Alpha-interferon in superficial bladder cancer: a Northern California Oncology Group Study.

Thirty-five patients with superficial transitional carcinoma of the bladder were treated intravesically with escalating doses of recombinant alpha-2-interferon administered weekly for 8 weeks. Of the 19 patients with high-grade intraepithelial neoplasia (17 carcinoma in situ [CIS], two severe dysplasia, all cytology positive), six (32%) had complete resolution of all histologic and cytologic evidence of disease (complete response). An additional three patients (16%) had complete resolution of CIS, but the interval appearance of a low-grade transitional cell neoplasm. Five (26%) had a partial response (complete resolution of all evidence of CIS on multiple bladder biopsies but persistently positive cytologic preparations). Sixteen patients with recurrent papillary tumors and extensive prior therapy were also treated. Four (25%) had a complete response. Twenty-three of the 35 patients had prior intravesical therapy. Seven of the 23 (30%) patients with prior intravesical chemotherapy or immunotherapy had a complete or partial response to interferon, while eight of the 12 patients (67%) without prior intravesical treatment responded. These responses were achieved with minimal local and systemic toxicity. Of the ten complete responders, five remain in continuous unmaintained remission for 18+ to 37+ months. Intracavitary alpha-2-interferon is an effective new treatment for some patients with bladder cancer.

Surreptitious diuretic ingestion and pseudo-Bartter's syndrome.

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.

Endometrial epithelial metaplasias: proliferations frequently misdiagnosed as adenocarcinoma. Report of 89 cases and proposed classification.

Endometrial epithelial metaplasia refers to the replacement of the normal endometrial glandular epithelium by cells that are either not encountered in the normal endometrium or, if present, are usually inconspicuous elements. Because these cells appear unusual or "atypical" and because they may line architecturally complex glands, this benign process is frequently confused with adenocarcinoma. This report concerns the clinical and light-microscopic findings in 89 patients whose endometria demonstrated some form of metaplasia. Most of these metaplastic changes could be placed in one of the following seven categories: 1) morules and squamous metaplasia; 2) syncytial papillary metaplasia; 3) ciliated cell metaplasia ("tubal" metaplasia); 4) eosinophilic metaplasia; 5) mucinous metaplasia; 6) hobnail metaplasia; or 7) clear cell metaplasia. The defining characteristics of each of these groups and their differential diagnoses are discussed. The majority of women whose endometria demonstrated metaplastic transformation were postmenopausal, and most had received some form of oral estrogen replacement therapy within 3 months of the time of curettage or endometrial biopsy.

Ovarian sex cord tumors with annular tubules: an ultrastructural study.

The ultrastructural features of two "sex cord tumors with annular tubules" are presented. The findings are compared with the reported fine structure of ovarian and testicular stromal cells and the cells of gonadal stromal neoplasms. The predominant cell in the "sex cord tumor with annular tubules" has some of the ultrastructural features found in gonadal stromal cells of either ovarian or testicular type; however, no Charcot-Bottcher crystals, lamellar bodies, crystalloids of Reinke, abundant smooth endoplasmic reticulum or complex plasma membrane interdigitations are observed in the tumor cells to suggest wither Sertoli or Leydig cell origin. The striking similarity between the predominant cell type and granulosa cells, as well as the presence of fibrillary material of the type seen in Call-Exner bodies, suggests a granulosa cell origin for these neoplasms. However, the presence of a sparsely distributed second cell type which closely resembles the dark cells in normal nonluteinized ovarian stroma indicates these tumors may arise from the nonspecialized ovarian stroma.

Atypical and malignant neoplasms showing lipomatous differentiation. A study of 111 cases.

