Differential diagnosis of ovarian tumors based primarily on their patterns and cell types.

The differential diagnosis of ovarian tumors is reviewed based on their patterns and cell types. This approach, which differs from the standard textbook discussion of each neoplasm as an entity, has practical value as differential diagnosis depends largely on the pattern or patterns and cell type or types of tumors. Awareness of the broad range of lesions that may exhibit particular patterns or contain one or more cell types is crucial in formulating a differential diagnosis. The following patterns are considered: moderate-to-large-glandular and hollow-tubular; solid tubular and pseudotubular; cords and ribbons; insular; trabecular; slit-like and reticular spaces; microglandular and microfollicular; macrofollicular and pseudomacrofollicular; papillary; diffuse; fibromatous-thecomatous; and biphasic and pseudobiphasic. The following cell types are considered: small round cells; spindle cells; mucinous cells, comprising columnar, goblet cell and signet ring cell subtypes; clear cells; hobnail cells; oxyphil cells; and transitional cells. The morphologic diversity of ovarian tumors poses many challenges; knowledge of the occurrence and frequency of these patterns and cell types in various tumors and tumor-like lesions is of paramount diagnostic importance. A specific diagnosis can usually be made by evaluating routinely stained slides, but much less often, special staining, immunohistochemical staining or, very rarely, ultrastructural examination is also required. Finally, clinical data, operative findings, and gross features of the lesions may provide important, and at times decisive diagnostic clues.

Cause-specific mortality coding. methods in the collaborative ocular melanoma study coms report no. 14.

Ascertainment of cause of death is often sought in clinical trials in which mortality is an outcome of interest. Standardized methods of coding all-cause and disease-specific mortality were developed and evaluated in the Collaborative Ocular Melanoma Study randomized trial of pre-enucleation radiation of large choroidal melanoma. All available clinical and pathologic materials documenting events prior to each reported death were reviewed systematically by a Mortality Coding Committee (MCC) to determine whether melanoma metastasis or local recurrence was present at the time of death. A level of certainty was assigned based on availability of local or central review of pathology materials. The outcome of the mortality coding protocol was evaluated both by assessing agreement between the judgment of the MCC and the presumed cause of death reported by the clinical center and, for a subset of patients, by assessing agreement between the MCC classification and the cause of death reported on the death certificate. As of July 31, 1997 (the cutoff date for the initial mortality report), 435 (95%) of 457 deceased patient files had been reviewed. The MCC classified 269 patients (62%) as dead with melanoma metastasis, 22 (5%) as dead with another malignant tumor, and 92 (21%) as dead with a malignant tumor of uncertain origin. Thirty-eight patients (9%) died with no evidence of malignancy; in 14 cases (3%), the presence or absence of malignancy could not be established due to lack of clinical information. Fair agreement (kappa = 0.34) was observed between the determinations of the MCC based on detailed review of materials and the cause of death reported on the death certificate, but death certificates alone underestimated the proportion of deaths due to metastatic choroidal melanoma. Detailed mortality coding identified difficulties associated with accurate reporting of cause-specific mortality in patients with choroidal melanoma.

Ovarian mucinous carcinoids including some with a carcinomatous component: a report of 17 cases.

