Search

The experience with uterine inflammatory myofibroblastic neoplasms with an unfavorable outcome is limited. We present the clinicopathologic features of 9 such cases, including 8 inflammatory myofibroblastic tumors (IMTs) and 1 epithelioid inflammatory myofibroblastic sarcoma (EIMS). Median patient age for the IMT group was 50.5 years; the patient with EIMS was 43 years old. Patients presented with abnormal uterine bleeding, presumed fibroids, pelvic pain, arthralgia and low-grade fever, as well as an incidental finding. Median tumor size for the IMTs was 8.5 cm. The borders were either infiltrative or well-circumscribed. Histologically, IMTs were purely fascicular or myxoid or showed predominance of one or the other pattern. Seven tumors were spindled, and 1 was both spindled and epithelioid. Tumors had variable nuclear atypia, ranging from grade 1 to 3. All tumors had an inflammatory infiltrate-predominantly lymphocytic, majority had necrosis (62.5%) and none had lymphovascular invasion. 7/8 (87.5%) tumors were positive for ALK-1 by immunohistochemistry (IHC). One tumor was negative for ALK-1 by IHC but was positive for ALK fusion by fluorescence in situ hybridization and had TNS1-ALK fusion by next-generation sequencing (NGS). Three other tumors with NGS testing showed one of the following ALK-fusion partners: FN1, DCTN1, and IGFBP5. The EIMS had infiltrative borders, myxoid and hyalinized patterns, epithelioid cells, and no lymphovascular invasion. This tumor was ALK-1 positive by IHC, had ALK rearrangement by fluorescence in situ hybridization and RANBP2-ALK fusion by NGS. Extrauterine disease at time of diagnosis was noted in 2/8 (25%) of IMTs, and in the single case of EIMS. Seven patients had surgery as primary treatment, 1 patient had neoadjuvant chemotherapy and 1 patient declined treatment. Patients with recurrence were treated with a combination of chemotherapy, targeted therapy, radiotherapy or hormonal therapy. Most patients (71.4%) recurred within 24 months (mos). Two thirds of patients were alive with disease at last follow up (mean 43.6 mos). The patient with EIMS was alive with disease at 22 mos. IMT referral cases were initially diagnosed as smooth muscle tumors in 87.5% of cases; while the EIMS was diagnosed as high-grade endometrial stromal sarcoma. Lack of consideration of IMT in the differential diagnosis of smooth muscle tumors with myxoid features can result in misdiagnosis and under-utilization of targeted therapy in these patients., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The self-limited nature of nodular fasciitis (NF) is well-known but its precise mechanism has not yet been clarified. We observed that "young" NF (preoperative duration <1 month) consistently contains a higher percentage (~80%) of USP6 break-apart FISH signals than "old" NF (preoperative duration >3 months) (~20%). Thus, we hypothesized that our original observation may reflect a connection with the self-limited nature of NF. Seventeen cases with reliable data concerning the onset were selected, thus approximating the lifetime of each tumor. Besides the USP6 interphase FISH examination, we also checked the most common MYH9-USP6 fusion using RT-PCR. Because of the known pathways of the tumorigenesis of NF, the mRNA level of USP6, TRAIL, IFN-beta, JAK1, STAT1, STAT3, JUN, and CDKN2A was measured using qRT-PCR. Regarding proteins, USP6, p16, p27, TRAIL, and IFN-beta were examined using immunohistochemistry. Targeted gene panel next-generation sequencing (NGS) of three cases was additionally performed. We found a strong negative correlation (p = 0.000) between the lifetime and percentage of USP6 break-apart signals and a strong positive relationship (p = 0.000) between USP6 break-apart signals and mitotic counts. Results of immunostainings, along with qRT-PCR results, favored the previously-suggested USP6-induced negative feedback mechanism through activation of TRAIL and IFN-beta, likely resulting in apoptosis and senescence of tumor cells harboring USP6 fusions. Targeted-NGS resulted in the detection of several variants, but no additional recurrent changes in the pathogenesis of these tumors. We revealed on a cellular level the USP6-induced negative feedback mechanism. In conclusion, we emphasize that in "old" NF, the percentage of USP6 break-apart FISH signals can be as low as 14-27% which can be very important from a differential diagnostic point of view. We emphasize that a careful examination and interpretation of the NGS data is needed before clinical decision-making on treatment., (© 2021. The Author(s).)