One-hundred-eleven cases of histopathologically atypical or malignant lipomatous lesions in the somatic soft tissue and retroperitoneum were studied. These consisted of 48 differentiated fatty neoplasms of the somatic soft tissues (DFT-S), 21 fatty neoplasms of the retroperitoneum (DFT-R), 33 myxoid liposarcomas from various sites and nine pleomorphic liposarcomas. DFT-S were defined as lipomatous lesions composed of mature fat and containing atypical stromal cells or lipoblasts. In the somatic soft tissues, this group included lesions that would be classified using published criteria as "atypical lipoma", "pleomorphic lipoma", "well-differentiated lipoma-like liposarcoma", and "sclerosing liposarcoma". All of the DFT-R met previously published criteria for "well differentiated liposarcoma" or "sclerosing liposarcoma". We found no consistent histologic differences between the DFT-S and DRT-R. No pure "round cell" liposarcomas were encountered although many myxoid liposarcomas had "round cell" areas. Follow-up data were available in 80 cases (72%) with a mean follow-up period of over 7 years. Among the DFT-S there were no uncontrollable recurrences, distant metastases, or tumor-related deaths. The depth of the neoplasm correlated with the tendency for local recurrence; no neoplasms primary in the subcutis recurred; 29% of the tumors recurred when they originated in the deep soft tissues or within the muscle. None of the recurrent tumors demonstrated "dedifferentiation." DFT-R had a recurrence rate of 67% and, although there were no distant metastases, nine patients (43%) died of tumor. Five retroperitoneal tumors dedifferentiated but did not metastasize. In light of this experience, we believe that the term "atypical lipoma" is warranted for the DFT-S and "well differentiated liposarcoma" is an appropriate label for the DFT-R. The overall mean survival for the 52 cases of liposarcoma (excluding DFT-S) was 13.6 years. The mean survival in "well differentiated liposarcoma" (11.25 years) was between that for myxoid liposarcoma (16.25 years) and that for pleomorphic liposarcoma (7 years). Six patients (29%) with myxoid liposarcoma developed local recurrences and 6 patients (29%) developed distant metastases and died. Metastasis was always associated with a round cell (or pleomorphic) component with increased numbers of mitotic figures in either the primary tumor or a local recurrence.

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 > 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 < 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 < or = 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 approximately 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 > or = 10 mf/10 hpf, four of 10 failed.(ABSTRACT TRUNCATED AT 400 WORDS)

Optically clear nuclei. An alteration of endometrial epithelium in the presence of trophoblast.

Examples of focal clearing of endometrial epithelial nuclei associated with the presence of trophoblastic tissue have been observed recently in our surgical pathology laboratories. These nuclear alterations were initially observed in endometria from first- and second-trimester spontaneous abortions, term pregnancies, and a uterus harboring choriocarcinoma. Subsequently, an identical change was seen in small foci of endometriosis removed during postpartum tubal ligation. The prominent vacuolated appearance to the nuclei resembled, in some cases, the inclusions seen in herpesvirus infection, but electron-microscopic study showed that the nuclear clearing was due to replacement of normal chromatin by a network of fine filamentous material rather than herpesvirus DNA. A subsequent review of 200 consecutive first-trimester abortions found less-striking degrees of this change in 7% of cases. The endometrial nuclear clearing was focal; often the endometrium also contained cells which demonstrated the Arias-Stella reaction. The etiology of this type of nuclear clearing is not known, but the fibrils may represent a thread-like substructure of normal chromatin which forms as a result of hormonal stimulation of endometrial epithelial cells.

The cells of giant cell tumor of tendon sheath resemble osteoclasts.

To determine whether the mononuclear cells (MC) and multinucleated giant cells (GC) of giant cell tumor of tendon sheath (GCTTS) exhibit evidence of monocyte/macrophage lineage, we studied their antigenic features (seven cases, paraffin sections; two cases, frozen sections) and enzymatic features in situ (four cases, plastic sections). Both MC and GC expressed a monocyte/macrophage phenotype: HLA-A,B,C+, HLA-DR+, T200+ (leukocyte common antigen), Leu-M3+ and Leu-3+. MC and GC also expressed similar enzymatic phenotypes which resembled that of osteoclasts. Both were rich in acid phosphatase and contained smaller, variable amounts of ATPase, beta-glucuronidase, alpha-naphthyl acetate esterase, and 5'-nucleotidase. Both lacked alkaline phosphatase. Reactive osteoclasts in plastic and paraffin sections were also T200+, a finding strongly supporting their bone marrow derivation and leukocytic differentiation. In plastic sections, osteoclasts were additionally reactive with macrophage antigen EBM11. In aggregate, these data suggest that GCTTS is a true histiocytic lesion of monocyte/macrophage lineage composed of phenotypically similar MC and GC that most closely resemble osteoclasts. We found no evidence that GCTTS cells resemble osteoblasts, fibroblasts, or synovial sarcoma cells. Furthermore, expression of the Ki-67 nuclear antigen by 1-2% of MC but not by GC suggests that the proliferating cells in GCTTS are restricted to its MC component.

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 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.

Primary mucinous adenocarcinoma of the endometrium. A clinicopathologic and histochemical study.

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.

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.

Malignant fibrous histiocytoma tumor cells resemble fibroblasts.

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.

Second opinions in surgical pathology.

