Uterine artery embolization with trisacryl gelatin microspheres in women treated for leiomyomas: a clinicopathologic analysis of alterations in gynecologic surgical specimens.

To characterize the histologic range of alterations due to uterine artery embolization with trisacryl gelatin microspheres in gynecologic specimens containing leiomyomas in detail, we report our clinicopathologic experience with 26 cases (longest postuterine artery embolization interval, 1.9 yr). Microspheres were observed in 85% of cases and could be seen up to 1.9 years after embolization. They were mainly present in leiomyomas and nonneoplastic myometrium but could be found in other nontargeted sites, such as the cervix, endometrium, ovaries, and fallopian tubes; however, infarction (present in 96% of cases) was confined to leiomyomas and did not involve other nonneoplastic tissues. The appearance of the infarcts was correlated with time after embolization, and coagulative necrosis/necrosis of indeterminate type was restricted to the early period after uterine artery embolization (before 10 wk postuterine artery embolization) whereas hyaline necrosis was seen predominantly in the late period (mostly after 10 wk, up to 1.9 yr). Of the 14 hysterectomy specimens with microspheres in extravascular spaces (almost all of which were in close proximity to the arteries), pseudoaneurysms were also focally present in 8 (57%) specimens. Microspheres were usually associated with mild inflammatory reactions, which persisted >1 year after embolization but did not become more severe over time. Morphologic and histochemical features of trisacryl gelatin microspheres were compared with other embolization agents, which can also be encountered in surgical specimens [polyvinyl alcohol (PVA) particles and PVA microspheres]. Trisacryl gelatin microspheres were negative with periodic acid-Schiff and orange-pink with Movat stains whereas PVA was positive with periodic acid-Schiff and black with Movat. Our study, the largest histologic analysis to date, confirms and extends the observations of earlier studies of trisacryl gelatin microspheres. In addition, we conclude that, as expected, the histologic appearance of microsphere-induced infarcts is a function of time, similar to healing of infarcts in nongynecologic sites. Pseudoaneurysms are a likely mechanism for the production of microspheres in extravascular spaces. Inflammation associated with microspheres can persist in gynecologic tissues but does not seem to result in the destruction of nontargeted sites. Finally, trisacryl gelatin microspheres can be distinguished from PVA particles and PVA microspheres based on a combination of morphologic features and histochemical stains.

Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors.