Mimickers of neuroendocrine neoplasms (NEN) include a number of important pitfall tumors. Here, we describe our experience with mesenchymal mimics of NENs to illustrate their spectrum and draw the attention particularly to a group of mesenchymal/non-epithelial neoplasms (MN) that combine epithelioid histology with neuroendocrine (NE-) features and peculiar genetic abnormalities. In a consultation series of 4498 cases collected between 2009 and 2021, 2099 neoplasms expressing synaptophysin and/or chromograninA were reviewed and analyzed. A total of 364 (18%) were diagnosed as non-NENs, while the remaining tumors were NEN. The group of mesenchymal/non-epithelial neoplasms with NE-features (MN-NE) included 31/364 (8%) cases. These mostly malignant neoplasms showed an epithelioid morphology. While all but one tumor expressed synaptophysin, mostly patchy, only 10/29 (34%) co-expressed chromograninA. A total of 13/31 (42%) of the MN-NE showed EWSR1-related gene fusions (6 Ewing sarcomas, 5 clear cell sarcomas, and 1 desmoplastic small round cell tumor, 1 neoplasm with FUS-CREM gene fusion) and 7 (23%) were SWI/SNF (SMARCB1 or SMARCA4)-deficient neoplasms. The remaining MN-NE included synovial sarcoma, sclerosing epithelioid mesenchymal neoplasm, melanoma, alveolar soft part sarcoma, solitary fibrous tumor, and chordoma. A total of 27/31 MN-NE were from the last 8 years, and 6 of them were located in the pancreas. Eleven MN-NE were initially diagnosed as neuroendocrine carcinomas (NECs). MN-NE with epithelioid features play an increasing role as mimickers of NECs. They mostly belong to tumors with gene fusions involving the EWSR1 gene, or with SWI/SNF complex deficiency. Synaptophysin expression is mostly patchy and chromograninA expression is infrequent in MN-NE of this series and data extracted from literature., (© 2021. The Author(s).)

Background: Phosphaturic mesenchymal tumors (PMTs) are rare neoplasms that are often associated with tumor-induced osteomalacia (TIO) due to excessive serum levels of fibroblast growth factor 23 (FGF23). PMTs share overlapping histologic features with other types of tumors; thus, accurate pathological diagnosis may be challenging. We performed an immunohistochemical examination of FGF23 expression in PMTs and other types of tumors, together with pertinent molecular analyses., Methods: Seven PMTs (5 with TIO and 2 without TIO) and 46 other types of bone and soft tissue tumors were retrieved, and immunohistochemistry was performed using a commercially available anti-FGF23 antibody. In addition, FGF23 mRNA expression was detected by reverse transcription-polymerase chain reaction (RT-PCR), using RNA extracted from formalin-fixed, paraffin-embedded tissues., Results: Immunohistochemical analysis of FGF23 expression showed distinct, punctate staining in the cytoplasm in 5 PMTs with TIO, whereas FGF23 expression was negative in the 2 PMTs without TIO and the other 46 tumors. FGF23 mRNA expression was detected in all 4 PMTs examined, as well as in 1 chondromyxoid fibroma and 1 myxoid liposarcoma. The real-time RT-PCR data showed that the relative expression levels of the FGF23 mRNA tended to be higher in PMTs with TIO than in PMTs without TIO, or in the chondromyxoid fibroma specimen., Conclusions: Our data suggested that the feasibility of immunohistochemical detection of FGF23 may depend on the level of secreted FGF23 from tumor cells. Thus, immunohistochemistry for FGF23 is an useful diagnostic adjunct for PMT, although its utility appears to be limited in cases without TIO.

Phosphaturic mesenchymal tumors (PMTs) are the most typical cause of tumor-induced osteomalacia (TIO) associated with mesenchymal neoplasms. Specifically, TIO is attributed to the production of phosphatonins, such as fibroblast growth factor 23 (FGF23), participating in the homeostasis of phosphate. Although immunohistochemistry (IHC) for FGF23 showed characteristic positive staining in PMTs, FGF23 antibodies that can be used for the reliable diagnosis of PMTs are hard to obtain in common pathology laboratories. Somatostatin receptor 2A (SSTR2A) has been previously proposed as an alternatively useful marker for the diagnosis of PMTs. However, SSTR2A is not commonly utilized in pathological laboratories. The CD56 marker is a useful alternative that is comparable to SSTR2A and is similar considering the sensitivity. Even in cases of PMTs originating in the bones, ethylenediaminetetraacetic acid-based decalcification for tissue processing does not seem to affect the IHC of CD56. As CD56 immunopositivity in mesenchymal tumors is limited, it also has some degree of specificity for PMTs. Thus, when PMTs are suspected, the use of CD56 is recommended.

