisely than that of clinical staging.

[A case of recurrent endometrial cancer successfully treated with oral administration of etoposide].

A 61-year-old female with recurrent endometrial cancer (serous papillary adenocarcinoma) was treated with etoposide because the pelvic tumor progressively increased in size with external beam irradiation. The etoposide (25 mg/day) was given orally for 10 days; the tumor decreased in size. And after an additional two courses of etoposide for 8 and 4 days, respectively, the tumor disappeared and the serum CA 125 level came to within normal limits. Because of moderate nausea and vomiting the etoposide could not be given for 14 days in the first 3 courses. Myelosuppression was not evident. Ten courses of etoposide (for 14 consecutive days a month) were followed without gastro-intestinal side effects, and the patient is alive with no evidence of recurrence at this writing. This case suggests that oral administration of etoposide may be effective for a patient with recurrent endometrial cancer, and this treatment could be administered on an outpatient basis.

Squamous cell carcinoma arising in a cystic teratoma presenting as a vulvar mass.

A case of squamous cell carcinoma arising in a cystic teratoma presenting as a vulvar mass is reported. This appears to be the first report of such a case.