Different immunohistochemical sex cord-stromal markers have been previously studied in various types of ovarian sex cord-stromal tumors; however, the sensitivity for sex cord-stromal lineage may vary between markers, and some markers may not be as sensitive in some types of sex cord-stromal tumors compared with other tumors in this spectrum of neoplasms. The goals of this study were to determine which immunohistochemical markers are the most sensitive and immunohistochemically robust for sex cord-stromal lineage within a given type of ovarian sex cord-stromal tumor, and to establish whether there are substantial differences of expression of these markers between different types of sex cord-stromal tumors. Immunohistochemical stains for markers which have known variable specificity for sex cord-stromal lineage [inhibin, calretinin, MART-1/melan-A, CD99, steroidogenic factor 1 (SF-1, adrenal 4-binding protein), and WT1], were performed in 127 cases of 5 different types of ovarian sex cord-stromal tumors: adult granulosa cell tumor (n=32), Sertoli cell tumor (n=27), Sertoli-Leydig cell tumor (n=18), steroid cell tumor (n=25), and fibroma/fibrothecoma (n=25). All cases in each type of sex cord-stromal tumor expressed SF-1. Inhibin and calretinin were expressed in all groups of tumors but with a lesser frequency (56% to 100% and 36% to 100% of cases, respectively). All types of tumors except steroid cell tumor expressed WT1. Fibroma/fibrothecoma was the only type of tumor that did not express CD99. The only tumor groups that showed expression of MART-1 were Sertoli-Leydig cell tumor (restricted to the Leydig cell component) and steroid cell tumor (94% and 96% of cases, respectively). The type of sex cord-stromal tumor that was least frequently positive for several of the different markers studied was fibroma/fibrothecoma. Among all tumor groups combined, inhibin and WT1 were the 2 markers showing the most diffuse expression. Likewise, the single marker showing the most optimal combination of diffuse and strong staining (immunohistochemical composite score: possible range, 1 to 12) varied between tumors: adult granulosa cell tumor-inhibin (score 10.0); Sertoli cell tumor-WT1 (score 10.8); Sertoli-Leydig cell tumor (Sertoli cell component)-WT1 (score 10.4); steroid cell tumor-inhibin (score 11.2); and fibroma/fibrothecoma-WT1 (score 8.9). We conclude that most immunohistochemical sex cord-stromal markers have sufficient sensitivity for sex cord-stromal lineage. Although each of the different types of sex cord-stromal tumors has a slightly unique immunoprofile in terms of frequency and extent of expression, these differences are relatively minor for most types of tumors with certain exceptions (eg, WT1 is not diagnostically useful in steroid cell tumor; CD99 is not diagnostically useful in fibroma/fibrothecoma; the only sex cord-stromal tumor for which MART-1 is diagnostically useful is steroid cell tumor; inhibin and calretinin are less diagnostically useful in fibroma/fibrothecoma than in the other types of tumors, but expression in fibrothecoma was higher than in fibroma). SF-1 is the most sensitive sex cord-stromal marker among the most common types of sex cord-stromal tumors. Given the findings relating to sensitivity and extent of expression in this study, and known specificity in the literature, the most informative sex cord-stromal markers to be used for the distinction from nonsex cord-stromal tumors are inhibin, calretinin, SF-1, and WT1 (the exact number of markers to be used should be based on the degree of difficulty of the case and level of experience of the pathologist); however, the utility of immunohistochemistry for the diagnosis of fibroma/fibrothecoma is somewhat limited.

SF-1 is a diagnostically useful immunohistochemical marker and comparable to other sex cord-stromal tumor markers for the differential diagnosis of ovarian sertoli cell tumor.

Immunohistochemistry can be an important part of the diagnosis of Sertoli cell tumor of the ovary, including distinction from non-sex cord-stromal tumors such as the sertoliform variant of endometrioid carcinoma and carcinoid. Several good markers for this differential diagnosis have been identified, particularly inhibin, Wilms tumor 1 gene product (WT1), epithelial membrane antigen, and chromogranin; however, many available markers have limitations to some degree. Steroidogenic factor 1 (SF-1; adrenal 4-binding protein; Ad4BP) is a nuclear transcription factor involved in gonadal and adrenal development. In the testes, SF-1 is expressed in Sertoli cells. Immunohistochemical expression of this marker in ovarian sex cord-stromal tumors, including utility for differential diagnosis, has not been rigorously evaluated. As an extension of our previous immunohistochemical studies of ovarian Sertoli cell tumor, expression of SF-1 and comparison with WT1 and inhibin were assessed in 111 primary ovarian tumors: 27 Sertoli cell tumors, 60 endometrioid tumors (including borderline tumors, conventional well-differentiated carcinomas, and sertoliform variants of carcinoma), and 24 carcinoids. SF-1 was expressed in 100% of Sertoli cell tumors but not in endometrioid tumors or carcinoid. WT1 was expressed in 100% of Sertoli cell tumors and 17% of endometrioid tumors; all carcinoids were negative. Inhibin was expressed in 96% of Sertoli cell tumors and 2% of endometrioid tumors (4% of conventional well-differentiated carcinomas); all carcinoids were negative. The extent of expression of all 3 markers was similar in Sertoli cell tumor but greatest for WT1: 63%, 96%, and 78% of cases showed expression of SF-1, WT1, and inhibin, respectively, in more than 50% of tumor cells. Immunohistochemical composite scores combining both extent and intensity of staining in positive cases were calculated for Sertoli cell tumor (possible range: 1-12). Combined extent/intensity of immunostaining was similar for all 3 markers, but WT1 showed the most robust immunoreactivity in positive cases (mean immunohistochemical composite scores for SF-1, WT1, and inhibin: 6.1, 10.8, and 7.8, respectively). We conclude that for the differential diagnosis with endometrioid tumors and carcinoid of the ovary, SF-1 is a sensitive and specific immunohistochemical marker for Sertoli cell tumor and that SF-1 is diagnostically comparable with other good sex cord-stromal markers.

