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Cell cycle regulatory protein expression by immunohistochemical assay may have diagnostic utility in the distinction of uterine leiomyosarcoma from leiomyoma variants. p16, p21, p27, and p53 protein expression was evaluated by immunohistochemistry on 44 atypical leiomyomas (mean follow-up, 50.8 mo), 16 leiomyosarcomas (mean follow-up, 29.7 mo), and 8 cellular leiomyomas (mean follow-up, 22.6 mo). Nuclear staining was semiquantitatively scored on 1 representative section per case as negative (0%), focal (0% to 33%), patchy (33% to 66%), or diffuse (66%). In addition, staining intensity was noted as weak, moderate, or strong. Proliferative index was gauged by Ki-67 and PHH3 immunohistochemical staining. One of 35 atypical leiomyoma patients with follow-up data developed an extrauterine recurrence 25.7 months after hysterectomy, whereas a second had intrauterine recurrence 24.9 months after myomectomy. Seven of 8 patients with leiomyosarcoma with follow-up had recurrence within the follow-up period, whereas there were no recurrences in patients with cellular leiomyoma. The Ki-67 proliferation index ranged from 0% to 25% in atypical leiomyoma (mean, 2%) and 6% to 50% in leiomyosarcoma (mean, 25%) with 0% to 10% in cellular leiomyoma (mean, 3%), whereas the PHH3 proliferation index ranged from 0% to 3% in atypical leiomyoma (mean,1%) and 0% to 10% in leiomyosarcoma (mean, 2%) with 0% to 2% in cellular leiomyoma (mean,1%). The atypical leiomyoma with extrauterine recurrence was diffusely positive for p21, but showed only weak focal (33%) staining for all other cell cycle markers. Uterine atypical leiomyomas, cellular leiomyomas, and leiomyosarcomas demonstrate a heterogenous pattern of cell cycle regulatory protein expression. Caution should be exercised in distinguishing leiomyosarcoma from atypical leiomyoma variants on the basis of cell cycle protein expression alone. In our study, cell cycle markers were not useful for predicting recurrence in atypical leiomyoma.

Atypical leiomyoma is a well-described smooth muscle neoplasm of the uterus. Only 1 study has addressed long-term clinical follow-up in a large series, and little is known about the adequacy of treatment by myomectomy. The surgical pathology archives were searched for consecutive cases of uterine atypical leiomyoma from 1992 to 2003. Glass slides were reviewed to confirm the diagnoses, and patient age, treatment modality, and clinical follow-up data were recorded. Fifty-one atypical leiomyomas with available glass slides and clinical follow-up data were identified. Thirty tumors exhibited diffuse, moderately to severely atypical cells, whereas 21 showed atypical cells in a more focal or patchy distribution. Twelve had ischemic-type necrosis. By the highest count method, 37 cases were found to have ≤1 MF/10 HPF, 13 showed 1 to 3 MF/10 HPF, and 1 was nearly entirely necrotic precluding mitotic assessment. Among cases in which adjacent non-neoplastic tissue was well visualized, all were found to have pushing margins (46 cases). The average tumor size was 6.8 cm (median 6.5 cm; range, 0.7 to 14 cm). The average patient age was 42.5 years (median 42 y; range, 21 to 72 y). In all cases, the initial diagnostic procedure was hysterectomy (34) or myomectomy (17). Average follow-up was 42 months (range, 0.3 to 121.8 mo). Of those treated with hysterectomy, 1 had recurrent atypical leiomyoma in the retroperitoneum at 87.5 months, 1 died of other causes, and the remaining 32 (94%) were free of disease. Of the myomectomy group, 82% had no evidence of recurrent disease on follow-up: 2 had residual atypical leiomyoma in the subsequent hysterectomy specimen; and 1 underwent second myomectomy for atypical leiomyoma with 2 subsequent successful pregnancies. Atypical leiomyoma has a low rate of extrauterine, intra-abdominal recurrence (

