Performance Characteristics of Endometrial Sampling in Diagnosis of Endometrial Carcinoma.

Outpatient endometrial biopsy can give false-negative results, with a 0.9% reported posttest probability for endometrial carcinoma (EC) after a negative result. Our objective was to determine if there has been any improvement in the performance characteristics of endometrial biopsy over the last 15 yr. All hysterectomy specimens with a diagnosis of EC or atypical hyperplasia (AH), reported between May 2011 and May 2015, were identified and cross-referenced for any negative endometrial sampling results during the 5 yr before hysterectomy. Negative endometrial samples were defined as either benign findings or insufficient/nondiagnostic, excluding those diagnosed as AH or EC and those for which follow-up sampling was recommended because of atypia. Of 1677 hysterectomy specimens showing AH or EC there were previous negative biopsies in 172: 116 benign and 56 insufficient/nondiagnostic. Over the same period 22,875 negative endometrial biopsy specimens were reported in our region. The posttest probability of having EC or AH in the hysterectomy specimen, given a negative endometrial biopsy result, was 0.74%. In a subset of 90 cases in which a negative biopsy was followed by a diagnosis of AH or EC in a hysterectomy specimen, the slides were independently reviewed. There were no cases where a diagnosis of carcinoma was missed. In 12 samples atypia or possible atypia was identified, and the level of agreement with the original diagnosis was excellent κ=0.83±0.05. In a prospective comparison of examination of 3 levels from each block versus a single slide in 319 cases, the routine preparation of additional slides did not yield clinically significant information. Although there has been evolution in the diagnostic criteria for AH and for recognition of morphologically subtle forms of AH or EC, our results demonstrate a significant lack of sensitivity of outpatient endometrial sampling in the diagnosis of endometrial malignancy/premalignancy. The sensitivity problems are mainly attributable to failure to sample abnormal endometrium. Independent review of slides or examination of additional levels did little to increase the diagnostic yield.

DICER1 and FOXL2 Mutation Status Correlates With Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors.

Sertoli-Leydig cell tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms. The only known recurrent genetic abnormality is DICER1 mutation, with rare mutations reported in FOXL2. We set out to establish a molecular classifier using DICER1 and FOXL2 somatic mutation status and clinicopathologic features in 42 SLCTs. Five tumors (12%) were well differentiated, 31 (74%) moderately differentiated, and 6 (14%) poorly differentiated. Eight (19%) had heterologous elements, and 2 (5%) showed retiform differentiation; all 10 were moderately differentiated. DICER1 RNase IIIb domain mutations were identified in 18/41 (44%; 17 moderately, 1 poorly differentiated), including all cases with retiform or heterologous elements. FOXL2 c.402C>G (p.C134W) mutation was identified in 8/42 (19%) tumors (5 moderately, 3 poorly differentiated). DICER1 and FOXL2 mutations were mutually exclusive. Median age for the cohort was 47 years (range, 15 to 90 y). Patients with DICER1 mutations were younger (median, 24.5 y; range, 15 to 62 y) than patients with FOXL2 mutation (median, 79.5 y; range, 51 to 90 y) (P<0.0001). Nine of 10 tumors with retiform or heterologous elements occurred in premenopausal patients (median, 26.5 y; range, 15 to 57 y). Patients with tumors that were wild type for DICER1 and FOXL2 (15/42, 37%) had an intermediate age (median, 51 y; range, 17 to 74 y). All tumors were FOXL2 positive by immunohistochemistry. Patients with FOXL2 mutation trended toward presenting more often with abnormal bleeding (P=0.13); DICER1-mutant patients trended toward having more androgenic symptoms (P=0.22). Our data suggest at least 3 molecular subtypes of SLCT with distinct clinicopathologic features: DICER1 mutant (younger, more androgenic symptoms, moderately/poorly differentiated, retiform or heterologous elements), FOXL2 mutant (postmenopausal, abnormal bleeding, moderately/poorly differentiated, no retiform or heterologous elements), and DICER1/FOXL2 wild type (intermediate age, no retiform or heterologous elements, including all well-differentiated tumors).

Endometrial Carcinomas With Clear Cells: A Study of a Heterogeneous Group of Tumors Including Interobserver Variability, Mutation Analysis, and Immunohistochemistry With HNF-1ß.