Phosphaturic mesenchymal tumour mixed connective tissue variant (PMTMCT) is a rare tumour occurring in bone and soft tissue that usually behaves in a benign manner. Elaboration of biologically active substances by this tumour gives rise to a paraneoplastic syndrome known as oncogenic osteomalacia, manifesting clinically as bone pain, generalized weakness and pathological fractures. Recognition of PMTMCT and its associated syndrome is important, as resection of the tumour in most instances results in prompt resolution of symptoms. Previously reported cases of this tumour have emphasized the consistent presence of certain histological features that are considered prerequisite for making the diagnosis of PMTMCT. We describe three cases of PMTMCT, of which two first presented with progressive symptoms of osteomalacia and one remained clinically silent aside from the symptom of a palpable lump. Our cases highlight the wide-ranging histological patterns displayed by these tumours, and draw attention to certain microscopic findings that until now have been given little if any mention. Tentacular growth pattern and satellite nodules appear to be common findings in PMTMCTs, and can make complete surgical excision of these tumours challenging. The ability of this otherwise histologically benign tumour to permeate vascular spaces has to our knowledge never been described previously. One tumour lacked the characteristic calcifying matrix of PMTMCT, suggesting that in some tumours this defining feature may be focal if not entirely absent. PMTMCT shares features with and can resemble a variety of bone and soft tissue neoplasms, requiring the surgical pathologist to be familiar with this entity.

Phosphaturic mesenchymal tumours (PMTs) are uncommon soft tissue and bone tumours that typically cause hypophosphataemia and tumour-induced osteomalacia (TIO) through secretion of phosphatonins including fibroblast growth factor 23 (FGF23). PMT has recently been accepted by the World Health Organization as a formal tumour entity. The genetic basis and oncogenic pathways underlying its tumourigenesis remain obscure. In this study, we identified a novel FN1-FGFR1 fusion gene in three out of four PMTs by next-generation RNA sequencing. The fusion transcripts and proteins were subsequently confirmed with RT-PCR and western blotting. Fluorescence in situ hybridization analysis showed six cases with FN1-FGFR1 fusion out of an additional 11 PMTs. Overall, nine out of 15 PMTs (60%) harboured this fusion. The FN1 gene possibly provides its constitutively active promoter and the encoded protein's oligomerization domains to overexpress and facilitate the activation of the FGFR1 kinase domain. Interestingly, unlike the prototypical leukaemia-inducing FGFR1 fusion genes, which are ligand-independent, the FN1-FGFR1 chimeric protein was predicted to preserve its ligand-binding domains, suggesting an advantage of the presence of its ligands (such as FGF23 secreted at high levels by the tumour) in the activation of the chimeric receptor tyrosine kinase, thus effecting an autocrine or a paracrine mechanism of tumourigenesis., (Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Connective tissue tumors located inside the abdomen are a rare heterogeneous group of tumors, except for gastro-intestinal stromal tumors. They may be benign, malignant, or intermediate in terms of biologic potential. Pathologists have to remember the list of all the lesions possibly involved, with their immunohistochemical characteristics, and to know which molecular analyses are needed, with which expected results, and by which team they can be performed. The main tumor types are discussed with diagnostic tools and treatment consequences., (Copyright © 2014. Published by Elsevier Masson SAS.)

GATA3 is a transcription factor important in the differentiation of breast epithelia, urothelia, and subsets of T lymphocytes. It has been suggested to be useful in the evaluation of carcinomas of mammary or urothelial origin or metastatic carcinomas, but its distribution in normal and neoplastic tissues is incompletely mapped. In this study, we examined normal developing and adult tissues and 2040 epithelial and 460 mesenchymal or neuroectodermal neoplasms for GATA3 expression to explore its diagnostic value in surgical pathology, using monoclonal antibody (clone L50-823) and Leica Bond automated immunohistochemistry. GATA3 was expressed in trophoblast, fetal and adult epidermis, adult mammary and some salivary gland and sweat gland ductal epithelia, urothelia, distal nephron in developing and adult tissues, some prostatic basal cells, and subsets of T lymphocytes. It was expressed stronger in fetal than in adult mesothelia and was absent in respiratory and gastrointestinal epithelia. In epithelial neoplasms, GATA3 was expressed in >90% of primary and metastatic ductal and lobular carcinomas of the breast, urothelial, and cutaneous basal cell carcinomas and trophoblastic and endodermal sinus tumors. In metastatic breast carcinomas, it was more sensitive than GCDFP. Among squamous cell carcinomas, the expression was highest in the skin (81%) and lower in cervical (33%), laryngeal (16%), and pulmonary tumors (12%). Common positivity was found in skin adnexal tumors (100%), mesothelioma (58%), salivary gland (43%), and pancreatic (37%) ductal carcinomas, whereas frequency of expression in adenocarcinomas of lung, stomach, colon, endometrium, ovary, and prostate was <10%. Chromophobe renal cell carcinoma was a unique renal tumor with frequent positivity (51%), whereas oncocytomas were positive in 17% of cases but other types only rarely. Among mesenchymal and neuroectodermal tumors, paragangliomas were usually positive, which sets these tumors apart from epithelial neuroendocrine tumors. Mesenchymal tumors were only sporadically positive, except epithelia of biphasic synovial sarcomas. GATA3 is a useful marker in the characterization of not only mammary and urothelial but also renal and germ cell tumors, mesotheliomas, and paragangliomas. The multiple specificities of GATA3 should be taken into account when using this marker to detect metastatic mammary or urothelial carcinomas.

