Genomic profile analysis of leiomyomas with bizarre nuclei and fumarate hydratase deficient leiomyomas: Strengths, weaknesses, and limitations of array-CGH interpretation.

A close relationship has been demonstrated between genomic complexity and clinical outcome in uterine smooth muscle tumors. We studied the genomic profiles by array-CGH of 28 fumarate hydratase deficient leiomyomas and 37 leiomyomas with bizarre nuclei (LMBN) from 64 patients. Follow-up was available for 46 patients (from three to 249 months, mean 87.3 months). All patients were alive without evidence of disease. For 51 array-CGH interpretable tumors the mean Genomic Index (GI) was 16.4 (median: 9.8; from 1 to 57.8), significantly lower than the mean GI in LMS (mean GI 51.8, p < 0.001). We described three groups: (1) a group with FH deletion (24/58) with low GI (mean GI: 11 vs. 22,4, p = 0.02), (2) a group with TP53 deletion (17/58) with higher GI (22.4 vs. 11 p = 0.02), and (3) a group without genomic events on FH or TP53 genes (17/58) (mean GI:18.3; from 1 to 57.8). Because none of these tumors recurred and none showed morphological features of LMS we concluded that GI at the cut-off of 10 was not applicable in these subtypes of LM. By integration of all those findings, a GI <10 in LMBN remains a valuable argument for benignity. Conversely, in LMBN a GI >10 or alteration in tumor suppressor genes, should not alone warrant a diagnosis of malignancy. Nine tumors were tested with Nanocind CINSARC® signature and all were classified in low risk of recurrence. We propose, based on our observations, a diagnostic approach of these challenging lesions.

Sex Cord-Stromal Tumors of the Ovary: An Update and Review. Part I - Pure Ovarian Stromal Tumors.

In two separate reviews, we review the time-honored but still frequently challenging features of ovarian sex cord-stromal tumors, and also emphasize new developments including unusual morphologic appearances that, despite the relative rarity of many of the tumors, result in a disproportionate number of differential diagnostic problems, variant immunohistochemical profiles, and specific molecular and syndromic associations. These neoplasms are also of historical interest as current knowledge is still based in significant part on the contributions of 2 giants of gynecologic pathology, Dr Robert Meyer and Dr Robert E. Scully. In part I, we present the major clinical, pathologic, and genomic features of the pure ovarian stromal tumors including comments on differential diagnosis and briefly note significant historical contributions. In part II we will discuss pure sex cord and sex cord-stromal tumors.

Sex Cord-Stromal Tumors of the Ovary: An Update and Review. Part II - Pure Sex Cord and Sex Cord-Stromal Tumors.

We review the time honored but still frequently challenging features of ovarian sex cord-stromal tumors and also emphasize new developments, including unusual morphologic appearances that, despite the relative rarity of many of the tumors, result in a disproportionate number of differential diagnostic problems, variant immunohistochemical profiles, and specific molecular and syndromic associations. These neoplasms are also of historical interest as current knowledge is still based in significant part to the contributions of 2 giants of gynecologic pathology, Dr Robert Meyer and Dr. Robert E. Scully. In part I, we reviewed the pure ovarian stromal tumors. Now, in part II, we present the major clinical, pathologic, and genomic features of pure sex cord and sex cord-stromal tumors.

Outcomes in ovarian Sertoli-Leydig cell tumor: A report from the International Pleuropulmonary Blastoma/DICER1 and Ovarian and Testicular Stromal Tumor Registries.

OBJECTIVE: Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT. METHODS: Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available. RESULTS: In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2-99.3%) compared to 67.1% (95% CI: 55.2-81.6%) for all stage IC and 60.6% (95% CI: 40.3-91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99-305.85). CONCLUSION: Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection.

An Unusual Endometrial Stromal Neoplasm With JAZF1-BCORL1 Rearrangement.