The natural history, classification, and nomenclature of ovarian serous tumors of low malignant potential (S-LMP) (serous tumors of borderline malignancy, atypical proliferating tumors) are controversial. To determine long-term outcome for patients with S-LMP and further evaluate whether S-LMP can be stratified into clinically benign and malignant groups, the clinicopathologic features of 276 patients with S-LMP andor =5 year follow-up were studied. The histology of the ovarian primary, extraovarian implants, and recurrent tumor(s) were characterized using World Health Organization criteria and correlated with FIGO stage and clinical follow-up. After censoring nontumor deaths, overall survival and disease-free survival for the 276 patients was 95% (98% FIGO stage I; 91% FIGO II-IV) and 78% (87% FIGO stage I; 65% FIGO stage II-IV), respectively. Unresectable disease (P0.001) and invasive implants (P0.001) were associated with decreased survival. When compared with typical S-LMP, S-LMP with micropapillary features were more strongly associated with invasive implants (P0.008) and decreased overall survival (P = 0.004), but patient outcome with micropapillary S-LMP was not independent of implant type. Stromal microinvasion in the primary tumor was also correlated with adverse outcome, independent of stage of disease, micropapillary architecture, and implant type (P = 0.03). There was no association between outcome and lymph node status. Transformation to low-grade serous carcinoma occurred in 6.8% of patients at intervals of 7 to 288 months (58%or = 60 months) and was strongly associated with increased tempo of disease and decreased survival (P0.001). S-LMP forms a heterogeneous group, morphologically and clinically distinct from benign serous tumors and serous carcinoma. The majority of S-LMP are clinically benign, but recurrences are not uncommon, and persistent disease as well as deaths occur. Progression to low-grade serous carcinoma is highly predictive of more aggressive disease. Other features associated with recurrent and/or progressive disease include FIGO stage, invasive implants, microinvasion in the primary tumor, and micropapillary architecture. These predictors tend to co-occur, and no single clinical or pathologic feature or combination of features identify all adverse outcomes. The small, but significant risk of progression over time to low-grade serous carcinoma emphasizes the need for prolonged follow-up in patients with S-LMP.

A recent trend in the classification of uterine smooth muscle neoplasms (USMNs) into clinically benign and clinically malignant groups has been to move from exclusive reliance upon mitotic index (MI) to an approach that incorporates additional histopathologic characteristics. In furtherance of this goal, we assessed a variety of histopathologic features of 213 problematic smooth muscle neoplasms for which we had > or = 2 years of clinical follow-up data or for which there was an unfavorable outcome. One hundred and thirteen of these patients have had a minimum follow-up of 5 years, and 48 have been followed for > or = 10 years. Cases eliminated from the study group included USMNs with a significant myxoid or epithelioid component and cases of intravenous leiomyomatosis. USMNs, whether cellular or not, with no cytologic atypia and with a mitotic index (MI = number of mitotic figures [mf]/10 high-power fields [hpf]) of or = 10 mf/10 hpf, four of 10 failed.(ABSTRACT TRUNCATED AT 400 WORDS)

We present the results of a clinicopathologic study of 20 patients with primary extrauterine endometrial stromal sarcoma (ESS). The sites of the primary neoplasm and the number of patients with sufficient follow-up for survival analysis are as follows: ovary (three of four), fallopian tube (one of one), pelvic cavity (six of eight), abdominal cavity (five of six), and retroperitoneum (one of one). Evaluation of all patients included the mitotic index (MI) and cytologic atypia. Thirteen of the sixteen patients eligible for survival analysis had tumors with an MI < 10 and would be classified as low-grade stromal sarcomas in the Norris and Taylor scheme. Eight (62%) of the 13 had one or more relapses; of these, three died of disease at 35, 108, and 120 months, respectively, and another patient was alive with disease at 96 months. The other four patients who were treated after a relapse showed no evidence of disease after relapse at 36, 57, 63, and 146 months, respectively. Two of the 13 patients had tumor considered unresectable at the time of diagnosis; both died of disease at 5 and 10 months, respectively. Neither MI nor cytologic atypia were predictive of tumor recurrence or death from tumor. We also extracted clinical and morphologic data from all previous reports of primary extrauterine ESS, combined them with our 20 patients, and then compared the combined group with 17 cases of primary high-stage uterine ESS we presented in an earlier report. Not surprisingly, the behavior of the primary extrauterine ESS was more reminiscent of high-stage primary uterine ESS than low-stage primary uterine ESS.

Although the categorization of proliferative breast lesions provides valuable information regarding subsequent risk of breast cancer, the ability of pathologists to classify such lesions in a reproducible fashion has not been adequately evaluated. To assess further interobserver reproducibility in the categorization of proliferative breast lesions, six pathologists each reviewed 24 proliferative ductal lesions and classified them as either usual hyperplasia (H), atypical hyperplasia (AH), or carcinoma in situ (CIS). Before evaluation of the study slides, all the participants were instructed to use the diagnostic criteria of Page and co-workers and were provided with both a written summary of these criteria and a set of teaching slides with representative examples of each type of lesion. Complete agreement among all six pathologists was seen in 14 cases (58%); five or more agreed in 17 cases (71%); and four or more arrived at the same diagnosis in 22 cases (92%). No pathologist consistently rendered more "benign" or "malignant" diagnoses than any other. After assigning numerical values for each diagnostic category (H = 1, AH = 2, CIS = 3), the scores for the group of 24 cases did not differ significantly by pathologist (p = 0.68; average score range, 1.7-2.0). Our results indicate that with the use of standardized criteria, interobserver concordance in the diagnosis of proliferative ductal breast lesions can be obtained in the majority of cases.