Endometrial clear cell carcinoma (CC) is an uncommon tumor and often carries a poor prognosis. It has histologic features that overlap with other endometrial carcinomas and is frequently misclassified. Accurate classification is crucial, however, to improve treatment options. The objectives of this study were (1) to assess diagnostic interobserver variability among 5 gynecologic pathologists for tumors originally diagnosed as CC or with a component of CC (n=44); (2) to determine the utility of immunohistochemical markers estrogen receptor and HNF-1ß; and (3) to detect mutations in select genes. Clinical data and morphologic features were also recorded. Agreement among reviewers was only moderate: only 46% of the original CC remained classified as such. After reclassification, estrogen receptor was positive in 8% of CC, 67% of endometrioid carcinomas (EC), and 47% of serous carcinomas (SC). Sensitivities of HNF-1ß in CC, SC, and EC were 62%, 27%, and 17%, respectively, whereas specificity for CC versus EC or SC was 78%. Mutations in PIK3CA, PIK3R1, PTEN, KRAS, and NRAS were detected in 41% of 37 cases that had adequate material for study. At least 1 mutation was identified in 33% of CC, 67% of EC, and 33% of SC. This group of patients had poor outcomes: 72% of the patients with follow-up information had died of disease. In summary, this study suggests that the current pool of CC is a heterogeneous group of tumors from the morphologic, immunophenotypic, and molecular point of views and that only a percentage of them represent true CC.

Selected topics in peritoneal pathology.

This essay considers selected peritoneal lesions many of which were the subject of studies coauthored by Dr Robert E. Scully. His article on multilocular peritoneal inclusion cysts has largely led to these lesions being considered non-neoplastic, eschewing the term cystic mesothelioma. These cysts are often associated with reactive mural mesothelial proliferations that can potentially lead to a misdiagnosis of mesothelioma. Clinical findings, such as a common association with endometriosis or prior operations, can prompt consideration of a reactive lesion. Mesothelial hyperplasia may be difficult to distinguish, when florid, from mesothelioma but a variety of gross and microscopic features will aid their recognition. Nodular peritoneal aggregates of histiocytes (sometimes admixed with mesothelial cells) may occasionally be a striking finding that can be misdiagnosed as a metastasis if the patient has a known neoplasm. Appreciation of their bland nuclear features and histiocytic nature, confirmed by immunohistochemical markers, facilitate the diagnosis. Various forms of peritonitis are briefly considered including sclerosing peritonitis, a process sometimes associated with luteinized thecomas (thecomatosis) of the ovaries, an entity first appreciated by Dr Scully. Mesotheliomas are briefly reviewed emphasizing the caution that should be used in applying the designation "well-differentiated papillary mesothelioma." Many interpret the latter as benign, but multifocal lesions must be thoroughly examined histologically because of potential overlapping features with malignant mesothelioma. The morphologic spectrum of malignant mesothelioma and its usually straightforward distinction from müllerian neoplasms is considered, as is its occasional presentation as a dominant ovarian mass. The spectrum of low-grade serous peritoneal neoplasms including the "psammocarcinoma" is reviewed. Finally, various benign müllerian lesions, particularly endometriosis and endosalpingiosis, may be conspicuous in peritoneal specimens and sometimes are grossly striking. The usual presence of benign endometrioid epithelium and stroma should facilitate the correct diagnosis of endometriosis, but in cases in which the stroma is atrophic or the sole component (stromal endometriosis), diagnostic problems may arise.

Primary intestinal-type glandular lesions of the vagina: clinical, pathologic, and immunohistochemical features of 14 cases ranging from benign polyp to adenoma to adenocarcinoma.