Characterization of acrylic polyamide plastic embolization particles in vitro and in human tissue sections by light microscopy, infrared microspectroscopy and scanning electron microscopy with energy dispersive X-ray analysis.

Vascular embolization is a well-established practice for the treatment of tumors and vascular lesions. Rounded beads (microspheres) of various materials (collagen, dextran and trisacryl-polymer-gelatin) were developed to solve problems encountered with earlier versions of embolic material. We performed histochemistry, Fourier transform infrared microspectroscopy and scanning electron microscopy with energy dispersive X-ray analysis on two uterine and one hepatic specimen with unidentified intravascular foreign material, and examined a reference embolization product for comparison. The hematoxylin and eosin stained tissue sections showed multiple foci with unidentified intravascular foreign material and fibrous obliteration of vessel lumens. Only one case had a clinical history of previous embolization but without specifying the material used. One case was submitted for identification of a 'parasite'. The material stained positively with Sirius red and mucicarmine, variably with Masson's trichrome stain and Movat pentachrome, and did not stain centrally with periodic acid Schiff with diastase. Infrared spectrophotometric analysis of the material from all three cases demonstrated the spectrum of acrylic polyamide plastic. A control sample of EmboGold exhibited infrared microspectroscopic spectra similar to the three tissue specimens. Analysis by scanning electron microscopy with energy dispersive X-ray analysis demonstrated some differences in elemental composition between the tissue sections and the selected reference material. To our knowledge, this is the first report of infrared spectrophotometric analysis with scanning electron microscopy with energy dispersive X-ray analysis of an acrylic polyamide plastic embolization product both in vitro and in human histologic tissue sections. In cases lacking appropriate clinical information, identification by these methods and/or a panel of special stains may assist pathologists unfamiliar with this material's light microscopic appearance.

Pseudoinfiltrative tubal metaplasia of the endocervix: a potential form of in utero diethylstilbestrol exposure-related adenosis simulating minimal deviation adenocarcinoma.

We report three cases of unusual tubal-type endocervical glandular proliferations simulating minimal deviation adenocarcinoma in women with a history of in utero diethylstilbestrol (DES) exposure. The lesions were characterized by haphazard glandular proliferations extending from 3.4 to 6.1 mm into the endocervical stroma and to the margins of excision in all cases. Most of the glands were small to medium-sized and round; some exhibited a moderate degree of cystic dilatation, and occasional glands had curvilinear profiles. The glandular epithelium displayed extensive tubal-type differentiation in all cases. In two cases, the glands lacked cytologic atypia and mitotic activity, and in one case, there was mild to moderate nuclear atypia with occasional mitotic activity. Immunohistochemical studies showed diffuse expression of estrogen and progesterone receptors and essentially no expression of p16 in two cases tested; there was no expression of CD10 in one case that was tested. The Ki-67 proliferation index was zero in one case and 25% in another. Human papillomavirus DNA was not detected by in situ hybridization in one case that was tested. The proliferations lacked features of mucinous and tubo-endometrioid types of minimal deviation adenocarcinoma. The clinicopathologic findings suggest the lesions are benign, and the association with in utero DES exposure raises the possibility that these could be a form of DES-related adenosis.

Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive "grungy" calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.

Cell clusters overlying focally disrupted mammary myoepithelial cell layers and adjacent cells within the same duct display different immunohistochemical and genetic features: implications for tumor progression and invasion.

