Richard L. Kempson

Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma.

A review of 256 cases of pathologic Stage I uterine adenocarcinoma treated at Stanford University Hospital revealed 26 cases of uterine papillary serous carcinoma (UPSC), a clinically aggressive and morphologically distinct variant of adenocarcinoma which closely resembles ovarian papillary serous carcinoma. These lesions are easily recognized by microscopic examination and typically feature a high degree of cytologie anaplasia and a papillary growth pattern. Invasion of the lymphatics has been a frequent finding. The relapse rate among patients with pathologic Stage I UPSC was 50% (13/26), five times the rate which would have been predicted by the incidence of UPSC. Patients with Stage I UPSC fared significantly worse than the group of nonpapillary grade II or grade III adenocarcinomas (p < 0.0001). Forty percent of Stage I UPSC patients had deep myometrial invasion, as compard with 12% of those with all other histologic types of adenocarcinoma (p p = 0.001). Women with UPSC deeply invading the myometrium tended to do worse than those with deeply invasive lesions of the more usual endometrioid type as reflected by relapse rates (after surgery alone) of 63% and 30%, respectively. Of seven Stage I corpus carcinoma patients whose initial site of failure was in the upper abdomen, six had UPSC. Thus, UPSC shares the tendency of its ovarian counterpart to spread over peritoneal surfaces. In addition to the original study group of 26 Stage I patients, 34 patients with more advanced stages of UPSC were also reviewed. Of these, 26 have been followed and four survive. Eleven of these women presented or relapsed with abdominal carcinomatosis. UPSC is a clinically aggressive neoplasm which should be distinguished from other types of primary endometrial adenocarcinoma. In cases of invasive UPSC the mode of spread, similar to that of ovarian surface epithelial carcinomas, suggests the need for adjuvant upper abdominal and pelvic irradiation or effective chemotherapy.

Problematic uterine smooth muscle neoplasms. A clinicopathologic study of 213 cases.

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 ≤ 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 ≤ 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 < 5 mf/10 hpf (usual leiomyomas) were also excluded unless they had unusual features or were associated with an adverse clinical outcome. Fifty-six patients were initially treated by myomectomy or another form of local tumor removal; the remainder had a hysterectomy. From a wide variety of light microscopic features assessed, the important predictors that emerged, using a variety of data exploratory techniques, were MI, the degree of cytologic atypia, and the presence or absence of coagulative tumor cell necrosis (CTCN). Stratification of the USMNs with respect to these three features resulted in a five-group classification of USMNs with the following major characteristics. Group 1: Of the 89 USMNs with an MI in the range 5 ≤ MI < 20 without CTCN and with no more than mild atypia, 88 were clinically benign. One patient with a tumor in this group died of metastatic disease 96 months after her uterine cervical primary neoplasm was removed. Combining our data with that in the literature, the failure rate in this group is ∼ 1/200 (0.5%). This low failure rate warrants the use of the label “leiomyoma with increased mitotic index” for USMNs with these histologic features. Two patients whose USMNs were characterized by mild atypia, no necrosis, and MI ≤ 5 developed identical-appearing pulmonary metastases and were judged in retrospect to have the syndrome “benign metastasizing leiomyoma.” Group 2: USMNs with no CTCN and diffuse moderate to severe atypia fell into two groups based on the MI. For those patients whose neoplasms had an MI ≤ =10 mf/10 hpf, four of 10 failed. These tumors we label “leiomyosarcoma.” For the patients with tumors demonstrating diffuse moderate to severe atypia, no CTCN, and an MI ≤ 10 mf/10 hpf, one of 46 failed. The patient who failed is alive with disease at 60 months. This failure rate of one in 46 (2%) warrants the term “atypical leiomyomas with a low risk of recurrence” for these tumors. Group 3: Twenty-four of 33 patients whose tumors demonstrated both diffuse moderate to severe atypia and CTCN failed. The failures occurred in all atypia-MI subsets. These neoplasms should be labeled “leiomyosarcomas.” Group 4: Eight patients had a USMN with insignificant cytologic atypia but CTCN. Four of these patients experienced a clinical relapse; all except one of the latter tumors had an MI ≤ = 10 mf/10 hpf. These findings would suggest that this group be labeled “leiomyosarcoma” when the MI exceeds 10 mf/10 hpf. Group 5: Five patients had USMNs with no CTCN and focal or multifocal moderate to severe atypia, and all had favorable outcomes. Two of the tumors had a mitotic index between 10 and 20. This study highlights the importance of using features other than mitotic index to predict clinical outcome in USMNs. Coagulative tumor cell necrosis emerged as a particularly crucial feature. An accurate MI determination in this classification scheme is less important.

Interobserver Reproducibility in the Diagnosis of Ductal Proliferative Breast Lesions Using Standardized Criteria

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.

Primary uterine endometrial stromal neoplasms. A clinicopathologic study of 117 cases.

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 11.3/6: Stage III.11/11: Stage IV, 6/7. Stage II patients are considered separately in the analysis. Thirtysix 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 < .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.

Smooth muscle tumors of the gastrointestinal tract and retroperitoneum. A pathologic analysis of 100 cases

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%.

Fibroxanthosarcoma of the soft tissues. A type of malignant fibrous histiocytoma

The clinical and pathologic features of 30 soft tissue tumors which have a storiform fibrous stroma and bizarre histiocytes and giant cells are reviewed. Because of the resemblance of these lesions to the fibrous histiocytomas and because three of the tumors metastasized, they have been designated as fibroxanthosarcomas. Local recurrence was also common. Fibroxanthosarcoma occurs in many areas of the soft tissues but most commonly in the extremities. Histologically, it resembles storiform fibrous xanthoma (dermatofibrosarcoma protuberans) but can be separated from this entity by the presence of anaplastic bizarre giant cells and numerous mitoses. A proposed nomenclature for the fibrous histiocytomas is also presented. It is concluded that fibroxanthosarcoma is a distinctive malignant fibrous histiocytoma with a bizarre histologic pattern which can be distinguished from other soft tissue sarcomas and from the other fibrous histiocytomas.

Uterine sarcomas: Classification, diagnosis, and prognosis

Abstract 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.

Perivascular epithelioid cell tumor ('PEComa') of the uterus: a subset of HMB-45-positive epithelioid mesenchymal neoplasms with an uncertain relationship to pure smooth muscle tumors.

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.

Ovarian Serous Tumors of Low Malignant Potential (Borderline Tumors): Outcome-Based Study of 276 Patients With Long-Term (???5-Year) Follow-Up

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 and ≥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 (P < 0.001) and invasive implants (P < 0.001) were associated with decreased survival. When compared with typical S-LMP, S-LMP with micropapillary features were more strongly associated with invasive implants (P < 0.008) 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% ≥ 60 months) and was strongly associated with increased tempo of disease and decreased survival (P < 0.001). 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.

Simultaneous presentation of carcinoma involving the ovary and the uterine corpus

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.