Primary intestinal-type glandular lesions of the vagina are rare. We report a series of 14 lesions, including 1 intestinal-type polyp without neoplastic features, 3 adenomas (2 with high-grade dysplasia), and 10 adenocarcinomas. Patients ranged in age from 20 to 86 years (mean 60 y) and presented with vaginal bleeding or a mass. No history of diethylstilbestrol exposure, adenosis, or endometriosis was elicited in any patient. The lesions were mostly polypoid, small (0.8 to 2.0 cm), and located in the posterior (6 cases) and lower (7 cases) vagina. One carcinoma metastasized to a para-aortic lymph node; the others were confined to the vagina. The neoplasms exhibited histologic features identical to those seen in primary large intestinal tumors, including variable numbers of goblet cells and in 1 case neuroendocrine cells. Five of the adenocarcinomas contained areas consistent with a precursor adenoma. In 3 cases, a benign urothelium-lined duct was adjacent to the lesion, and in 2 patients benign intestinal-type epithelium was present; no other potential benign precursor lesions were seen. Immunohistochemical analysis was performed on 6 cases; the tumors were positive for CDX-2 (6/6), CK20 (5/6), CEA (5/5), CK7 (4/6), and CA-125 (2/4) and were negative for ER (0/6) and p16 (0/2). Clinical outcome data were available in 3 patients with adenocarcinomas; 1 died of disease in <1 year, and 2 were alive with no evidence of disease at 2 and 7 years. The pertinent literature is reviewed, and the potential origin and differential diagnosis of these lesions are discussed.

Recurrent intestinal mucinous borderline tumors of the ovary: a report of 5 cases causing problems in diagnosis, including distinction from mucinous carcinoma.

Intestinal mucinous borderline tumors (IMBTs) of the ovary are generally associated with a highly favorable outcome and rarely recur. We describe 5 cases of IMBT initially treated by cystectomy or by salpingo-oophorectomy that was likely incomplete, with subsequent recurrences. Three cases were received in consultation, and in each of these, the clinical and intraoperative findings were worrisome for mucinous carcinoma, and diagnostic difficulty was encountered by the referring pathologist. The patient age ranged from 28 to 69 (median 53) yrs. All tumors were clinically Stage I at presentation; in at least 3 cases, extensive adhesiolysis was required during their removal. A pathologic diagnosis of IMBT was made in 4 cases; the remaining tumor was inadequately sampled (3 blocks from a 7.5-cm tumor showed predominantly benign to focally borderline mucinous epithelium). A total of 8 recurrences, all as IMBT, developed at mean follow-up of 26 (range, 6-102) mo; 6 of these occurred within ≤2 yr. In 4 cases, removal of recurrent tumor required an extensive operation because of bowel and/or vaginal involvement. Residual ovarian stroma was identified in all recurrences. There was no evidence of invasive mucinous carcinoma, pseudomyxoma peritonei, or a primary tumor elsewhere (including appendix) in any of the cases. Our findings indicate that patients with IMBTs who undergo cystectomy or oophorectomy requiring adhesiolysis are at increased risk of recurrence, which may occur early, be multiple, and potentially require extensive resection if sites such as bowel or vagina are involved. Recurrences of IMBT that develop in this setting likely represent regrowth of incompletely resected IMBT, or arise within residual ovarian tissue. This is the first detailed clinicopathologic study of such cases.

Reproducibility of histological cell type in high-grade endometrial carcinoma.

Subclassification of endometrial carcinoma according to histological type shows variable interobserver agreement. The aim of this study was to assess specifically the interobserver agreement of histological type in high-grade endometrial carcinomas, recorded by gynecological pathologists from five academic centers across Canada. In a secondary aim, the agreement of consensus diagnosis with immunohistochemical marker combinations was assessed including six routine (TP53, CDKN2A (p16), ER, PGR, Ki67, and VIM) and six experimental immunohistochemical markers (PTEN, ARID1A, CTNNB1, IGF2BP3, HNF1B, and TFF3). The paired interobserver agreement ranged from κ 0.50 to 0.63 (median 0.58) and the intraobserver agreement from κ 0.49 to 0.67 (median 0.61). Consensus about histological type based on morphological assessment was reached in 72% of high-grade endometrial carcinomas. A seven-marker immunohistochemical panel differentiated FIGO grade 3 endometrioid from serous carcinoma with a 100% concordance rate compared with the consensus diagnosis. More practically, a three-marker panel including TP53, ER, and CDKN2A (p16) can aid in the differential diagnosis of FIGO grade 3 endometrioid from endometrial serous carcinoma. Our study demonstrates that the inter- and intraobserver reproducibility of histological type based on morphology alone are mostly moderate. Ancillary techniques such as immunohistochemical marker panels are likely needed to improve diagnostic reproducibility of histological types within high-grade endometrial carcinomas.