Only rare primary mucinous (goblet cell) carcinoids of the ovary have been reported, and their clinicopathologic features have not been well delineated. The authors studied 17 examples from patients 14 to 74 years of age. The clinical presentations were similar to those of ovarian neoplasms in general. The tumors ranged from 0.8 to 30 cm in diameter. In six cases the tumor was in the wall of a mature cystic teratoma, appearing grossly as solid nodules or areas of thickening in four of them, six tumors were entirely solid, and five were solid associated with other types of cystic tumor. The tumors were divided into three groups on the basis of their microscopic features. Six neoplasms, designated "well differentiated," were composed of small glands, many of which floated in pools of mucin. The glands were lined by goblet cells and columnar cells, some of which were of neuroendocrine type. Three tumors, designated "atypical," were characterized by crowded glands, some of which were confluent, small islands with a cribriform pattern, and scattered microcystic glands. The glands were lined by cuboidal to columnar cells, some of them neuroendocrine, admixed with goblet cells. Eight tumors, designated "carcinoma arising in mucinous carcinoid," contained islands and larger nodules of tumor cells, or closely packed glands, as well as single cells, mainly of the signet ring cell type. Most of the cells were devoid of mucin and were severely atypical with marked mitotic activity. Necrosis was present in all eight tumors. Seven of the eight tumors with a carcinomatous component contained at least minor foci of well-differentiated mucinous carcinoid; the eighth contained only foci of atypical mucinous carcinoid. The neuroendocrine nature of a variable proportion of the cells in all three groups was demonstrated by staining for neuroendocrine markers. The mucinous nature of other cells was confirmed by mucicarmine or Alcian blue stains. The ovary contained an intrinsic component of trabecular and insular carcinoid, and of strumal carcinoid in one case each, an adjacent mature cystic teratoma in six cases, mucinous cystadenocarcinoma in three cases, and borderline mucinous cystic tumor, borderline Brenner tumor, and epidermoid cyst in one case each. Fifteen tumors were stage I, one was stage II, and one was stage III. The last two tumors had a carcinomatous component. Follow-up data were available for 15 patients; 12 were alive and free of tumor 2.3 to 14 years (average, 4.7 years) after the ovarian tumor was excised. One patient, whose tumor had a carcinomatous component, died 3 years postoperatively of unrelated causes. Two patients, both of whom had a carcinomatous component in their tumor, died 9 and 12 months postoperatively. Primary mucinous carcinoids must be distinguished from metastatic mucinous carcinoid tumors from the appendix or elsewhere. Features supporting an ovarian origin are the additional presence in the specimen of teratoma or an ovarian surface epithelial tumor, an absence of blood vessel or lymphatic space invasion, and confinement to a single ovary. Similar features help to distinguish mucinous carcinoids from Krukenberg tumors. Mucinous carcinoids should also be distinguished from strumal carcinoids, which can contain mucinous glands, and insular carcinoid tumors that arise rarely in the wall of a mucinous cystic neoplasm. Although the number of cases in this series is small, the follow-up data suggest that the degree of differentiation, particularly the presence of frank carcinoma, is an important prognostic factor.

Mucinous tumors of the ovary: a clinicopathologic study of 196 borderline tumors (of intestinal type) and carcinomas, including an evaluation of 11 cases with 'pseudomyxoma peritonei'.

Mucinous ovarian neoplasms other than cystadenomas and adenofibromas have been classified as either borderline tumors or carcinomas for many years. Borderline tumors have been subdivided more recently into endocervical-like (mullerian) and intestinal forms. Such a distinction is rarely made in the mucinous carcinoma category. We did not encounter a pure endocervical-like carcinoma in the present series. Criteria for distinguishing an intestinal-type mucinous borderline tumor from a mucinous carcinoma have been controversial. In this study of 164 mucinous borderline tumors of intestinal type and 32 mucinous carcinomas, the former were further subdivided into 74 cases with epithelial atypia only and 90 with focal intraepithelial carcinoma. Of the 67 stage I tumors in the borderline (with atypia) category, all 49 with follow-up data were clinically benign; in the seven cases that had been designated stage III, the intraoperative appearance was that of "pseudomyxoma peritonei," which was fatal in four cases. Most of these tumors, however, were probably metastatic to the ovary rather than truly primary borderline tumors, although failure to examine the appendix in six cases compromised their interpretation. All 90 mucinous borderline tumors that had foci of intraepithelial carcinoma were recorded as stage I, but two of the 69 patients with follow-up data (3%) had fatal recurrences. Both of these tumors were incompletely staged, however, and one had ruptured intraoperatively. Thirty-two invasive carcinomas were subdivided into 12 expansile and 20 infiltrative subtypes; within the latter category seven tumors were only microinvasive. All 12 carcinomas with only expansile invasion were stage I; none of the 10 with follow-up data recurred. All seven microinvasive infiltrative carcinomas were stage I; none of the five with follow-up data recurred. One of five patients with stage I infiltrative carcinomas that were more than microinvasive and were adequately followed had a fatal recurrence, but staging had been incomplete in that case. Seven of the remaining eight infiltrative carcinomas were higher than stage I: five of the six (83%) with follow-up data persisted or recurred and were fatal. Considering all stages, increasing tumor grade in the carcinoma category correlated with an unfavorable outcome. However, grade did not influence prognosis in stage I carcinomas. Among 13 stage I cases in all categories with either preoperative or intraoperative tumor rupture and follow-up data, one recurred, a tumor in the borderline with intraepithelial carcinoma category. "Pseudomyxoma peritonei" is an ill-defined term and should not be used as a pathologic diagnosis. The presence of mucin in the abdominal cavity requires careful histologic evaluation to characterize it for prognostic purposes. Adequate and sometimes extensive sampling of mucinous ovarian tumors, the appendix and the peritoneum in cases of "pseudomyxoma peritonei" is necessary to achieve an accurate diagnosis and prognosis.