INTRODUCTION: Our previous studies detected focal disruptions in myoepithelial cell layers of several ducts with carcinoma in situ. The cell cluster overlying each of the myoepithelial disruptions showed a marked reduction in or a total loss of immunoreactivity for the estrogen receptor (ER). This is in contrast to the adjacent cells within the same duct, which were strongly immunoreactive for the ER. The current study attempts to confirm and expand previous observations on a larger scale. METHODS: Paraffin sections from 220 patients with ER-positive intraductal breast tumors were double immunostained with the same protocol previously used. Cross-sections of ducts lined by > or = 40 epithelial cells were examined for myoepithelial cell layer disruptions and for ER expression. In five selected cases, ER-negative cells overlying the disrupted myoepithelial cell layer and adjacent ER-positive cells within the same duct were separately microdissected and assessed for loss of heterozygosity and microsatellite instability. RESULTS: Of the 220 cases with 5698 duct cross-sections examined, 94 showed disrupted myoepithelial cell layers with 405 focal disruptions. Of the 94 cases, 79 (84%) contained only ER-negative cell clusters, nine (9.6%) contained both ER-negative and ER-positive cell clusters, and six (6.4%) contained only ER-positive cell clusters overlying disrupted myoepithelial cell layers. Of the 405 disruptions, 350 (86.4%) were overlain by ER-negative cell clusters and 55 (13.6%) were overlain by ER-positive cell clusters (P < 0.01). Microdissected ER-negative and ER-positive cells within the same duct from all five selected cases displayed a different frequency or pattern of loss of heterozygosity and/or microsatellite instability at 10 of the 15 DNA markers. CONCLUSIONS: Cells overlying focally disrupted myoepithelial layers and their adjacent counterparts within the same duct displayed different immunohistochemical and molecular features. These features potentially represent an early sign of the formation of a biologically more aggressive cell clone and the myoepithelial cell layer breakdown possibly associated with tumor progression or invasion.

Tenosynovial (extraarticular) chondromatosis: an analysis of 37 cases of an underrecognized clinicopathologic entity with a strong predilection for the hands and feet and a high local recurrence rate.

Tenosynovial chondromatosis is a multinodular cartilaginous proliferation that arises from the tenosynovial membranes. This report describes the clinical, radiologic, and histopathologic findings in 37 cases of this uncommon entity. There were 17 males and 20 females, ranging in age from 20 to 86 years (mean and median age, 46 years). The process involved tenosynovium of the fingers (n = 19), feet (n = 8), wrists (n = 4), ankles (n = 2), hand, not otherwise specified, or palm (n = 2), knee (n = 1), and forearm (n = 1). Signs of disease or symptoms were present for 5 weeks to 18 years (median duration, approximately 2 years) before surgical excision. The two most common complaints were a painless mass and a mass that was mildly tender with pressure. None of the tumors had clinical, radiologic, or histopathologic evidence of articular or bone involvement. Histologically, all tumors consisted of a multinodular cartilaginous proliferation involving tenosynovium and/or subsynovial connective tissue. Mild or moderate atypia, as encountered in chondroma of soft parts and synovial chondromatosis, was a frequent finding. Follow-up information was available for 16 patients (43%). Only two patients with follow-up information remained disease free after their initial surgical procedure. Seven patients had one recurrence and seven patients had two or more recurrences. Tenosynovial chondromatosis appears to be an extraarticular counterpart of synovial (intraarticular) chondromatosis. Our review indicates this process is often confused with chondroma of soft parts, in part, because both entities have a predilection for the hands and feet. Diagnosis of this underrecognized entity is of clinical importance because of the high local recurrence rate.

A subset of morphologically distinct mammary myoepithelial cells lacks corresponding immunophenotypic markers.