Papillary proliferation of the endometrium: a clinicopathologic study of 59 cases of simple and complex papillae without cytologic atypia.

Papillary proliferation of the endometrium (PPE) without cytologic atypia is uncommon and has only been studied in detail by Lehman and Hart in 2001. On histologic examination, PPE ranges from simple papillae with fibrovascular cores, often involving the surface of endometrial polyps, to complex intracystic proliferations; some consider the latter to be analogous to nonatypical complex hyperplasia. To further characterize PPE, with emphasis on the risk of and features associated with concurrent or subsequent neoplasia, the clinicopathologic features of 59 cases without cytologic atypia were studied. The cases were classified into 2 groups according to the degree of architectural complexity and extent of proliferation. Group 1 consisted of those with localized simple papillae. Simple papillae were defined as those with short, predominantly nonbranching stalks; those with occasional secondary branches and/or detached papillae were also included in this group. Localized proliferations were those with 1 or 2 foci involving the surface or the subjacent glands of polyps or nonpolypoid endometrium. Group 2 consisted of those with complex papillae and/or those with diffuse and crowded intracystic papillae. Complex papillae were those with either short or long stalks, with frequent secondary and complex branches. Diffuse proliferation was defined as presence of 3 or more foci within a specimen or involvement of >50% of the endometrial polyp by simple or complex PPE. Any coexistent or subsequent hyperplasia of conventional type (World Health Organization classification) or adenocarcinoma was recorded. The age of patients ranged from 23 to 82 years (median, 53 y); 36 (61%) were postmenopausal. The majority presented with abnormal vaginal bleeding. Sixteen patients (27%) were receiving hormonal preparations including 5 who were treated with a progestogen for preexisting endometrial hyperplasia or low-grade endometrioid adenocarcinoma. The histologic diagnosis of PPE was made in 49 biopsies and in 10 hysterectomy specimens. Thirty-six cases (61%) were classified as group 1 and 23 (39%) as group 2. In 47 cases (80%), there was a coexisting endometrial polyp, 39 (66%) of which were involved by the PPE. Fifty-three cases (90%) had coexisting epithelial metaplastic changes, 41 (77%) of which were involved by the PPE. The most common type of metaplasia was mucinous (41 of 59 cases, or 69%). Follow-up information was known for 46 patients (78%). Coexistent or subsequent nonatypical and atypical hyperplasia was found in 8 (17%) and 6 cases (13%), respectively. In 6 of the 46 cases (13%), a low-grade endometrioid adenocarcinoma was present either in the original specimen or during follow-up. In contrast to group 1 PPE, those with group 2 features were significantly associated with concurrent or subsequent premalignant lesions (nonatypical and atypical hyperplasia) or carcinoma (P<0.0001). This study indicates that localized and architecturally simple PPEs confined to a completely removed polyp are usually associated with a benign outcome and may be appropriately labeled as "benign papillary proliferation of the endometrium." Lesions with architecturally complex papillae, especially when extensive, have an increased risk of concurrent or subsequent endometrial hyperplasia and carcinoma and should probably be regarded as analogous to atypical complex hyperplasia, and the term "complex papillary hyperplasia" is appropriate. As the distinction between simple and complex PPE may be difficult in small endometrial aspirational samples, consideration for curettage should be given to ascertain whether the lesion has been completely removed.

Mutation of FOXL2 in granulosa-cell tumors of the ovary.

BACKGROUND: Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The pathogenesis of these tumors is unknown. Moreover, their histopathological diagnosis can be challenging, and there is no curative treatment beyond surgery. METHODS: We analyzed four adult-type GCTs using whole-transcriptome paired-end RNA sequencing. We identified putative GCT-specific mutations that were present in at least three of these samples but were absent from the transcriptomes of 11 epithelial ovarian tumors, published human genomes, and databases of single-nucleotide polymorphisms. We confirmed these variants by direct sequencing of complementary DNA and genomic DNA. We then analyzed additional tumors and matched normal genomic DNA, using a combination of direct sequencing, analyses of restriction-fragment-length polymorphisms, and TaqMan assays. RESULTS: All four index GCTs had a missense point mutation, 402C-->G (C134W), in FOXL2, a gene encoding a transcription factor known to be critical for granulosa-cell development. The FOXL2 mutation was present in 86 of 89 additional adult-type GCTs (97%), in 3 of 14 thecomas (21%), and in 1 of 10 juvenile-type GCTs (10%). The mutation was absent in 49 SCSTs of other types and in 329 unrelated ovarian or breast tumors. CONCLUSIONS: Whole-transcriptome sequencing of four GCTs identified a single, recurrent somatic mutation (402C-->G) in FOXL2 that was present in almost all morphologically identified adult-type GCTs. Mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs.