Inhibin-alpha CD99, HEA125, PLAP, and chromogranin immunoreactivity in testicular neoplasms and the androgen insensitivity syndrome.

We investigated 115 testicular and 3 epididymal tumors and 6 cases of the complete androgen insensitivity syndrome (AIS) for the expression of inhibin-alpha, CD99, HEA125, PLAP, and chromogranin, using monoclonal antibodies and standard immunhistochemical techniques. Ihibin-alpha was detected in the neoplastic cells in 27 of 27 primary Leydig cell tumors (LCTs), 1 of 1 metastatic LCT, 6 of 20 Sertoli cell tumors (SCTs), 4 of 5 juvenile granulosa cell tumors (GCTs), and 2 of 5 unclassified sex cord-stromal tumors (USCSTs). Except for 2 choriocarcinomas, the choriocarcinomatous component of 1 mixed germ cell tumor, and a small focus of inhibin-positive syncytiotrophoblast in 1 embryonal carcinoma, inhibin-a immunoreactivity was not present in the neoplastic cells of the 38 remaining testicular germ cell tumors; 11 B-cell and 1 T-cell lymphomas; 1 granulocytic sarcoma; and 1 rhabdomyosarcoma of the testis; 1 adenoma of the rete testis, and 3 adenomatoid tumors of the epididymis. Inhibin-alpha immunoreactivity was present in the Sertoli cells and Leydig cells in 5 testicular hamartomas and in 1 Sertoli cell adenoma in 6 cases of AIS; both Sertoli and Leydig cells were also positive in the extranodular testicular parenchyma present in 2 of these cases. CD99 was detected in 10 of 15 primary LCTs, 1 of 7 SCTs, 3 of 5 JGCTs, and in 1 of 5 USCSTs but was not found in any tumor outside the sex cord-stromal category. HEA125 immunostaining was not detected in sex cord-stromal tumors; however, 3 of 12 seminomas, 3 of 12 embryonal carcinomas, 6 of 8 yolk sac tumors, and 1 of 2 teratomas were HEA125 positive. PLAP was not detected in sex cord-stromal tumors except for 4 of 15 primary LCTs but was present in most germ cell tumors. Chromogranin immunostaining was present in the sex cord-like element in 1 of 5 USCSTs, 1 of 8 YSTs, 1 of 2 teratomas, and in 1 of 1 rete adenoma, and in normal adjacent rete testis. In conclusion, although inhibin-alpha and PLAP, and, to a somewhat lesser extent, CD99 and HEA125 immunostaining are helpful in the differential diagnosis of certain testicular neoplasms that are difficult to distinguish on morphologic grounds, chromogranin is far less helpful in this context.

The International Society of Gynecological Pathologists. Its founding and early years.

The International Society of Gynecological Pathologists was founded in 1976 to facilitate an exchange of knowledge about gynecological disease throughout the world. The Society moved quickly to schedule companion meetings with established international and regional pathology and gynecology societies, including the International Academy of Pathology, its United States-Canadian Division, and the International Federation of Gynecology and Obstetrics, and to sponsor smaller meetings within individual countries. In 1981 the Society founded this journal, and in 1983, at the invitation of the World Health Organization, it assumed the responsibility of revising the WHO classifications of tumors of the female genital tract. The foundation of the Society appears to have been solid in view of its present robust health.