Stromal prostate tumors are rare neoplastic proliferative lesions that have been classified into prostatic stromal tumor of uncertain malignant potential (STUMP) and prostatic stromal sarcoma (SS) based on these criteria: stromal cellularity, presence of mitotic figures, necrosis, and stromal overgrowth. A prostatic stromal tumor of uncertain malignant potential (STUMP) is a non-epithelial, mesenchymal spindle-cell tumor that can be classified as a specialized stromal tumor of the prostate. STUMPs have the capability to diffusely infiltrate the prostate gland and extend into adjacent tissues. Furthermore, they often recur and this is why they are considered as neoplastic entities. STUMPs usually tend to be not aggressive, but occasional cases have been reported with an extension into adjacent tissues. A few cases develop a sarcomatous dedifferentiation. A 67-year-old male referred to the Department of Urology, Sapienza Rome University, with acute urinary retention (AUR) and bladder overdistention. Digital rectal examination (DRE) showed the presence of a severe prostatic hyperplasia and a transvesical prostatic adenomectomy (TVPA) was performed. The pathological evaluation performed at the Department of Pathology, Sapienza Rome University, revealed an incidental diagnosis of prostatic STUMP. The patient's follow-up is made every year with transrectal ultrasonography and nuclear magnetic resonance with spectroscopy, and every two years with a transperineal prostate biopsy to exclude a progression to a stromal sarcoma. After 5 years of follow-up the STUMP is still detectable but there is no sign of sarcoma. As a result of its relative rarity and lack of long-term follow-up, the prognosis of STUMP is unclear. Therapy varies from a wait-and-see approach to a radical retropubic prostatectomy.

The BCL-6 proto-oncogene encodes a transcriptional repressor protein. Among normal tissues, BCL-6 expression is confined to germinal center B-cells and a subpopulation of T-helper cells. Little is known about BCL-6 expression in mesenchymal tissues. We examined a series of solitary fibrous tumor (SFT) and other mesenchymal tumors for BCL-6 expression. Immunohistochemistry for BCL-6 was performed on 64 mesenchymal tumors [26 SFT (19 benign/uncertain, 7 malignant), 6 synovial sarcomas (SS), 5 gastrointestinal stromal tumors (GIST), 5 malignant peripheral nerve sheath tumors (MPNST), 5 leiomyosarcomas (LMS), 9 leiomyomas (LM) 4 desmoid tumors (DT), 4 perineuriomas (PN)]. Nuclear immunoreactivity was considered positive. Six BCL-6 positive SFT were also tested for BCL-6 gene rearrangement/amplification by FISH. Nuclear expression of BCL-6 was seen in 13/26 SFT, 5/5 LMS, 1/9 LM, 5/6 SS, 1/5 GIST, 1/5 MPNST, 1/4 PN, and 0/5 DT. BCL-6 expression was significantly more frequent in malignant (6/7) as compared with benign/uncertain SFT (6/19) (p=0.02) and in LMS (5/5) as compared with LM (1/9) (p=0.003). FISH for BCL-6 rearrangement/amplification was negative in all tested cases. We have observed BCL-6 expression in 50% or more of SFT, SS, and LMS, and in a lesser percentage of LM, GIST, MPNST and PN. Significantly more frequent expression of BCL-6 in malignant compared with benign/uncertain SFT and in LMS compared with LM suggests abnormalities in the BCL-6 signaling pathway may contribute to malignant transformation in at least some mesenchymal tumors. It is unlikely that BCL-6 expression in mesenchymal tumors is due to BCL-6 gene amplification or rearrangement.