INTRODUCTION: Immunostaining for smooth muscle actin (SMA) is commonly used to elucidate mammary myoepithelial (ME) cells, whose presence or absence is a reliable criterion for differentiating in situ and invasive carcinomas. However, some morphologically distinct ME cells fail to stain for SMA. This study intended to assess whether these SMA-negative cells also lack the expression of other ME cell markers. METHODS: Hematoxylin/eosin and SMA immunostained sections from 175 breast cancer patients were examined. Three cases were found to harbor ducts that showed morphologically distinct ME cell layers, but showed no SMA immunostaining in at least one-third of the layer or the entire layer. Eight additional consecutive sections from each case were stained for SMA, using a black chromogen, and each was then re-stained for one of eight additional markers supposed to exclusively or preferentially stain ME cells, using a red chromogen. SMA-negative ME cells were re-examined for the expression of other markers. RESULTS: SMA-negative ME cells in two cases also failed to display immunoreactivity for other markers, including calponin, CD10, smooth muscle myosin heavy chain, protease inhibitor 5 (maspin), Wilms' tumor-1, and cytokeratins 5, 14, and 17 (CK5, CK14, and CK17). However, in one case SMA-negative ME cells displayed immunoreactivities for maspin, CK5, CK14, and CK17. The distribution of these ME cells is independent of ductal size, length, and architecture. CONCLUSIONS: A subset of morphologically identifiable ME cells lack the expression of nine corresponding immunophenotypic markers, suggesting that ME cells might also be subject to different normal and pathological alterations.

Synovial-type giant cell tumors of the vertebral column: a clinicopathologic study of 15 cases, with a review of the literature and discussion of the differential diagnosis.

Synovial and tenosynovial giant cell tumors only rarely arise in close proximity to the axial skeleton; to date, fewer than 30 examples have been reported in the English-language medical literature. In this report we describe the clinical, radiologic, histopathologic, and immunohistochemical findings in 15 cases retrieved from our files. The study group comprised 7 males and 8 females, ranging in age from 17 to 44 years (mean age, 32 years). The tumors involved the cervical (n = 11), thoracic (n = 1), lumbar (n = 2), and sacrococcygeal (n = 1) regions and ranged in size from 1.0 to 6.0 cm in greatest dimension (median size, 3 cm). Symptoms were present for 2 months to at least 2 years, with the most common complaint being pain localized to the spinal region (n = 12). Ten patients also had radicular symptoms. Radiologic studies, available for 11 cases, usually demonstrated a mass involving the posterior aspect of adjoining vertebrae. Bony abnormalities (including scalloping, erosion, and destruction), facet joint and soft tissue involvement, and extradural extension were typically present. Histologically, all tumors contained a proliferation of epithelioid (histiocytoid) cells, admixed with varying numbers of osteoclast-like giant cells, siderophages, xanthoma cells, lymphocytes, and some spindled fibroblast-like cells. Only 1 tumor had the classic villiform architecture of pigmented villonodular synovitis. The remaining 14 tumors had a nodular appearance with varying amounts of collagen. Seven of these had definite histological evidence of infiltrative growth, and 6 had some features that warranted concern for possible infiltration. Only 1 tumor had findings fully compatible with a localized synovial-type giant cell tumor/nodular (teno)synovitis. All tumors had mitotic activity, with mitotic counts ranging from 1 to 21 mitotic figures per 50 high-power fields (HPFs) (mean mitotic count, 5 mitotic figures/50 HPFs). Immunohistochemistry was performed on 5 tumors, and immunoreactivity was present for CD68, CD163, and vimentin. Limited immunoreactivity for muscle actin (HUC1-1) was also noted. Follow-up information was available for 9 of the 15 patients (60%). Five patients had no evidence of recurrent or persistent disease 4 months to 9 years after undergoing either a local excision with gross total tumor removal (with or without irradiation) or a wide en bloc resection. Four patients had persistent disease after undergoing either an incomplete resection or biopsy with spinal fusion procedure. All 4 of these patients had additional surgical intervention (accompanied by irradiation in 2 instances), but only one was known to be disease-free at last follow-up (10 years after gross total tumor removal). No patient has experienced a metastasis or died of disease. The best predictor of outcome was gross total tumor removal at the surgical outset.