Background Post-radiotherapy atypical vascular lesions (AVL) in mammary skin show significant clinical and histopathologic overlap with well-differentiated angiosarcoma (AS) and pose a considerable diagnostic and managerial challenge when encountered. Objective We review Stanford's experience with diagnosing AVL and formulate a clinicopathologic approach to these lesions. Methods We performed a clinicopathologic study on 11 cases that were initially diagnosed as AVL and examined whether there are specific clinical or histopathologic features that delineate AVLs from well-differentiated AS. Results Clinically, all patients were women with a mean age of 68.1 years, had a history of infiltrating breast carcinoma, and were treated by excision with postoperative radiation therapy. All lesions were located in mammary skin within the prior radiation field. The clinical presentation included erythema, telangiectasias, papules, plaques, and nodules. All patients were diagnosed with AVL on initial biopsy. Six patients showed no recurrence or progression of disease following incomplete excision with no further therapy (3/6) or re-excision with negative margins (3/6). The remaining 5 patients were shown to have AS in the re-excision specimen. The patients diagnosed with AS were older and had a shorter interval from radiation as compared to those who did not experience an adverse outcome. Histologically, all initial biopsy specimens were transected and were characterized by complex, anastomosing vascular proliferations with dilated spaces. Each case was morphologically evaluated according to the AVL criteria of Fineberg and Rosen. Three cases met all of the criteria for AVL, and these patients showed no progression of disease. The remaining cases met most but not all diagnostic criteria for AVL and showed some features of AS, but fell short of a definitive diagnosis of AS, including the 5 cases that were subsequently diagnosed as angiosarcoma. Limitations This retrospective study utilized a small number of cases from a single consultation service; therefore, some inherent selection bias may exist. Conclusion We could not identify unequivocal clinical or histologic criteria that allows for a sharp separation between AVL and AS. Dermatologists and pathologists need to be aware of the overlap between AVL and well-differentiated AS and all patients who receive a diagnosis of AVL should undergo complete excision with close clinical follow-up and biopsy of any new lesions.

Objective The purpose of this multicenter, double-blind, randomized, parallel-group study was to determine the effect of thirteen 28-day cycles of drospirenone combined with estradiol, compared with estradiol alone, on the endometrium of postmenopausal women. Design Postmenopausal women not on hormone therapy but with an intact uterus were enrolled (N = 1,147); 1,142 were evaluated. Participants were randomly assigned to treatment with 1.0 mg of estradiol alone (E(2) monotherapy) or 1.0 mg of estradiol plus 0.5, 1.0, 2.0, or 3.0 mg of drospirenone (DRSP/E(2)). Endometrial biopsies were performed at baseline, at 7 months if indicated, and at study end in the 13th month. Safety was evaluated with peripheral blood samples for hematology, liver and renal function, and lipids, along with vital signs and interval medical evaluations. Results When compared with estradiol alone, combinations of drospirenone and estradiol were effective in protecting against endometrial hyperplasia. The probability of hyperplasia was 0.060 (95% CI, 0.043-0.078) for the E(2) monotherapy group, 0.007 for the 2-mg DRSP/E(2) group, and nonsignificant for the remaining drospirenone/estradiol groups. Endometrial bleeding decreased in all treatment groups over time. The combination of drospirenone and E(2) relieved menopausal symptoms and resulted in improvements in health-related quality-of-life measures. There were no significant adverse events, and effects on triglycerides, total cholesterol, and high-density lipoprotein cholesterol were positive. Conclusions The use of drospirenone combined with estradiol provides protection against endometrial hyperplasia, reduces endometrial bleeding with time, and relieves menopausal symptoms. There were no safety issues and blood pressure was reduced in women with hypertension.