Endometrial stromal tumors represent the second most common category of uterine mesenchymal tumors. Several different histologic variants and underlying genetic alterations have been recognized, one such being a group associated with BCORL1 rearrangements. They are usually high-grade endometrial stromal sarcomas, often associated with prominent myxoid background and aggressive behavior. Here, we report an unusual endometrial stromal neoplasm with JAZF1-BCORL1 rearrangement and briefly review the literature. The neoplasm formed a well-circumscribed uterine mass in a 50-yr-old woman and had an unusual morphologic appearance that did not warrant a high-grade categorization. It was characterized by a predominant population of epithelioid cells with clear to focally eosinophilic cytoplasm growing in interanastomosing cords and trabeculae set in a hyalinized stroma as well as nested and fascicular growths imparting focal resemblance to a uterine tumor resembling ovarian sex-cord tumor, PEComa, and a smooth muscle neoplasm. A minor storiform growth of spindle cells reminiscent of the fibroblastic variant of low-grade endometrial stromal sarcoma was also noted but conventional areas of low-grade endometrial stromal neoplasm were not identified. This case expands the spectrum of morphologic features seen in endometrial stromal tumors, especially when associated with a BCORL1 fusion and highlights the utility of immunohistochemical and molecular techniques in the diagnosis of these tumors, not all of which are high grade.

Cystic Walthard Nests of the Peritoneal Diaphragm: A Report of 3 Cases of a Common Process at an Unusual Site and Occurring in Patients With Endometriosis.

Nests of cells resembling urothelium, eponymously named "Walthard nests," are well-known incidental findings over the fallopian tube and occasionally undergo cystification resulting in clinical detection and surgical removal. Only rarely is this process noted outside the pelvic peritoneum. Herein we describe cystic Walthard nests occurring in the diaphragmatic peritoneum of three patients (aged 25, 36, and 39 yr) undergoing surgical evaluation for presumed endometriosis. In each case, small pearly white nodules on the diaphragmatic peritoneum were noted and biopsied. Microscopic examination revealed cystic spaces filled with pale eosinophilic secretion. The cysts were lined mostly by stratified transitional cells with pale eosinophilic to focally clear cytoplasm. Umbrella cells were focally present in all cases, and 1 showed focal glandular differentiation resembling cystitis glandularis. In areas, the epithelial cells became flattened and attenuated and nuclei were bland. By immunohistochemistry, all were positive for GATA3, cytokeratin 7, and BEREP4 and negative for cytokeratin 20, estrogen receptor, and WT-1. Walthard nests can rarely occur outside the pelvic peritoneum where they may be noted incidentally during surgery for other indications. This should be readily distinguished pathologically from other peritoneal lesions but lack of significant prior comment of them occurring on the diaphragm may result in diagnostic difficulty.

Sclerosing stromal tumour: a clinicopathological study of 100 cases of a distinctive benign ovarian stromal tumour typically occurring in the young.

AIMS: Since the sclerosing stromal tumour (SST) of the ovary was first described in 1973, few studies have expanded upon its histological features or overlap with other tumours. We thus investigate these aspects based on our experience with 100 cases. METHODS AND RESULTS: The patients, 14 of whom were pregnant, ranged from 12 to 63 years (median = 26 years). Ten patients had hormonal manifestations (seven oestrogenic, three androgenic). Bilateral ovarian involvement was present in two cases. Size ranged from 1 to 23 cm (mean = 8.4 cm). Most tumours were solid and white with focal yellow areas; oedema with cystic degeneration (seen in 25 cases) resulted in eight being predominantly cystic. On microscopic examination, alternating cellular and paucicellular areas (pseudolobulation) were prominent in 94 cases but seen to a limited degree in the remaining neoplasms. Admixed spindled and luteinised cells were present in all tumours, but 13 demonstrated mainly spindled cells and 19 demonstrated mainly lutein cells; 14 of the latter were from pregnant patients. The stroma was typically oedematous or collagenous, but in 14 cases was prominently hyalinised and, in four, myxoid. Prominent vascularity was present in most cases. The mitotic rate ranged from 0 to 8/10 high-power fields (HPF), but most demonstrated <1/10 HPF. CONCLUSIONS: The differential diagnosis of SST is broad, including fibromas, thecomas, solitary fibrous tumours, pregnancy luteomas, myxomas, other ovarian sex cord-stromal tumours with sclerosis and, rarely, Krukenberg tumours. Strict adherence to the requirement of pseudolobulation, prominent (usually ectatic) vessels, and lutein cells and fibroblasts admixed in a jumbled manner, will distinguish the neoplasm from others in the differential.