Differential diagnosis of monophasic synovial sarcoma requires the detection of specific biological markers. In this study we evaluated the presence of molecular alterations in 15 monophasic synovial sarcomas. Multiple changes affecting chromosome arms were detected by CGH-array in all microdissected cases available, and an association between gain or loss of specific regions harbouring cancer progression-associated genes and aneuploid status was found. The most frequent alteration was loss of 3p including 3p21.3-p23 region that, however, did not involve the promoter regions of the corresponding genes, RASSF1 and MLH1. Using Real-Time PCR, mRNA levels of both resulted moderately high compared to normal tissue; however, the weak to absent protein expression suggests RASSF1 and MLH1 post-transcription deregulation. Moreover, immunohistochemical analysis revealed that both mesenchymal and epithelial antigens were present in diploid tumours. These findings confirm the genetic complexity of monophasic synovial sarcoma and underline the need to integrate different analyses for a better knowledge of this tumour, essential to investigate new diagnostic and prognostic markers.

Ectomesenchymal chondromyxoid tumour (ECT) of the anterior tongue was first described in 1995. To date, only 23 cases have been reported in the literature. Two new cases of ECT have been described, with immunohistochemical analysis including cytokeratin (CK) profile, GFAP, S-100 protein, SMA, CD-57, EMA, desmin and Ki67. Tumour cells showed intense and diffuse staining for GFAP and diffuse staining for S-100 protein. Pan-keratin, high- and low-molecular-weight CK, CK 7, 8, 18, 19 and 20 were negative. Tumour cells were also negative for desmin, SMA, CD-57 and EMA. Ki67 was positive in only scattered cells. The findings of the present study support the suggested ectomesenchymal origin for ECT, rather than myoepithelial salivary gland origin. The low Ki67 expression is in agreement with the low growth rate, small size and lack of mitotic activity in the present cases, as well as in those previously described.

A few uncommon but distinctive tumors may preferentially involve the paratestis. The 3 unusual tumors that represent the focus of this discussion are the ovarian-type epithelial tumors (OTET), the desmoplastic small round cell tumor (DSRCT), and the melanotic neuroectodermal tumor of infancy (MNTI). The OTETs are testicular homologues of their more common namesake counterparts that arise in the ovary. Most frequent of these are serous tumors of borderline malignancy, with fewer cases of serous carcinomas or other forms of mullerian differentiation. DSRCT is an increasingly recognized, aggressive, "small blue cell" neoplasm with distinctive clinical and pathologic features. These polyphenotypic tumors characteristically, but not invariably, arise in intimate association with the serosal membrane of the peritoneal cavity and harbor a signature translocation-t(11;22)(p13,q12). In the paratestis they often involve the surface of the epididymis. The MNTI is an enigmatic, histologically distinctive, low-grade neoplasm occasionally encountered in the epididymis. Recognition of its features is essential to avoid misdiagnosis as a more aggressive "small blue cell" neoplasm and consequent therapeutic mismanagement. Primary hematopoietic tumors of the paratesticular structures are rare. There appears to be a tendency for young men to have low-grade lymphomas with an indolent course and older patients to develop higher-grade tumors. Plasmacytoma and granulocytic sarcoma of the paratestis are even more rare and are often susceptible to misinterpretation. Finally, metastatic tumors and a variety of other very rare neoplasms are discussed.

Interstitial cells of Cajal (ICC) are implicated in the regulation of gut peristalsis and are immunostained by antibodies against Kit (CD117), a tyrosine kinase receptor. Most gastrointestinal mesenchymal tumors (GIMTs) are of uncertain histogenesis, although many are CD34-positive. CD34 was found to colocalize with vimentin (Vim) and the Kit-positive networks of cells within and around neural plexi, indicating that ICC can be Vim- and CD34-positive. ICCs appear to be the only Kit+CD34+Vim+ cell in the gut. Formalin-fixed, paraffin-embedded tissues from 43 GIMTs were immunostained for Kit, CD34, Vim, PGP 9.5 (PGP, a neural marker), muscle-specific actin (MSA), and other markers including desmin (Des). Eight tumors were myoid (MSA+Des+Vim-Kit-CD34-), and one was a schwannoma (PGP+S100+Vim+Kit-CD34-), but 34 tumors were of uncertain histogenesis (gastrointestinal stromal tumors, GIST), exhibiting neither a complete myoid nor a schwannian immunophenotype. All 34 were Vim+, and 33/34 were either Kit (n = 30) or CD34 (n = 23) immunoreactive. Of these 34 GIST, 24 were negative for all myoid and neural markers, 6 were PGP+S100-, and 4 were MSA+Des-. The Kit+CD34+Vim+ immunophenotype of GIST suggests that they originate from, or have differentiated into, ICC-like cells; the term ICC tumor (ICCT) is suggested. Kit is a more sensitive marker than CD34 for ICCT, but both are required in tumor identification. All clinically malignant GISTs were pathologically malignant (size, mitoses) but also showed loss of either CD34 or Kit. "Blind" examination of electron micrographs in 10 tumors showed them to be heterogeneous. Some had features seen in normal ICC, but cells could not be positively identified as being adult ICC. GIMT may therefore be classifiable into those with pure myoid, schwannian (or neural) differentiation, but the majority are of ICC origin or show ICC differentiation immunophenotypically (ICCT).