The family of lesions thought to be composed at least in part of perivascular epithelioid cells, characterized as HMB-45-positive epithelioid cells with clear to eosinophilic granular cytoplasm and a propensity for a perivascular distribution, includes some forms of angiomyolipoma and lymphangioleiomyomatosis, as well as clear cell "sugar" tumor (CC-SUGAR). When composed predominantly or exclusively of epithelioid cells, it has been suggested that these lesions be classified as "perivascular epithelioid cell tumors" (PEComa). Four cases of uterine PEComa have been described in the literature, three of which exhibited aggressive behavior. We report the clinical, histologic, and immunohistochemical features of eight more examples of uterine PEComa. Patients ranged in age from 40 to 75 years (mean 54 years). Most patients presented because of abnormal uterine bleeding, and grossly a mass was present in the uterine corpus. Morphologically, the tumors could be divided into two groups (A and B). Group A tumors demonstrated a tongue-like growth pattern similar to that seen in low-grade endometrial stromal sarcoma and were composed of cells that tended to have abundant clear to eosinophilic pale granular cytoplasm, diffuse HMB-45 expression, and focal muscle marker expression. Group B tumors were composed of epithelioid cells with less prominent clear cell features, smaller numbers of which were HMB-45-positive. They also featured extensive muscle marker expression and a lesser degree of the endometrial stromal sarcoma growth pattern seen in group A tumors. Two of the four patients with group B tumors had pelvic lymph nodes involved by lymphangioleiomyomatosis, and one of these patients had the tuberous sclerosis complex. Seven of the eight patients with PEComas were treated by hysterectomy. All eight patients are alive and well, although follow-up of >2 years was available only for two patients. Uterine epithelioid smooth muscle tumors and low-grade endometrial stromal sarcomas were compared with the PEComas. Group A PEComas, group B PEComas, and epithelioid smooth muscle tumors were all parts of a continuous histologic spectrum, with group A PEComa at one end of the spectrum and epithelioid smooth muscle tumors at the other, while group B tumors shared features of both. PEComa was histologically and immunohistochemically distinct from endometrial stromal sarcoma. Our data and a review of the literature indicate that PEComa is a subset of HMB-45-positive epithelioid mesenchymal tumors of the uterus with an uncertain relationship to pure smooth muscle tumors. Although none of the patients in this study experienced recurrence during a short follow-up period, some reported in the literature have had recurrences; consequently, we think uterine PEComa should be considered a tumor of uncertain malignant potential until long-term outcome data for a larger number of patients become available.

The clinicopathologic, immunohistochemical, and flow cytometric characteristics of 34 cases of mammary carcinoma with metaplasia were compared with those of 20 cases of pure sarcoma of the breast. All 20 of the latter tumors showed the pattern of malignant fibrous histiocytoma. There were 20 cases of carcinoma with mesenchymal metaplasia, 7 cases of carcinoma with mixed epithelial (squamous) and mesenchymal metaplasia, and 7 cases of carcinoma with epithelial metaplasia (four mixed ductal/squamous and three pure squamous cell carcinomas). No patient with pure sarcoma had lymph node metastases develop; all nodal metastases were found in patients who had carcinoma with metaplasia, although in one case the carcinomatous component was seen only within a lymph node metastasis. Epithelial antigens were found not only within the epithelial elements of all cases of carcinoma, but also within the apparent mesenchymal elements of 44% of the carcinomas showing divergent differentiation. Flow cytometric analysis of eight cases of carcinoma with mesenchymal metaplasia showed aneuploidy/tetraploidy in six neoplasms. For patient management purposes, the distinction of pure sarcoma from carcinoma with metaplasia is important, but additional subclassification of carcinoma with metaplasia is of greater biologic than clinical interest.

We have presented an unusual case of chondroblastoma mimicking a malignant tumor. Retrospective review of radiographs obtained 19 years before the diagnosis gave us a unique opportunity to follow the natural history of this atypical lesion.

We present the results of a clinicopathologic study of 109 patients with endometrial stromal sarcoma and eight patients with endometrial stromal nodule. Of the 109 patients with endometrial stromal sarcoma, follow-up was obtained on 93 (85%). The stage distribution of the patients with stromal sarcoma and the number of patients with follow-up (numerator) compared to the total number of patients in each stage (denominator) are: Stage 1, 73/85; Stage II, 3/6; Stage III, 11/11; Stage IV, 6/7. Stage II patients are considered separately in the analysis. Thirty-six percent of the Stage I patients experienced one or more relapses. Of these, six (23%) died of disease from 11 to 360 months from diagnosis (median, 79 months). Nine (35%) were alive with disease. Of the eleven Stage III patients, eight had one or more relapses and of these, six died of disease. Of the six Stage IV patients, five had one or more relapses and of these, three died of disease. The outcome differences between Stages I, III, and IV are statistically significant (p less than .01). Microscopic features evaluated included the mitotic index (MI = number of mitoses/10 high-power fields) and cytologic atypia. Forty-five percent of Stage I patients who had both rare mitotic figures and minimal atypia had one or more relapses and of these, two (13%) died of disease at 85 and 360 months, respectively. Thus, neither MI nor cytologic atypia were predictive of tumor recurrence for patients with Stage I tumors.