Uterine smooth muscle tumors of uncertain malignant potential (STUMP): a clinicopathologic analysis of 16 cases.

BACKGROUND: The current World Health Organization classification indicates that a uterine smooth muscle tumor that cannot be histologically diagnosed as unequivocally benign or malignant should be termed "smooth muscle tumor of uncertain malignant potential" (STUMP). STUMPs represent a heterogeneous group of rare tumors that have been the subject of only a few published studies, some of which lack detailed clinicopathologic details and/or follow-up data. More recently, it has been suggested that immunohistochemical staining may be helpful in the diagnosis of STUMPs. DESIGN: The clinicopathologic features of 16 cases of STUMP that exhibited usual smooth muscle differentiation, diagnosed between 1992 and 2006 from 11 hospitals, were studied and classified into 4 subgroups using terminology and criteria described by Stanford investigators. Immunohistochemical stains for p16, p53, MIB1 (ki-67), and estrogen and progesterone receptors were performed. The results were compared with those in the literature. RESULTS: The tumors were classified as follows: 6 as "atypical leiomyoma with limited experience", 7 as "smooth muscle tumor of low malignant potential", 2 as "atypical leiomyoma, low risk of recurrence," and 1 as "mitotically active leiomyoma, limited experience." Follow-up was 21 to 192 months (mean, 80.8 and median, 51.5). Only 2 tumors recurred, at 15 and 51 months, respectively; both were atypical leiomyoma with limited experience (multifocal moderate-to-severe atypia, no tumor cell necrosis, and mitotic counts of 4 and 5 mitotic figures /10 high-power fields, respectively). Both tumors had areas that were indistinguishable from benign leiomyoma and both had diffuse immunoreactivity for p16 and p53. Six other tumors that had focal staining for these markers all had a benign outcome. Both patients with recurrence were alive at last follow-up (at 40 and 74 mo). All the other patients were alive and disease-free. CONCLUSIONS: This and other studies suggest that uterine tumors classified as STUMPs using criteria proposed by Stanford investigators are usually clinically benign but should be considered tumors of low malignant potential because they can occasionally recur, in some cases, years after hysterectomy. After a mean follow-up of 80.8 months, only 2 of 16 tumors in this study recurred. Both of the latter tumors fulfilled the criteria for atypical leiomyoma with limited experience. Notably, the 2 recurrent tumors were the only ones that were strongly immunoreactive for p16 and p53, supporting earlier observations that these markers may be helpful in the prediction of the behavior of STUMPs. Patients diagnosed with STUMPs should receive long-term surveillance.

Luteinized thecomas (thecomatosis) of the type typically associated with sclerosing peritonitis: a clinical, histopathologic, and immunohistochemical analysis of 27 cases.