Basement membranes (BMs) in 201 soft tissue tumours were quantified using computerized image analysis of tissues immunostained for laminin and type IV collagen. The purpose of the study was to compare and quantify the extent of BM deposition in a large and varied group of benign and malignant tumours. Laminin and type IV collagen gave similar results. The difference between benign and malignant was statistically highly significant (P = 0.0001), with greater deposition in benign tumours. BM deposition was homogeneous in benign tumours and heterogeneous in sarcomas and appeared to correlate with the degree of differentiation. Some poorly differentiated sarcomas showed cytoplasmic laminin staining but little or no extracellular BM. Immunohistochemical evaluation of BM has some advantages over electron microscopy; specialized equipment is not needed and since large samples can be studied with little sampling error, heterogeneity can be studied more readily. Subjective visual assessment gives a good overall indication of the extent of BM deposition and in many situations is likely to be a suitable alternative to image analysis. Because of staining heterogeneity, BM immunohistochemistry is unlikely to be of significant value in the diagnosis of specific types of sarcoma.

Desmoplastic small round cell tumor (DSRCT) typically occurs in the abdomen but may also present at other sites. We report six cases of paratesticular DSRCT. The patients, who ranged in age from 17 to 37 (mean, 28) years, presented with a scrotal mass (five cases) or testicular pain (one case). Grossly, the tumors were white to tan and firm. Typically, they involved the paratesticular soft tissue, serosal surfaces and the epididymis near the junction with the rete testis. Microscopically, the tumors consisted of nests of mitotically active "small blue cells" with scant cytoplasm embedded in a densely fibrotic stroma. Two tumors showed focal tubule formation; one of these also formed rosettes. The tumors exhibited the typical immunophenotype of DSRCT (positivity for keratin, vimentin, desmin, and neuron-specific enolase but nonreactivity with HBA-71 and anti-S-100). Four tumors metastasized to lymph nodes (retroperitoneal, cervical, and two unspecified); pulmonary metastases occurred in one of these cases and in one patient without lymph node metastases. One of the above patients treated with chemotherapy, died of disease at 16 months. The patients with pulmonary metastases (one of whom also had lymph node metastases) were treated with aggressive chemotherapy and are alive and apparently disease-free at 2.5 and 3 years, respectively. Three of the six patients, two of whom had known metastases, were lost to follow-up. The DSRCT of the paratestis has histologic and immunohistochemical features identical to its abdominal counterpart and must be differentiated from other "small blue cell" tumors of the paratesticular region.

Ectomesenchymal chondromyxoid tumor is a newly described benign neoplasm that presents clinically as a firm, painless, slow-growing mass that typically involves the anterior dorsal tongue. It has been reported to occur over a wide age range (9 to 78 years) and has no apparent sex predilection. Histologically, the tumor is composed of a well-circumscribed, unencapsulated lobular proliferation of fusiform and polygonal cells in a chondromyxoid matrix. Features such as multilobulated nuclei, foci of cellular atypia, and infiltration may be present. Though disturbing, these do not appear to indicate malignant behavior. We report three cases of ectomesenchymal chondromyxoid tumors that confirm the previously described clinical, histologic, and immunohistochemical features. In addition, we describe the ultrastructural features of one of the cases.

The translocation t(X;18)(p11;q11) is seen in > 80% of synovial sarcomas (SS) with informative karyotypes. The breakpoints of the t(X;18) have been cloned and shown to involve two novel genes, SSX (at Xp11) and SYT (at 18q11), which produce a chimeric SYT-SSX transcript as a result of the translocation. Recently, SSX has been shown to be duplicated, with both copies, SSX1 and SSX2, located within distinct subregions of Xp11. We performed a reverse transcriptase polymerase chain reaction (RT-PCR) assay for both chimeric SYT-SSX transcripts in a series of 35 SS (29 monophasic, 6 biphasic) to assess its usefulness in molecular diagnosis and to evaluate the incidence of molecular variants. Of the 35 cases, 29 (83%) showed a specific SYT-SSX RT-PCR product, using a consensus primer for SSX1 and SSX2 Upon excluding three negative cases that had poor quality RNA, the proportion of positives rose to 91% (29/32). The 29 positive cases were further studied using primers specific for either SSX1 or SSX2; 19 cases were positive for SYT-SSX1 and 10 for SYT-SSX2. The relationship of histological subtype (monophasic versus biphasic) to SSX1 or SSX2 involvement was not statistically significant. In a single histologically unremarkable monophasic SS, a slightly larger SYT-SSX2 RT-PCR product was observed. Sequencing of this novel variant showed a 129-bp segment inserted between the usual SYT and SSX2 fusion points, of which 126 bp were derived from a more proximal (5') portion of SSX2 The 3 bp immediately 5' to the fusion point could not be assigned to either SYT or SSX2 and may represent an insertion-deletion or a cryptic splicing event. This fragment maintains the reading frame of the chimeric product and encodes a predicted protein larger by 43 amino acids, which nevertheless replaces the region homologous to the transcriptional repression domain Kruppel-associated box, recently recognized in the 5' portion of the SSX genes, with all but the 3' end of the SYT transcript. Thus, a diagnosis of SS may be confirmed in > 90% of cases using RT-PCR detection of the chimeric transcript resulting from the t(X;18), and the incidence of molecular variants appears low.