Myxoid and fibrous endometrial stromal tumors of the uterus: a report of 10 cases.

Ten endometrial stromal tumors of the uterus with a prominent myxoid or fibrous appearance, or both, that led to problems in interpretation are reported. The patients were 32 to 52 (mean 39) years of age. Three presented with dysfunctional uterine bleeding and one with abdominal pain. An enlarged uterus or a pelvic mass was palpated in five patients; the tumor was an incidental postpartum finding in one patient. All patients underwent hysterectomy. The tumors ranged from 4 to 20 cm in greatest dimension. Six were soft, polypoid intracavitary masses and four were predominantly intramyometrial; two were gelatinous. On microscopic examination, nine tumors infiltrated the myometrium (stromal sarcomas) and one was well circumscribed (stromal nodule). Six tumors had a predominantly fibrous component with the neoplastic cells separated by variable amounts of collagen; extensive areas of hyalinization were present in three tumors. Two tumors were predominantly composed of hypocellular areas with an abundant myxoid matrix, and two had both components in roughly equal proportions. Alcian blue staining was positive, with the staining eliminated by hyaluronidase predigestion, in the myxoid areas. The typical morphologic features of endometrial stromal neoplasia were present focally in four tumors. All of them contained numerous small thin-walled vessels. Vimentin and smooth muscle actin were positive in nine of nine and seven of nine tumors, respectively, whereas desmin was negative in six of nine tumors and only focally positive in the other three. One patient had omental nodules at the time of the initial diagnosis and another had a pelvic recurrence 2 years after hysterectomy. Follow-up information is unavailable or short in the other cases. These tumors should be considered of endometrial stromal origin in view of the typical location of most of them, their growth pattern, content of characteristic arterioles, presence of typical endometrial stromal neoplasia in the primary or recurrent tumor in some cases, and absence of evidence of origin from a cell type other than endometrial stroma. These tumors may be identical, in some instances at least, to tumors referred to in the older literature as "myxofibrosarcomas."

Adult granulosa cell tumor of the ovary with foci of hepatic cell differentiation: a report of four cases and comparison with two cases of granulosa cell tumor with Leydig cells.

We report four ovarian granulosa cell tumors of the adult type containing small foci of hepatic cell differentiation. The patients ranged in age from 35 to 54 years and had unilateral adnexal masses. The smallest tumor was 4.0 cm in diameter and the largest, 11.0 cm in diameter. Three tumors were solid and cystic, and one was cystic. Microscopic examination showed typical patterns of adult granulosa cell tumor, with the additional finding of scattered islands of large cells with abundant eosinophilic, slightly granular cytoplasm and central round nuclei containing single prominent nucleoli. Bile pigment was detected in canaliculi between some of the large cells in three tumors. The hepatic cells were positive immunohistochemically for cytokeratin (CAM 5.2) and epithelial membrane antigen in two cases and alpha-fetoprotein in one of two cases. Carcinoembryonic antigen was stained in a canalicular pattern in two cases. Staining for vimentin and alpha-inhibin was negative. Liver cells in granulosa cell tumors must be differentiated from Leydig cells, which are found very rarely in granulosa cell tumors, and luteinized stromal and granulosa cells, which are present more commonly in these tumors; all three of the latter cell types are positive for alpha-inhibin.

Oxyphilic tumors of the female and male genital tracts.

A great variety of oxyphilic tumors and tumor-like lesions occur in the female and male genital tracts, particularly in the former. The ovary is the site of a wider range of oxyphilic tumors than any other organ. Not only are its most highly specialized steroid hormone-secreting tumors and tumor-like lesions often completely or predominantly oxyphilic, but occasionally its epithelial cancers have a large component of oxyphilic cells. Several rare germ-cell tumors can also be completely or extensively oxyphilic and, being a common site of metastasis, the ovary can harbor a number of metastatic oxyphilic tumors. The lower female genital tract shares some of the problems in differential diagnosis with the ovary, and can be involved by a variety of mesenchymal oxyphilic tumors as well. In the male genital tract, the testis may be the site of a number of the same oxyphilic tumor types encountered in the ovary, but much less frequently, partly because the testis is an uncommon site of metastatic spread.