When to obtain opinions in anatomic pathology is a complex issue. The authors discuss the cognitive process of morphologic interpretation, the influence of expertise on the need for a second opinion, the role of ego, and the impact of economic factors on the patterns of consultation.

Carcinomas with metaplasia and sarcomas of the breast.

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.

Conservative treatment of borderline ovarian tumors.

Of 61 patients with stage IA borderline ovarian tumors, 41 were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy, and 20 were treated by a variety of more limited operations, including cystectomy with (one patient) and without (three patients) a contralateral ovarian wedge biopsy, and unilateral salpingo-oophorectomy with (six patients) and without (ten patients) a contralateral wedge biopsy. In the group treated conservatively, there were 11 serous, seven mucinous, and two mixed seromucinous borderline tumors, whereas in the total abdominal hysterectomy and bilateral salpingo-oophorectomy treatment group there were 26 serious, 12 mucinous, and three mixed seromucinous borderline tumors. After a mean follow-up of 89 months (range 36 to 244 months), subsequent borderline neoplasms had developed in three patients (15%) with serious borderline tumors initially treated conservatively and in two patients (5%) with serous or mixed seromucinous borderline tumors initially treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. No patient with a mucinous borderline tumor treated either conservatively or with total abdominal hysterectomy and bilateral salpingo-oophorectomy developed a subsequent neoplasm. All 61 patients in the study group are alive and free of disease, including those who developed recurrent neoplasm.

The differential diagnosis of endometrial adenocarcinoma. Some viewpoints concerning a common diagnostic problem.

Histological criteria which we have found useful for diagnosing endometrial adenocarcinoma are presented and guidelines are developed for separating adenocarcinoma from benign proliferations which can mimic carcinoma, including endometrial hyperplasia with atypia, endometrial epithelial metaplasias, secretory endometria and disintegrating endometrium. The problem of distinguishing endometrial adenocarcinoma from other malignancies is also discussed.

The nephrotic syndrome in massive obesity: a study by light, immunofluorescence, and electron microscopy.

The morphologic features observed in the renal biopsy specimens from three patients with massive obesity complicated by the nephrotic syndrome are described. In the two patients with active disease, the majority of the glomeruli showed focal to extensive fibrin deposition both within and adjacent to capillary loops, associated with adhesions to Bowman's capsule, with a variable endocapillary proliferative response. In the patient with inactive disease, the majority of the glomeruli appeared normal. However, fibrin-like material, similar to that seen in the active phase, was infrequently found ultrastructurally in the subendothelial portion of the capillary loops. Subendothelial vacuolated material was also observed. Although intravascular coagulation was suggested in this disorder, only minor coagulation abnormalities were discovered. In two of the patients, the massive proteinuria has resolved with weight reduction.

Kartagener syndrome: report of a case with mesangiocapillary glomerulonephritis.

The first known case of Kartagener syndrome associated with glomerulonephritis is reported. Mesangiocapillary glomerulonephritis was diagnosed in this patient several months before her death. This report also includes a review of the recent literature dealing with Kartagener syndrome and mesangiocapillary glomerulonephritis and a consideration of the possible relationship of infection to the cause of mesangiocapillary glomerulonephritis.

Pure mesenchymal neoplasms of the uterine corpus: selected problems.

The first part of this review includes a discussion of some issues in decision analysis as it applies to uterine mesenchymal tumors, as well as a discussion of some of the morphologic features and histochemical techniques that may be used to determine whether a mesenchymal tumor is demonstrating smooth muscle or endometrial stromal differentiation. Also included in the first part are caveats that the pathologist should observe before interpreting mesenchymal tumors of the uterus. The second part of the paper is devoted to morphologic diagnostic criteria and differential diagnosis.

The cytodiagnosis of malignant lymphomas and Hodgkin's disease in cerebrospinal, pleural and ascitic fluids.

One hundred twenty-six fluids from 98 patients with malignant lymphomas have been examined cytologically. The overall accuracy was 88 per cent with only one false positive in 126 fluids. False negatives were highest in the cerebrospinal fluid, which may reflect poor exfoliation of malignant lymphoma cells when the leptomeninges are involved. We have found exfoliative cytology to be an accurate method of diagnosing lymphomatous involvement of the leptomeninges, pleura and peritoneum and when a cytologic diagnosis of involvement by lymphoma is made it is almost as accurate as a histologic diagnosis. Nuclear characteristics and selected histochemical methods will allow classification of many types of lymphoma in bytologic preparations.