Müllerian Mucinous Cystadenomas of the Ovary: A Report of 25 Cases of an Unheralded Benign Ovarian Neoplasm Often Associated With Endometriosis and a Brief Consideration of Neoplasms Arising From the Latter.

A subset of ovarian mucinous tumors demonstrates müllerian-type epithelium, with such lesions variably designated "endocervical-like" and seromucinous since their popularization based on a report of borderline examples in 1989. While müllerian mucinous borderline tumors and carcinomas have been highlighted in the literature, there has been minimal attention given to benign müllerian mucinous tumors, particularly müllerian mucinous cystadenomas. Given the paucity of literature describing the features of müllerian mucinous cystadenomas/cystadenofibromas, diagnostic difficulties may arise when papillary features are present and in cases that show a subtle transition from endometriosis. We thus reviewed 25 cases of müllerian mucinous cystadenoma/cystadenofibroma to highlight the notable characteristics of this entity, including gross, cytologic, and architectural features that aid in the distinction from müllerian mucinous borderline tumors as well as, rarely, metastatic tumors. The patients ranged in age from 26 to 85 yr old. Bilateral ovarian involvement was frequent (40%). The ovaries ranged from 2.3 to 26 cm in greatest dimension. Most were multicystic (18 cases) and contained tenacious mucoid material (14 cases). All cases demonstrated predominantly columnar mucinous epithelium with abundant pale-pink cytoplasm. A minor component of ciliated and endometrioid epithelium was seen in 15 and 2 cases, respectively. Broad papillary formations were frequently encountered (9 cases) as was epithelial papillary tufting comprising <10% of the tumor (6 cases). Endometriosis was present in 9 cases, with a transition from endometriosis to mucinous epithelium noted in 8 cases. This series highlights the morphologic features of a relatively uncommon, benign, endometriosis-associated ovarian tumor that may be confused with a müllerian mucinous borderline tumor or bland metastatic mucinous tumors. It also provides an argument for the terminology "müllerian mucinous cystadenoma" or "cystadenofibroma" rather than "seromucinous cystadenoma" due to the frequent association with endometriosis as well as the dominant mucinous epithelium.

Embryonal rhabdomyosarcoma of the uterine corpus: a clinicopathological and molecular analysis of 21 cases highlighting a frequent association with DICER1 mutations.

Herein we evaluated a series of 21 embryonal rhabdomyosarcomas of the uterine corpus (ucERMS), a rare neoplasm, to characterize their morphology, genomics, and behavior. Patients ranged from 27 to 73 (median 52) years and tumors from 4 to 15 (median 9) cm, with extrauterine disease noted in two. Follow-up (median 16 months) was available for 14/21 patients; nine were alive and well, four died of disease, and one died from other causes. Most tumors (16/21) showed predominantly classic morphology, comprised of alternating hyper- and hypocellular areas of primitive small cells and differentiating rhabdomyoblasts in a loose myxoid/edematous stroma. A cambium layer was noted in all; seven had heterologous elements (six with fetal-type cartilage) and eight displayed focal anaplasia. The remaining five neoplasms showed only a minor component (≤20%) of classic morphology, with anaplasia noted in four and tumor cell necrosis in three. The most frequent mutations detected were in DICER1 (14/21), TP53 (7/20), PI3K/AKT/mTOR pathway (7/20), and KRAS/NRAS (5/20). Copy-number alterations were present in 10/19 tumors. Overall, 8/14 DICER1-associated ucERMS showed concurrent loss of function and hotspot mutations in DICER1, which is a feature more likely to be seen in tumors associated with DICER1 syndrome. Germline data were available for two patients, both DICER1 wild type (one with concurrent loss of function and hotspot alterations). DICER1-associated ucERMS were more likely to show a classic histological appearance including heterologous elements than DICER1-independent tumors. No differences in survival were noted between the two groups, but both patients with extrauterine disease at diagnosis and two with recurrences died from disease. As no patients had a known personal or family history of DICER1 syndrome, we favor most DICER1-associated ucERMS to be sporadic.

Hyperreactio Luteinalis (Multiple Luteinized Follicle Cysts): A Report of 10 Cases.