During an investigation of soft tissue fibrohistiocytic tumors, seven cases were found which we believe represent a new and specific diagnostic subgroup of the fibrous histiocytomas. All patients were adults (mean 52.6 years), only one of whom was younger than age 40. There were four females and three males; all were Caucasian. The tumors, which occurred in the retroperitoneum, anterior chest wall, anterior abdominal wall, femoral area, and oral cavity, were large, averaging 8.5 cm., and although appearing encapsulated, were microscopically infiltrative. The common histologic feature of all cases was a diffuse and at times intense neutrophilic infiltrate unassociated with tissue necrosis, in combination with bland and anaplastic appearing histiocytes. The presence of this acute exudative reaction is a unique feature of these lesions, and was present not only in the original tumors, but in recurrences and metastatic foci as well. Other cell types including foam cells, lymphocytes, plasma cells, eosinophils, Reed-Sternberg-like and ganglion-like cells were commonly present. A storiform fibrous pattern, a hallmark of the fibrous histiocytomas was seen at some time in all but one case. The treacherous aspect of these lesions was their bland initial histologic appearance. The foci of foam cells associated with the inflammatory elements often led to a diagnosis of a benign inflammatory reaction or xantho-granuloma. However, follow-up has confirmed the aggressive and neoplastic nature of these lesions. The clinical course was usually protracted with multiple recurrences and eventual metastases. All patients died of their tumor, the average survival being 53 months; four patients survived over 5 years. At this time, we propose the term inflammatory fibrous histiocytoma to designate these lesions.

Between 1959 and 1975, 256 patients with pathologic Stage I uterine adenocarcinoma were treated at Stanford University Hospital, Stanford, California. One hundred ninety-three patients were initially treated with surgery, and 63 received preoperative radium, reflecting different treatment philosophies of physicians operating at Stanford. Relapse rates for the two treatment groups were 9% (17 of 193) and 14% (9 of 63), respectively (P = 0.24). In both groups of patients, relapse rates were correlated with grade, although for those treated with initial surgery myometrial invasion was a much better predictor of relapse. Only one of the 127 patients without demonstrable myometrial invasion suffered a possible relapse. Sixteen of 66 patients with myometrial invasion (24%) relapsed after treatment. A review of the histologic material revealed 26 of 256 cases with a special histologic variant termed uterine papillary serous carcinoma, which was associated with a high relapse rate (50%) and a marked tendency for upper abdominal spread. It was found that the use of preoperative intracavitary radium was not demonstrated to be of value. Histologic information obtained from the hysterectomy specimen can be used to determine patients at high risk for relapse who may benefit from adjuvant treatment based on our understanding of the natural history of endometrial carcinoma.

A patient with profound hypokalemia satisfied the criteria for Bartter's syndrome, including hyperreninemia, aldosteronism, normal blood pressure, and hyperplasia of the juxtaglomerular apparatus. Two screening tests of urine and one of plasma for diuretic agents gave negative results. A third urinary sample gave negative results for thiazide but positive for furosemide; the fourth and fifth samples gave negative results for furosemide but positive for thiazide. Urinary prostaglandin excretion was normal. We conclude that this apparent case of Bartter's syndrome was caused by long term surreptitious diuretic ingestion and suggest this may occur more frequently than is generally appreciated.

Primary osteogenic sarcoma of the bladder is an extremely rare disease. Fewer than 30 cases of tumors of the bladder containing bone or cartilage have been reported. Only 14 cases of well-documented primary osteogenic sarcoma of the bladder appear in the world's literature. The authors describe the first detailed description of such a patient treated with radiotherapy and chemotherapy as well as provide a review of this rare and interesting entity.

Examples of focal clearing of endometrial epithelial nuclei associated with the presence of trophoblastic tissue have been oberved recently in our surgical pathology laboratories. These nuclear alterations were initially observed in endometria from first and second trimester spontaneous abor