Ovarian serous borderline tumors with micropapillary and cribriform patterns: a study of 40 cases and comparison with 44 cases without these patterns.

A group of investigators have proposed that the presence of micropapillary or cribriform patterns within ovarian serous tumors diagnosed as borderline according to World Health Organization (WHO) criteria identifies a subset of these neoplasms that are apt to be associated with invasive peritoneal implants and therefore should be designated as "micropapillary carcinoma." The authors of the current article identified 40 serous borderline tumors that showed one or both of these patterns, using the earlier investigators' published criteria for so-called micropapillary carcinoma, and compared them with 44 tumors that lacked these patterns (controls). Twenty-six patients with micropapillary tumors were aged 21 to 76 years (mean 38); 11 with cribriform tumors were aged 34 to 79 years (mean 60); and 3 with tumors having both patterns were aged 21 to 58 years (mean 38); the control patients were aged 22 to 83 years (mean 54). An advanced stage, bilaterality, and ovarian surface growth were features of the "micropapillary" tumors more often than of the control tumors. Except for a postoperative death related to sepsis, all 11 patients with Stage I tumors with either or both patterns who were followed until their death, or for at least 5 years (mean 7.9 years), survived without evidence of disease; a twelfth patient had a recent removal of recurrent pelvic tumor at 2.8 years and was alive at 3.3 years. Six of the eight patients with Stage II or III tumors with either or both patterns who were followed for at least 5 years (mean 7.5 years) survived disease-free. No deaths from tumor or progressive recurrences occurred in 27 control cases with 5-14 (mean 7.9) years of follow-up data. The two tumor-related deaths in the entire series, one from a micropapillary tumor and one from a cribriform tumor, occurred in patients who had Stage III tumors with invasive peritoneal implants. No patient with "micropapillary" tumors and noninvasive implants had progressive disease. Two women with "micropapillary" tumors and two control subjects had stable recurrent tumor or a newly developed tumor in a contralateral ovary that had been spared during the initial operation. Our findings confirm those of previous investigators that noninvasive serous tumors with a micropapillary or cribriform pattern or both patterns may be accompanied by invasive peritoneal implants more often than tumors without such patterns and that in such cases the disease is likely to be progressive and fatal. Since so-called micropapillary carcinomas lack obvious stromal invasion within the ovary, and their prognosis when they spread to the peritoneum is much closer to that associated with typical Stage II and III serous borderline tumors than to that associated with similarly staged serous carcinomas, the authors believe that this newly described category of tumors should remain as a subset within the borderline category, with a notation that their prognosis is poor if they are associated with invasive peritoneal implants.

Carcinoma of the fallopian tube: a clinicopathological study of 105 cases with observations on staging and prognostic factors.

One hundred five cases of carcinoma of the fallopian tube were subjected to a clinicopathological study to investigate the validity of various prognostic factors. A higher stage of tumor, an absence of closure of the fimbriated end of the tube, and an age of 66 years or older were the major predictors of a shorter length of recurrence-free postoperative survival in a univariate analysis. In a multivariate analysis, however, stage was a highly significant prognostic factor, absence of fimbriated-end closure, marginally significant, and older age, not significant. Within Stage I cases the presence or absence of invasion of the tubal wall, the depth of invasion when present, and the location of the tumor within the tube (fimbrial or nonfimbrial) appeared to be prognostically important. These findings strongly suggest that the FIGO staging system should be expanded to permit staging of noninvasive tubal carcinomas and fimbrial carcinomas, which cannot be staged according to the current system, and that depth of invasion of the tubal wall merits future investigation as an additional prognostic factor.

Ovarian endometrioid-like yolk sac tumor treated by surgery alone, with recurrence at 12 years.