Hyperreactio luteinalis is a rare entity arising in pregnancy and in the setting of gestational trophoblastic diseases (ie choriocarcinoma, molar pregnancy) that presents with, typically, bilateral ovarian enlargement due to numerous follicle cysts. While the phenomenon is benign and spontaneously regresses following delivery or treatment, a specimen may be seen in pathology when oophorectomy or cystectomy is performed to exclude malignancy or to manage acute complications such as torsion. Such resections may exhibit overlapping microscopic features with cystic granulosa cell tumors. We thus reviewed 10 cases of hyperreactio luteinalis in the setting of pregnancy, the largest pathologic cohort to date, to highlight notable features of this disorder. Patients ranged from 22 to 30 yr old. Most patients (n=6) presented at time of cesarean section with incidentally discovered ovarian masses. Three patients presented in the postpartum period, and 1 underwent surgery at 28 wk gestation due to the finding of a unilateral ovarian mass. The ovaries ranged from 8.5 to 29 cm and were multicystic and bilateral in 8 of the cases. Histologic examination demonstrated multiple, variably sized cystic follicles lined by a granulosa cell layer of varying thickness and theca cells with marked eosinophilic cytoplasm. Stromal edema was often prominent, with theca cells occasionally noted in nests, cords, and as single cells in foci of edema. Mitoses were generally seen more often in the granulosa cell layer (mean=2.6 per high power fields) compared with the theca cell layer (mean=1 per 10 high power fields). This series documents the key features of hyperreactio luteinalis that differentiate it from the other benign mass forming lesions encountered in pregnancy, most notably large solitary follicle cyst of pregnancy and puerperium, as well as cystic granulosa cell tumors, especially the juvenile variant, which may also present during pregnancy. Of particular use in differentiating them from juvenile granulosa cell tumor is the absence of pale or vacuolated cytoplasm and solid growth of granulosa cells in cases of hyperreactio luteinalis.

Follicle Cysts of the Ovary: A Report of 30 Cases of a Common Benign Lesion Emphasizing its Unusual Clinical and Pathologic Aspects.

The common ovarian follicle cyst is typically straightforward from both clinical and pathologic perspectives, but may have a variety of unusual features from both aspects at various stages of life. Lack of familiarity with these may lead to diagnostic quandaries, the most common of which is distinguishing between a follicle cyst and cystic granulosa cell tumor of either adult or juvenile type. We reviewed 30 cases of follicle cysts, all sent in consultation, to highlight unusual aspects of a common lesion. Patients ranged from 3 d to 47 yr old. Clinical presentations included precocious puberty, pelvic pain, or an incidentally discovered pelvic mass, including those occurring in neonates and in 2 adults with pituitary adenomas, one of which was diagnosed 3 yr after presentation with the ovarian cyst. Size ranged from 0.5 cm (deflated) to 18.5 cm, with 7 exceeding 8 cm in greatest dimension. Twelve cases demonstrated small satellite cystic follicles in the wall of the dominant cyst. The granulosa cell layer varied in thickness and mitotic activity (which ranged from 1 to 36 per 10 HPF), but uniformly displayed round nuclei that lacked nuclear grooves. Luteinization of the granulosa cell layer, theca layer, or both was seen across all clinical scenarios, with unluteinized cysts being most common in precocious puberty patients. This series documents that although typically smaller, a subset of follicle cysts are the same size as cystic granulosa cell tumors and the 2 entities may be grossly indistinguishable. Helpful clues to the diagnosis of follicle cyst are the lack of nuclear grooves (vs. adult granulosa cell tumor) and lack of invagination of granulosa cells into the cyst wall (vs. both forms of granulosa cell tumor). Mitoses in the granulosa cells are of no aid in the differential with either form of granulosa cell tumor as follicle cysts may exhibit brisk mitotic activity. Our series highlights some of the unusual clinical aspects, one relatively well known-an association with isosexual precocity, but 2 not as widely known, those occurring in neonates and those due to a pituitary adenoma, the latter sometimes not being discovered until a few years after presentation with a follicle cyst.

Adenomatoid Tumor of the Uterus: A Report of 6 Unusual Cases With Prominent Cysts Including 4 With Diffuse Myometrial Involvement, 4 With Uterine Serosal Involvement, and 2 Presenting in Curettage Specimens.