The immunohistological distribution of collagen types I, II, III, and VI in five cases of extraskeletal chondroma was examined and compared with that in six cases of enchondroma. In addition, the composition of crystals deposited in three cases of extraskeletal chondroma were biophysically analyzed with special attention to the relationship between the collagen types of the matrix and the crystal deposition. In extraskeletal chondroma, immunoreactivity of type II collagen in the extracellular matrix and type VI collagen in the pericellular area, which were strongly and diffusely recognized in the normal hyaline cartilage and enchondroma, was diminished. Instead, additional types of collagen, types I and III, were demonstrated in the matrix. Electron roentgenographic microanalysis and infrared light spectroscopic analysis revealed that calcium pyrophosphate dihydrate (CPPD) was included in the crystals of extraskeletal chondroma. CPPD crystals were observed in/around collagen types I and III. The possible relationship between the difference of collagen composition in the matrix and the CPPD crystal deposition is discussed.

Three cases of desmoplastic small round cell tumor (DSRCT) with multiphenotypic differentiation, primary in the pleura, are presented. This is a previously unrecognized site for this tumor type. Two patients were male and one female aged 29, 24, and 17 years. All presented with chest pain and were found to have pleural-based tumors associated with pleural effusion. Abdominal involvement was not present in any of the cases. Histologically, the tumor showed the characteristic features of intra-abdominal DSRCT, including angulated nests of small cells embedded in a vascular fibroblastic stroma, focal rhabdoid phenotype, and areas of central necrosis. The neoplastic cells showed evidence of epithelial, mesenchymal, and neural differentiation with characteristic dot-like positivity for vimentin and desmin topographically corresponding to perinuclear aggregates of intermediate filaments identified on electron microscopy in one case. Two patients died of disease 2 years and 15 months after presentation, respectively, and one patient is alive with disease 18 months after presentation. The histogenesis of DSRCT is unknown. Most previously reported cases involved the peritoneum or tunica vaginalis, suggesting a histogenetic relationship to the mesothelium. The occurrence of these tumors in the pleura lends further support to this theory.

The expression of insulin-like growth factor I (IGF-I) was analysed immunohistochemically in a series of 211 breast cancers with special emphasis on its relationship to conventional prognostic factors and long-term prognosis. Altogether, IGF-I was expressed by the tumour cells in 91% of the breast carcinomas, and by stromal cells in 29%. The expression of IGF-I in cancer cells was weakly related to a high proportion of intraductal growth (P = 0.032), distinct tumour margins (P = 0.048) and high S-phase fraction (P = 0.074). In a univariate analysis, IGF-I expression in cancer cells was significantly related to a high survival probability in the entire cohort (P = 0.0144) as well as in the axillary lymph node positive tumours (P = 0.0286). Alternatively, expression of IGF-I in the stromal cells was related to metastasis at the time of diagnosis (P = 0.05), tumour diameter (P = 0.04), DNA ploidy (P = 0.07) and nuclear pleomorphism (P = 0.025), but it was without prognostic significance in a univariate analysis (P > 0.1). In a multivariate analysis, the conventional prognostic factors were superior to IGF-I expression in predicting the disease outcome, albeit expression of IGF-I in tumour stroma showed some independent prognostic significance in axillary lymph node negative tumours. The results suggest that IGF-I expression is related to malignant histopathological features in breast cancer, and expression of IGF-I has independent prognostic significance in the early phases of the disease.