We describe the case of a stage Ia endometrioid-like yolk sac tumor (YST) of the ovary, which was originally misdiagnosed as a malignant struma ovarii and not treated with adjuvant chemotherapy. After 12 years, a contralateral dermoid cyst was excised along with a small omental nodule of partially necrotic and calcified endometrioid-like YST. No tumor was detected in several other biopsy specimens, and a peritoneal lavage was negative for tumor cells. Since there was no evidence of remaining tumor and the serum alpha-fetoprotein (AFP) level was normal after the second operation, the patient was followed. Serial serum AFP levels remained normal for 4 months. At a second-look laparotomy after 4 months, a small tumor nodule was removed from the cul-de-sac. Postoperatively, the patient received three cycles of BEP chemotherapy. The long disease-free interval after the first operation in spite of the presence of occult spread to the omentum and to the pouch of Douglas in this case indicates that some endometrioid-like YSTs may have an indolent course. The present case underscores the importance of careful surgical staging and of long-term follow-up in cases of primitive germ cell tumors of the ovary.

Ovarian small cell tumors: an electron microscopic review.

Small cell tumors of the ovary are uncommon but represent an important group to recognize in the differential diagnosis of primary and metastatic ovarian neoplasms. In some cases the correct diagnosis cannot be confidently made on the basis of clinical setting, routine light microscopy, and immunohistochemistry, and electron microscopy may be supportive or definitive in establishing cell type. The cell type is often important in choosing optimal therapy and in predicting prognosis. The authors performed electron microscopy on a moderate number of ovarian small cell tumors and here describe and illustrate the diagnostic features of representative examples of various types. The ultrastructural features of the metastatic tumors, such as embryonal rhabdomyosarcoma, neuroblastoma, and melanoma, are identical to those of their respective primary tumors, are well known, and usually pose no problem in diagnosis. On the other hand, the ultrastructural features of some primary ovarian small cell tumors may present a more difficult differential diagnosis, because they have features that are subtle and/or in common. Exemplary of tumors in this category are diffuse adult granulosa cell tumor, endometrial stromal sarcoma, and small cell carcinomas of the hypercalcemic and pulmonary (oat cell) types. Distinguishing among them may be difficult but is possible, and electron microscopy may be a valuable supplement to the diagnostic information obtained from the clinical presentation, light microscopy, immunohistochemistry and, in some tumors, cytometric analysis of these neoplasms.

Mixed endometrial stromal and smooth muscle tumors of the uterus: a clinicopathologic study of 15 cases.

Uterine tumors composed of a prominent component of smooth muscle (SM) and endometrial stroma (ES) (so-called stromomyomas) have received little attention in the literature. The features of 15 of these tumors, defined as those containing more than 30% of each component, were evaluated. Many of the tumors were referred because of problems in the differential diagnosis. Patient age ranged from 29 to 68 years (mean, 46 years). The tumors ranged from 3 to 27 cm (average 9.6 cm) in diameter, and most were grossly well circumscribed. The sectioned surfaces often had soft, tan-yellow areas admixed with firm, whorled areas. Microscopic evaluation disclosed that nine tumors were well circumscribed, and six had infiltrating tongues typical of endometrial stromal sarcoma (ESS). The endometrial stromal component, which predominated in five cases, typically was characterized by a diffuse growth of closely packed, minimally atypical small cells accompanied by numerous arterioles and was desmin-negative in all cases tested, except for rare desmin-positive cells in three tumors. Five tumors showed sex-cord-like differentiation in these areas. The smooth muscle component, which predominated in seven cases, was composed predominantly of spindle cells in disorganized short fascicles, longer fascicles, or nodules with prominent central hyalinization. This component appeared benign, except in one case with moderate cytologic atypia, focal tumor cell necrosis, and 4 mitotic figures/10 high-power fields. The smooth muscle component was strongly desmin-positive in all the tumors tested. Follow-up of more than 1 year was available for seven patients. Six patients were alive and well, but one tumor with infiltrative borders recurred at 48 months as a pure endometrial stromal sarcoma. Mixed endometrial stromal and smooth muscle tumors should be distinguished from highly cellular leiomyomas, pure endometrial stromal tumors, and "uterine tumors resembling ovarian sex cord tumors," at least until knowledge of their clinicopathologic features is more complete. For treatment purposes, these tumors should be reported as endometrial stromal nodules or as endometrial stromal sarcomas with smooth muscle differentiation and any unusual features of either component recorded in a notation.