We evaluated the clinicopathologic features of 6 adenomatoid tumors of the uterus with unusual features. All the tumors differed grossly from the usual adenomatoid tumor, typically being ill-defined and occupying >50% of the myometrium, essentially replacing it in 4. The neoplasm extended to the endometrium in 2 cases and in one of these it formed an intracavitary mass; in both the tumor was first diagnosed in a curettage. In the other 4 cases, the adenomatoid tumor was discovered in a hysterectomy specimen performed for irregular vaginal bleeding (3 patients), and the finding of a pelvic mass on a computed tomography scan in a patient with right lower quadrant pain. The tumors extended to the uterine serosa in the form of small grape-like vesicles or cysts in 4 cases. All tumors contained the typical small often irregularly shaped spaces but also had prominent cysts. When cysts involved the serosa, the microscopic appearance mimicked that of peritoneal inclusion cysts. In one case with serosal involvement, a prominent papillary pattern was also present. The cysts were typically closely packed with minimal intervening stroma but were occasionally separated by conspicuous smooth muscle bundles. The stroma in one case was extensively hyalinized. Two tumors were focally infarcted. A striking, but minor, solid growth in which the tumor cells were arranged in tightly packed nests or interanastomosing cords and trabeculae was seen in 2 tumors. The unusual gross and microscopic features of these tumors can cause significant diagnostic difficulty and bring into the differential diagnosis entities that are usually not realistic considerations. The presentation of 2 tumors in a curettage specimen represents an unusual clinical aspect.

The contributions of Juan Rosai to testicular pathology with personal remembrances.

The authors summarize their personal interactions with someone for whom they had unbounded admiration, Dr. Juan Rosai. This varied from daily review of cases, to sharing the platform at meetings, being under his tutelage as an author, and co-directing postgraduate courses. These all highlighted the remarkable knowledge of medicine Dr. Rosai had, imparting as he did diagnostic pearls and remarks on the literature including the history of our discipline, often laced with a well-honed sense of humor. The contributions he made to the pathology of the testis are then considered beginning with his role in highlighting a tumor, at the time not particularly well publicized, spermatocytic seminoma. He wrote two major papers on it, one on standard clinical and pathologic aspects, and one on its ultrastructure. The first was associated with his diligent investigation of a prior paper reporting an unusually high number of malignant examples of this tumor but on review that was explained by their representing malignant lymphoma. The organizational skills of Dr. Rosai, and attention to detail, were second to none and shown perhaps most notably with his organizing many courses, but they were also illustrated early in his career when he moderated a symposium on germ cell tumors of the testis which laid the framework for the classification and nomenclature of premalignant lesions. Finally, his almost career-long interest in the entity he codiscovered, Rosai-Dorfman disease, was associated with his reporting testicular involvement by that disorder in his later years. This giant figure in pathology will stand forever in the top tier with other greats who have contributed to the field.

Female adnexal tumors of probable Wolffian origin: morphological, immunohistochemical, and molecular analysis of 15 cases.

Female adnexal tumors of probable Wolffian origin are rare and present a diagnostic challenge due to their morphological and immunohistochemical overlap with more common ovarian and broad ligament entities. We evaluated the morphological, immunohistochemical, and molecular features of 15 tumors of probable Wolffian origin. Patients ranged from 32 to 69 (mean 47) years and tumors from 1.8 to 30 (mean 10) cm. All except one arose in para-adnexal soft tissues. Follow-up was available for six patients, five of whom were alive and well, while the sixth, who had extra-adnexal disease at diagnosis, died from unrelated causes. The following patterns were noted: tubular (all tumors), solid 11/15 (73%), sieve-like 7/15 (47%), and reticular 1/15 (7%). A myxoid background was present in 3/15 (20%) of tumors and eosinophilic luminal secretions in 11/15 (73%). Most tumors (12/15, 80%) had low-grade nuclear atypia, while three showed foci with scattered high-grade atypia. Mitotic index ranged from 0 to 17 (mean 4) per ten high-power fields. Tumors were positive for pankeratin and negative for TTF-1. EMA, GATA3, and PAX8 were positive in 2/10 (20%; focal), 3/15 (20%; focal), and 1/15 (7%; focal) of tumors, respectively. CD10, SF-1, calretinin, inhibin, ER, PR, cytokeratin 7, and WT1 were variably expressed. Pathogenic mutations were rare and included STK11 (n = 3), APC (n = 1), and MBD4 (n = 1). Copy number variations were detected in the three tumors with STK11 mutations and a myxoid background. These data demonstrate that female adnexal tumors of probable Wolffian origin are morphologically and immunohistochemically diverse, but infrequently harbor pathogenic mutations. However, their lack of mutations in contrast to their mimickers may be a valuable tool in diagnostically difficult cases.