Expression of the CD30 antigen in lymphoid neoplasms and reactive lesions were examined immunohistologically using the monoclonal antibody BerH2. CD30 antigen was expressed in 17 of 18 patients with Hodgkin's disease (HD), all of three anaplastic large cell lymphomas (ALCL), 11 of 52 T-cell malignant lymphomas (TML) including ALCL, 13 of 153 B-cell malignant lymphomas (BML) including ALCL, two of three malignant histiocytosis and one of four plasmacytomas. Although a single case of small cell lymphoma was positive, in cases of mixed cellular morphology, neoplastic cells of larger or more pleomorphic nuclei tended to be stained more extensively and intensively. This antigen is expressed in TML significantly more often than in BML (P < 0.05). CD30 antigen was expressed less frequently at clinical stage I than those of stages II to IV. There was no significant relationship between CD30 antigen expression and that of proliferating cell nuclear antigen or CD43 antigen in non-Hodgkin's lymphomas (NHL). The CD30 antigen expression did not affect the prognosis of NHL overall, but in high grade TML, CD30 antigen-positive individuals tended to have a more favorable prognosis than those that were negative. In reactive diseases, some plasma cells, immunoblasts, interdigitating cells, follicular center cells and histiocytes were stained positively, but not always, and with variable intensity. These results suggest that CD30 antigen is expressed in various cell lineages to some extent and may relate to cellular activation in some instances. When making the histopathologic diagnosis of HD or NHL including ALCL, CD30-positive cell should be carefully interpreted.(ABSTRACT TRUNCATED AT 250 WORDS)

Reliable indicators of behavior in stromal tumors of the gastrointestinal tract have yet to be elucidated. Aggressive behavior has been associated with large size, hypercellularity, tumor necrosis, nuclear atypia, and high mitotic rate. Recently, new methods of measuring proliferation have been developed that exploit the phenomenon of cell cycle specific protein synthesis. In this study the expression of the S-phase specific nuclear protein proliferating cell nuclear antigen (PCNA) is tested as an indicator of malignancy. Sixteen stromal tumors of the stomach were reviewed for tumor size, cellularity, nuclear atypia, mitotic rate, necrosis, vascular invasion, and predominant cell type. Local recurrence and/or mortality were ascertained with a minimum follow-up of 5 yr. An immunohistochemical assay for PCNA was performed on a paraffin section of tumor and the percentage of positively stained cells ("PCNA index") was determined. Among the nine men and seven women, age 37 to 80 (median 66) yr, two had local recurrences that were treated surgically with no metastases. Only positive resection margin correlated with local recurrence. Two other patients developed distant metastases at 8 and 15 mo and died. Mortality did not correlate with age, sex, size, cellularity, necrosis, cell type, and vascular invasion. High grade nuclear atypia (2/2 versus 1/14, P = 0.02) and high mitotic rate (20.5 versus 5.5 per 40 hpfs, P = 0.01) did correlate with mortality. PCNA index did not correlate with local recurrence, but was sharply higher in fatal cases (6.4 versus 1.2, P = 0.001). Both fatal tumors had PCNA values above 6.0, and all others had values of 4.0 or less. The PCNA index is a proliferative marker that may have prognostic value in gastric stromal tumors.

A case study of desmoplastic small round cell tumor with divergent differentiation in a 13-yr-old boy is presented. Clinical, cytologic, histologic, immunohistochemical, and ultrastructural findings are reported. There was a close correlation between the various histologic and cytologic patterns. Immunohistochemical studies revealed strong positivity of many of the tumor cells for cytokeratin, vimentin, and desmin. Ultrastructurally, some of the tumor cells contained aggregates of cytoplasmic intermediate filaments. Fine-needle aspiration biopsy may suggest the diagnosis of desmoplastic small round cell tumor. Confirmation of the diagnosis may be provided by immunohistochemistry and electromicroscopy.

A 43-year-old man presented with decreased range of motion in his left knee and a painful medial joint mass that was grossly visible. Arthroscopy demonstrated a mobile, flat mass 3 cm in diameter in the knee joint that seemed to be loosely tethered to the synovium. The mass was excised, and light microscopic examination demonstrated a biphasic synovial sarcoma. There was no transition with the attached normal synovium. Immunohistochemically, the epithelial component was intensely positive for epithelial membrane antigen and cytokeratins (CAM 5.2 and AE 1/AE 3), and the spindle cell component was focally positive for these markers. The patient has no evidence of disease 9 years after only local excision. Although the term synovial sarcoma suggests a relationship to normal synovium, only rarely has truly intraarticular disease been reported.

An unusual case of isolated exophytic elastic tissue nevi in the scrotal region of a 64-year-old man is described. The histological and ultrastructural findings were those of abundant abnormal elastic fibers and increased reticulin in the dermis. This hamartomatous lesion possesses clinical and histological features previously undescribed in connective tissue nevi.