Histologic specimens of all patients undergoing hysterectomy for clinical Stage I adenocarcinoma of the endometrium at Stanford University Hospital between 1959 and 1975 were reexamined. From this group 256 acceptable cases of adenocarcinoma confined to the uterine corpus (Pathologic Stage I) were identified. In patients treated with initial surgery, relapse rate was highly correlated with depth of myometrial invasion (P = 0.0001) and also with the histologic grade of the uterine adenocarcinoma (P = 0.008). Twenty-six patients (10%) had lesions with papillary architecture and anaplastic cytology similar to papillary serous carcinoma of the ovary. These women with uterine papillary serous carcinoma (UPSC) had a 50% relapse rate and accounted for one-half the treatment failures ( 13 26 ) in the entire study group. Six of the seven upper abdominal relapses in this study were in patients with UPSC, suggesting that this histologic variant may behave more like ovarian serous carcinoma than the usual endometrial adenocarcinoma. Twenty-one patients (9%) had endometrial carcinomas with extensive mucinous differentiation (mucinous carcinoma), while 38% of all the cases of endometrial carcinoma showed at least some focal mucin production. Twenty percent showed focal squamous differentiation. Neither mucinous nor squamous differentiation, as we have applied these designations, were significantly correlated with relapse rate. Among the patients undergoing hysterectomy for clinical Stage I adenocarcinoma, 99 patients were found on review to have lesions which fell short of our current criteria for diagnosis of carcinoma in the uterine corpus and were reinterpreted as metaplasia and/or hyperplasia. None of these patients subsequently developed clinical relapse. The results of this study suggest a need for modification in the FIGO grading system for endometrial cancer and also support a definition of well-differentiated endometrial carcinoma more restrictive than that commonly employed.

Twenty-nine patients had simultaneous malignant epithelial neoplasms of the uterine corpus and ovary. Three groups were defined on the basis of tumor histology: Group A: those with endometrioid carcinoma in both the uterus and ovary; Group B: those with special variants of corpus carcinoma (papillary, clear cell, mucinous) and identical neoplasms in the ovary; and Group C: those whose uterine and ovarian carcinomas were of dissimilar histologic types. Sixteen women had endometrioid carcinoma in both sites. The median age at diagnosis, 41 years, was younger than is usual for corpus or ovarian cancer. For all 16 patients, the grade of the ovarian endometrioid carcinoma was similar to that of the endometrioid carcinoma of the uterine corpus. Seven patients had bilateral ovarian neoplasms. Only one patient had myometrial invasion by the corpus carcinoma. No patient with simultaneous ovarian and uterine endometrioid carcinoma, regardless of grade, has died of cancer although one vaginal relapse was treated successfully. This excellent survival of patients with simultaneous endometrioid carcinomas is better than would be expected for either Stage III adenocarcinoma of the endometrium or Stage II ovarian carcinoma. These simultaneously occurring endometrioid neoplasms of ovary and endometrium are considered to be separate primary tumors. The morphologic reasons for this view and therapeutic implications are discussed. In contrast to the patients with endometrioid carcinoma, the eleven patients with other histologic types of carcinoma in the ovary and corpus were older (median age, 61 years) and more often post-menopausal (90%). These neoplasms were more aggressive, with frequent deep myometrial involvement (63%), tubal involvement (27%), and extension to other pelvic tissues (36%) at the time of initial diagnosis. Six of these 11 patients succumbed to their cancer despite surgical therapy and radiation. The distribution of tumor in some of these patients with nonendometrioid types of carcinoma is suggestive of a single primary with metastases. The therapeutic implications of these findings are discussed. Cancer 50:163–170, 1982.

A so-called “endometrial” adenocarcinoma of the prostate has been studied by light and electron microscopy, and by histochemical techniques. The previously proposed utricular origin and estrogen dependence of such tumors is questioned. Strong acid phosphatase staining, and the ultrastructural demonstration of multivacuolated, lipid, and lysosome-containing tumor cells, suggest a prostatic ductal origin for this type of carcinoma despite the histologic similarity to carcinoma of the endometrium.

The design and details of a prospective, randomized study protocol involving bipedal lymphography, and exploratory laparotomy with selective node biopsy in patients with apparently localized adenocarcinoma of the prostate are presented. The analysis includes the results of selected diagnostic tests, and an assessment of the accuracy of clinical vs. surgical staging in 50 unselected patients. Lymphatic metastases were found at the time of diagnostic laparotomy in 18 of the 50 patients (36%). Both increasing size (advanced T stage) and decreasing differentiation of the primary tumor were associated with an increased incidence of lymph node metastases. Of 25 patients with T1 and T2 tumors (Stage B), and 25 patients with T3 tumors (Stage C), lymphatic dissemination was found in 20 and 52%, respectively. Eleven of 20 patients (55%) with poorly differentiated tumors had lymph node metastasis, compared with only 2 or 11 patients (18%) with well-differentiated tumors. Twelve patients had a change in their clinical stage following exploratory laparotomy; in eight the stage was increased and in four it was decreased. Of 18 patients with lymphatic metastases, some of which were extensive and most of which were associated with increased serum acid phosphatase values, no evidence of concurrent bony or visceral dissemination was found. Although preliminary, this finding should stimulate the search for effective treatment in these patients who were previously thought to be incurable on the basis of probable vascular dissemination.