The nature of the distinctive ovarian lesion often associated with sclerosing peritonitis, initially considered a variant of luteinized thecoma in the paper describing this phenomenon, remains uncertain, as does its long-term prognosis. We describe the features of 27 cases, including immunohistochemical analysis of 13 cases. Sclerosing peritonitis was documented in 25 cases. Patients ranged in age from 10 months to 85 years, and typically presented with abdominal distension and pain with ascites and sometimes bowel obstruction. The ovarian lesions, clinically bilateral in 24 cases, ranged from 2 to 31 cm and often had a striking cerebriform aspect. Microscopically, mitotically active spindle cells with weakly luteinized cells, variable edema, and entrapped follicles were typical. The spindle cells were focally positive with calretinin in 2 cases, CD56 in 2, AE1/3 in 4, smooth muscle actin in 12, and desmin in 8 cases, and negative with alpha-inhibin, epithelial membrane antigen, beta-catenin, CD34, and transforming growth factor-beta, with focal nuclear positivity for estrogen receptor in 5 and progesterone receptor in 11 cases. Luteinized cells were positive with alpha-inhibin, calretinin, and/or CD56. The peritoneal lesions were strongly positive with AE1/3 and exhibited focal weak or moderate positivity with estrogen receptor or progesterone receptor in 4 of 8 cases each. Follow-up in 20 cases (mean: 5.9 y) disclosed no evidence of spread of the ovarian lesion, but 3 patients died of sclerosing peritonitis. The findings fail to allow definitive classification of the ovarian lesions, and we prefer at present to retain their current designation as a subtype of luteinized thecoma, but to allow for the possibility of a non-neoplastic nature, feel it reasonable to have the designation "thecomatosis" as a parenthetical alternative. We have documented for the first time that sclerosing peritonitis is not invariably associated with the distinctive ovarian pathology present in these cases.

Primary endometrioid adenocarcinoma of the vagina: a clinicopathologic study of 18 cases.

Vaginal adenocarcinoma is the second most common primary cancer of the vagina, yet there has been very little study of most subtypes other than clear cell carcinoma. We reviewed 18 cases of primary vaginal endometrioid adenocarcinoma, in our experience the second most common subtype. The patients ranged from 45 to 81 years of age (mean 60). Most presented with vaginal bleeding, and had had a prior hysterectomy. Five had a history of unopposed estrogen therapy but none had a history of intrauterine diethylstilbestrol exposure. The tumors were at the vaginal apex in 10 cases, in the posterior wall in 3, the lateral wall in 3, and the anterior wall in 1. On microscopic examination, each of the tumors had a pure or predominant component of typical endometrioid adenocarcinoma. There was squamous metaplasia in 4 cases, mucinous metaplasia in 4, and prominent nonvillous papillae in 2. The tumors were grade 1 of 3 in 4 cases, grade 2 in 13, and grade 3 in 1. Eleven cases were FIGO stage I, 5 stage II, and 2 stage IV. Vaginal endometriosis was identified in 14 cases, and is important in indicating a primary vaginal tumor, rather than secondary spread from the endometrium. Other subtypes of adenocarcinoma (such as serous when the tumor has a papillary pattern) and atypical forms of endometriosis, including polypoid endometriosis, are the most common other differential diagnostic considerations. The prognosis seems to be good in low-stage patients, with 11 patients alive and well and 2 alive with recurrent disease.

The pathology of endometriosis: a survey of the many faces of a common disease emphasizing diagnostic pitfalls and unusual and newly appreciated aspects.

Although the histologic diagnosis of endometriosis is usually straightforward, many diagnostic problems can arise as a result of alterations or absence of its glandular or stromal components. The diagnostic difficulty in such cases can be compounded by tissue that is limited to a small biopsy specimen. The appearance of the glandular component can be altered by hormonal and metaplastic changes, as well as cytologic atypia and hyperplasia. Although the last 2 findings are often referred to collectively as "atypical endometriosis," they should be separately recognized as their premalignant potential likely differs. In some cases, the endometriotic glands are sparse or even absent (stromal endometriosis). The stromal component can be obscured or effaced by infiltrates of foamy and pigmented histiocytes, fibrosis, elastosis, smooth muscle metaplasia, myxoid change, and decidual change. Occasional findings in endometriosis that may raise concern for a neoplasm include necrotic pseudoxanthomatous nodules, polypoid growth (polypoid endometriosis), bulky disease, and venous, lymphatic, or perineural invasion. Inflammatory and reactive changes within, adjacent to, or at a distance from foci of endometriosis can complicate the histologic findings and include infection within endometriotic cysts, pseudoxanthomatous salpingitis, florid mesothelial hyperplasia, peritoneal inclusion cysts, and Liesegang rings. The histologic diagnosis of endometriosis can also be challenging when it involves an unusual or unexpected site. Five such site-specific problematic areas considered are endometriosis on or near the ovarian surface, superficial cervical endometriosis, vaginal endometriosis, tubal endometriosis, and intestinal endometriosis, including the important distinction of an endometrioid carcinoma arising from colonic endometriosis from a primary colonic adenocarcinoma. Finally, endometriotic foci can occasionally be intimately admixed with another process, such as peritoneal leiomyomatosis or gliomatosis, resulting in a potentially confusing histologic appearance.