The malignant fibrous histiocytomas (MFHs) are a histologically heterogeneous group of sarcomas that have been postulated to be derived from, or have the capacity to differentiate into, histiocytes. To determine whether MFH tumor cells actually express the features of histiocytes, i.e., bone marrow-derived cells of monocyte-macrophage lineage, we studied the antigenic and enzymatic phenotype of 13 MFHs in situ using frozen and plastic sections, respectively. Five pleomorphic three fibrous, two myxoid, two giant cell, and one histiocytic MFH were studied. While tumor cells in 12 of 13 cases were positive for HLA-A,B,C, tumor cells in all cases failed to express antigens present on bone marrow-derived macrophages, i.e., leukocyte common antigen (L3B12), HLA-DR, Leu-M3, and Leu-3a. Interestingly 8 of 13 cases were positive for CALLA. Although nonspecific, this may prove useful in differential diagnosis. Enzyme histochemistry demonstrated that tumor cells in 9 of 13 cases were positive for membrane 5' nucleotidase (5'N+). Four of these were also alkaline phosphatase positive (ALKP+). All cases were either negative or weakly positive for acid phosphatase (ACIDP) and alpha-naphthyl acetate esterase (ANAE). Tumor cells were unreactive for alpha-naphthyl butyrate esterase (ANBE) and adenosine triphosphatase (ATP). These findings indicate that MFH tumor cells do not express the enzymatic profile of cells of monocyte/macrophage lineage which are membrane 5'N-/ALKP- and ACIDP+/ANAE+/ANBE+/ membrane ATP+. In fact, these data suggest a similarity to fibroblasts which are membrane 5'N+, variably ALKP+, weakly ACIDP+/ANAE+, and ANBE-/membrane ATP-. Osteoclast-like giant cells present in two cases did express a histiocytic phenotype, suggesting that they are reactive elements not derived from admixed tumor cells. These results suggest that MFHs are primitive mesenchymal neoplasms, most likely sarcomas composed of poorly differentiated fibroblasts, and are unrelated to true histiocytic neoplasms.

A 45-year-old woman presented with an apparently nonfunctioning strumal carcinoid of the ovary. On ultrastructural examination the cells in the solid parts of the tumor as well as in the "follicular" areas contained dense-core secretory granules, indicating that this neoplasm is a pure carcinoid tumor. The thyroid-like appearance in areas is due to the accumulation of secretory material within unusually dilated acinar spaces. This study raises the question whether any strumal carcinoid contains thyroid tissue since the cells forming the follicle-like spaces in this tumor contain dense-core granules.

A patient with a clear cell sarcoma of tendons and aponeuroses arising in the left sacral area is reported. The tumor grossly contained two black foci that had pigment with the staining characteristics of melanin on light microscopy. Electron microscopy of these areas showed the pigment to be within melanosomes. This is the second report of a neoplasm diagnosed as clear cell sarcoma in which melanin was demonstrated; the possibility that the tumor represents a soft tissue variant of malignant melanoma is discussed. It is suggested that clear cell sarcoma is a heterogeneous entity, and that a number of different soft tissue neoplasms may present with a clear cell pattern, making diagnosis and classification difficult.

Of 256 patients with carcinoma confined to the uterine corpus at the time of hysterectomy treated in the period 1959-1975 at Stanford University Hospital, 98 patients (38%) had neoplasms which demonstrated at least focal intracytoplasmic mucin. In 21 carcinomas (9%), intracytoplasmic mucin production was the dominant form of differentiation--a group which we designate primary mucinous carcinoma of the endometrium. Freedom from relapse and frequency of myometrial invasion were not statistically different for patients whose neoplasms contained intracytoplasmic mucin, regardless of the amount of mucin present, when compared with cases of nonmucin-containing carcinoma. Using histochemical methods, it was impossible reliably to distinguish between the intracytoplasmic mucin produced by carcinomas arising in endometrium and that produced by carcinomas primary in the endocervix. Differential biopsy and fractional curettage are stressed as useful tools in making this clinically important distinction. Since both benign mucinous metaplasia and mucinous carcinoma may arise in the endometrium, it is important to establish histopathologic criteria by which the malignant lesions may be recognized. The use of criteria illustrated in this paper (which include architectural complexity of proliferation, epithelial stratification, loss of epithelial polarity, and nuclear atypicality) resulted in the recognition of mucin producing proliferations which as a group manifest a 50% incidence of myometrial invasion.