Cellular fibromas of the ovary: a study of 75 cases including 40 mitotically active tumors emphasizing their distinction from fibrosarcoma.

Cellular fibroblastic tumors of the ovary are currently classified as either cellular fibroma (CF) or fibrosarcoma. The former are characterized by bland nuclei, 3 or fewer mitotic figures per 10 high-power fields (MFs/10 HPFs), and a low malignant potential, whereas fibrosarcomas usually have severe nuclear atypia, > or = 4 MFs/10 HPFs, and an aggressive clinical course. The prognosis of cellular fibromatous tumors with > or = 4 MFs/10 HPFs and low-grade cytology is not established and it is the purpose of this study to investigate that aspect. It has been our anecdotal experience that otherwise typical CFs with > or = 4 MFs/10 HPFs usually have a benign clinical course, suggesting that such tumors should be regarded as "mitotically active cellular fibroma" (MACF) rather than fibrosarcoma. Seventy-five cellular fibromatous neoplasms were analyzed to determine their clinicopathologic features and the appropriateness of "MACF" as a designation for otherwise typical CFs with > or = 4 MFs/10 HPFs. The mean age of patients with CF (n = 35, 0 to 3 MFs/10 HPFs) and MACF (n = 40, > or = 4 MFs/10 HPFs) was 51 and 41 years, respectively. Patients most commonly presented with symptoms related to a pelvic mass. All tumors were unilateral. The mean tumor size of CFs was 8.0 cm and 9.4 cm for MACFs. The majority of the tumors were solid; approximately one-third of them had a cystic component. Ovarian surface adhesions, involvement of the ovarian surface, or both, was present in 6% of CFs and 10% of MACFs. Eleven percent of CFs and 13% of MACFs were associated with extraovarian involvement. All tumors consisted of cellular, intersecting bundles of spindle cells with bland nuclear features. The mean highest mitotic count for MACFs was 6.7 MFs/10 HPFs (range 4 to 19 MFs/10 HPFs). Follow-up of 3 months to 12 years (mean 4.75 y) was available in 18 of the 40 patients with MACFs and was uneventful in all cases. We conclude that cellular fibromatous neoplasms with bland cytology and elevated mitotic counts are associated with favorable patient outcome and should be diagnosed as MACF rather than fibrosarcoma, which usually have moderate to severe atypia and elevated mitotic rates. As prior observations have shown that even typical CFs can occasionally recur locally, particularly if they are associated with rupture or adherence, long-term follow-up for patients with CFs and MACFs is appropriate.

Skeletal muscle-like and rhabdoid cells in uterine leiomyomas.

We describe eight unusual uterine leiomyomas characterized by a component of cells that suggested skeletal muscle differentiation or resembled the rhabdoid cells of extrarenal rhabdoid tumors. All of the tumors were referred because of problems in differential diagnosis, particularly distinction from an epithelioid smooth muscle tumor, a smooth muscle tumor of uncertain malignant potential, or a tumor with skeletal muscle differentiation. The patients were aged 27 to 50 (mean, 38) years, and the presenting clinical features and gross appearance of the tumors were similar to those of typical uterine leiomyomas. On microscopic examination, seven of the tumors were well circumscribed, whereas one showed slight irregularity of its margin. The characteristic feature of the tumors was a variable number of rounded, polygonal, or strap-shaped cells with abundant deeply eosinophilic cytoplasm and fibrillar, or occasionally hyaline, intracytoplasmic globules. Cytoplasmic cross-striations were not identified. The cells usually had eccentric, round-to-oval nuclei with conspicuous nucleoli. A variable number of the rhabdoid/skeletal muscle-like cells, as well as cells without these features, contained multiple or multilobed, pleomorphic, hyperchromatic nuclei, thus qualifying the tumors as leiomyomas with bizarre nuclei. Foci of hydropic change were present in all of the tumors. The mitotic index was low (<1 mitotic figure/10 high-power fields) and necrosis was absent in all the tumors. The rhabdoid/skeletal muscle-like cells were immunoreactive for desmin and h-caldesmon, but not for cytokeratin (AE1/AE3) or skeletal muscle markers (myoglobin, Myo-D1, or myogenin). Intracytoplasmic whorls of intermediate filaments were observed in the cells of one case examined by electron microscopy; there was no ultrastructural evidence of skeletal muscle differentiation. The histologic, immunohistochemical, and ultrastructural features indicated that the peculiar cells in these leiomyomas likely represented smooth muscle cells with an unusual phenotype rather than the cells of uterine tumors with skeletal muscle differentiation, extrarenal rhabdoid tumors, or epithelioid smooth muscle tumors. An association with leiomyomas with bizarre nuclei also was suggested.