One hundred smooth muscle tumors arising in the gastrointestinal tract and retroperitoneum were reviewed in an attempt to define criteria for the diagnosis of leiomyosarcoma in these sites. On the basis of aggressive behavior, 56 of these neoplasms were diagnosed as leiomyosarcoma. Mitoses were found to be the most useful indicator of malignancy; all of the tumors with five or more mitoses/10 HPF behaved aggressively and smooth muscle tumors with this degree of mitotic activity should be diagnosed as leiomyosarcoma. A paucity of mitoses, however, is no assurance of benignity as nearly 40% of the leiomyosarcomas in this series had fewer than five mitoses/10 HPF. Tumor cell necrosis was closely associated with aggressive behavior even when mitoses were infrequent and it is doubtful that benign smooth muscle tumors develop extensive tumor cell necrosis. In the absence of the requisite number of mitoses or tumor necrosis, it is difficult to distinguish some leiomyosarcomas from leiomyomas, but tumor size, cellularity and cellular atypia may be helpful parameters when assessed together. The importance of these criteria in different anatomical sites is discussed. It is emphasized that the criteria for the diagnosis of leiomyosarcoma of the uterus do not apply to non-uterine smooth muscle tumors. The actuarial 2-year survival rate was as follows: gastric leiomyosarcoma, 40%; small intestinal leiomyosarcoma, 60%; and retroperitoneal leiomyosarcoma, 16%.

A gonadoblastoma associated with dysgerminoma that occurred in the gonad of a 17 year old phenotypic female has been studied with the electron microscope. Ultrastructurally the nests of gonadoblastoma contain two cell types, namely, large vesicular cells and small epithelium-like cells. The large vesicular cells are similar to the normal oocyte and the neoplastic cell of the dysgerminoma. Their ultrastructure supports origin from germ cells. The smaller cells are ultrastructurally similar to sex cord mesenchymal cells of the granulosa-Sertoli type. The hyaline material around and within the nests is similar to the material in Call-Exner bodies and is composed of masses of fibrils containing cell fragments. These fibrils form in the cytoplasm of stromal cells, which apparently undergo degeneration. It is postulated that gonadoblastoma results from abnormal proliferation of germ cells, which induce the sex cord mesenchymal cells around the germ cells to differentiate into granulosa-Sertoli-like cells.

Uterine sarcomas often present diagnostic problems. In addition, the plethora of names for the same tumor or groups of tumors makes it difficult to correlate diagnostic and therapeutic data. We have proposed a modification of the classification of Ober that we think offers a simple, straightforward, histogenetically accurate terminology for this group of tumors. It also permits as detailed a subclassification of each group of tumors as now seems warranted. To test this classification and the available diagnostic criteria, the uterine sarcomas at Barnes Hospital in St. Louis have been evaluated. Leiomyoma and leiomyosarcoma can be accurately separated in most instances. Smooth muscle tumors that have invaded contiguous organs or blood vessels are malignant. If invasion is not present the mitotic rate is evaluated. Tumors with less than 5 mitoses per 10 high power fields (HPF) are benign. Those with higher mitotic counts are malignant. The prognosis for leiomyosarcomas with greater than 10 mitoses per 10 HPF is poor and metastases are frequent. The behavior of smooth muscle tumors with mitotic counts between 4 and 9 per 10 HPF is less certain, but some tumors with this level of mitotic activity will metastasize. Patients with malignant mixed Miillerian tumors of the homologous type that are small and not invasive or have invaded the myometrium only superficially may be cured by hysterectomy. If the tumors are large and highly invasive, the outlook is almost hopeless in spite of any form of therapy. Heterologous malignant mixed Miillerian tumors with chondrosarcoma as the heterologous element and without significant invasion may also be cured. In our series the presence of osteoid, bone, or rhabdomyoblasts indicated a highly malignant neoplasm with fatal outcome. All such tumors were large at the time of initial diagnosis. The infiltrating stromal tumors with mitotic counts of about 20 per 10 HPF all metastasized; those with 5 per 10 HPF or less have not metastasized or recurred after therapy. This provides a sharp dividing point between endolymphatic stromal myosis and endometrial stromal sarcoma. The behavior of tumors with mitotic counts of 6 to 20 per 10 HPF is unknown, but they may have a better prognosis than stromal tumors with higher counts.

Two patients with cystinosis in end stage renal failure received renal transplants from parental (heterozygous) donors. Although initial renal function was excellent, rapid glomerular insufficiency ensued between the third and sixth post-transplant months, without the reappearance of the Fanconi syndrome. Biopsies disclosed nephron loss, interstitial edema and fibrosis, and moderate infiltration with lymphocytes, plasma cells, and blast cells. The glomeruli showed mild to marked membranous and proliferative changes. One biopsy specimen demonstrated intracellular deposits of cystine crystals. These changes do not permit an assessment of the relative roles of systemic cytinosis, cell-mediated immune rejection, or antibody-mediated damage. The implications of these findings for future transplants in cystinotic children are discussed.