Aggressive behavior of stage I ovarian mucinous tumors lacking extensive infiltrative invasion: a report of four cases and review of the literature.

Previous studies have indicated that mucinous carcinomas of the ovary associated with extraovarian spread at the time of presentation or follow-up almost always have extensive infiltrative invasion within the primary tumor. We present four cases of stage I ovarian mucinous tumors that lacked extensive infiltrative invasion but were associated with an unexpectedly aggressive behavior. The patients were 18, 20, 41, and 45 years of age at presentation. All four of them presented with an abdominal mass or increased abdominal girth. The tumors were all stage Ia, 17 to 37 centimeters in maximal dimension, and typically multicystic with solid areas. The number of blocks per centimeter of tumor diameter was 0.65, 0.88, 0.92, and 1.0 in the four tumors, respectively, a degree of sampling within that recommended in previous studies. Clinical findings supported that they were primary tumors rather than metastatic from an occult primary tumor. On microscopic examination, the tumors all contained foci of intraepithelial carcinoma and foci of invasion as follows: expansile invasion only (two cases), expansile invasion and microinvasive carcinoma (one case), and microinvasive carcinoma only (one case). The expansile invasion was extensive in each of the three cases in which it was present. On follow-up, each patient experienced recurrent disease 7 months to 4.5 years after diagnosis, including hematogenous spread to lung and/or bone and liver in three patients. Three of four patients developed intraperitoneal spread. Three of four patients died of disease, and one patient is alive with persistent disease. Although ovarian mucinous tumors with only expansile invasion or only microinvasive carcinoma are usually associated with an excellent prognosis, this study indicates that these tumors can rarely behave in an aggressive fashion with hematogenous spread and a fatal outcome. Some of these tumors may have contained unsampled foci of infiltrative invasion. Although the optimum level of sampling in mucinous tumors remains to be determined, we recommend additional sampling of tumors in which the initial sections reveal intraepithelial carcinoma, microinvasive carcinoma, expansile invasion, or combinations thereof.

Malignant peritoneal mesothelioma in women: a study of 75 cases with emphasis on their morphologic spectrum and differential diagnosis.

Seventy-five malignant mesotheliomas of the peritoneum in women were reviewed to highlight their morphologic spectrum. The patients ranged from 17 to 92 (mean, 47.4) years of age. The clinical presentation was usually abdominal or pelvic pain, abdominal swelling (sometimes due to ascites), or a pelvic mass. On microscopic examination, the majority of the tumors had only an epithelial morphology, but 4 were biphasic and 1 was sarcomatoid. The most common epithelial patterns were tubular and papillary (which often coexisted), but 5 tumors were purely diffuse; 2 had cells with abundant glassy eosinophilic cytoplasm (so-called deciduoid mesothelioma). The cells in the tubular and papillary patterns were generally cuboidal with scant to moderate amounts of eosinophilic cytoplasm. Nuclear atypia was usually only mild, although a minority of cases had moderate or even, occasionally, severe atypia. Many tumors had foci that, viewed in isolation, resembled so-called well-differentiated papillary mesothelioma, and accordingly that diagnosis should be made cautiously. Unusual features were lymphoid follicles (13 cases), striking myxoid stroma (5 cases), prominent foamy histiocytes (5 cases), and a striking vascular proliferation (1 case). The varied morphology of peritoneal malignant mesotheliomas may raise a broad differential diagnosis, but in most cases the resemblance to other tumors is limited. Histochemistry, immunohistochemistry, and electron microscopy may provide important aid, particularly when tissue is limited, but should be needed only occasionally.