High-grade transformation of low-grade endometrial stromal sarcomas lacking YWHAE and BCOR genetic abnormalities.

High-grade histologic transformation of low-grade endometrial stromal sarcoma (LGESS) is rare. Here, we describe the clinicopathologic features and gene fusion status of 12 cases (11 primary uterine corpus and 1 primary vaginal), 11 diagnosed prospectively from 2016, and 1 retrospectively collected. Targeted RNA sequencing and/or fluorescence in situ hybridization was employed in all cases. High-grade transformation was seen at the time of initial diagnosis in eight patients and at the time of recurrence in four patients, 4-11 years after initial diagnosis of LGESS. High-grade morphology consisted of generally uniform population of round to epithelioid cells with enlarged nuclei one to two times larger than a lymphocyte, visible nucleoli, and increased mitotic index (range, 6-30; median, 16 per 10 high-power fields); there was often an associated sclerotic and/or myxoid stroma. Estrogen receptor, progesterone receptor, and CD10 expression was absent or significantly decreased (compared with the low-grade component) in the high-grade foci of five tumors. One tumor demonstrated positive (diffuse and strong) cyclin D1 and BCOR staining. p53 staining was wild type in both components of all eight tumors tested. JAZF1-SUZ12 (n = 6), JAZF1-PHF1 (n = 3), EPC1-PHF1, (n = 1), or BRD8-PHF1 (n = 1) fusions were detected in 11 tumors; no fusions were found in one by targeted RNA sequencing. Patients presented with FIGO stages I (n = 4), II (n = 4), III (n = 1), and IV disease (n = 2). Median overall survival calculated from the time of histologic transformation was 22 months (range, 8 months to 8 years) with five patients who died of disease 8-18 months after transformation. High-grade transformation may occur in LGESS with JAZF1 and PHF1 rearrangements at the time of or years after initial diagnosis. Such high-grade transformation is characterized by nuclear enlargement, prominent nucleoli, and increased mitotic index compared with typical LGESS. Histologic high-grade transformation may herald aggressive behavior.

SWI/SNF protein and claudin-4 expression in anaplastic carcinomas arising in mucinous tumours of the ovary and retroperitoneum.

AIMS: Anaplastic carcinoma arising in a mucinous tumour of the ovary and rarely in the retroperitoneum is an uncommon neoplasm with three morphological patterns; rhabdoid, sarcomatoid and pleomorphic. We investigated expression of switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complex components and claudin-4 expression. METHODS AND RESULTS: Twenty-two ovarian and three retroperitoneal mucinous tumours were investigated using antibodies against SMARCB1, SMARCA4, SMARCA2, ARID1A and claudin-4. Loss of nuclear staining for any SWI/SNF protein was observed in the anaplastic component of nine of 25 (36%), with retained expression within the mucinous component of all tumours. Five (56%) showed loss of more than one protein, with dual loss of SMARCA4 and SMARCA2 in two, loss of SMARCA2 and ARID1A in two and loss of SMARCB1 and SMARCA2 in one. Retained expression of claudin-4 was seen in 39% of the anaplastic carcinomas and within the mucinous component of all tumours. Rhabdoid morphology was associated with poor prognosis [stages III or IV disease (six of six, 100% versus four of 14, 29%; P = 0.0108] and death from disease (three of four, 75% versus one of 13, 8%; P = 0.0223). Although loss of a SWI/SNF protein was not significantly associated with death from disease (three of five, 60% versus one of 12, 8%; P = 0.0525), it showed a trend in correlation with poor prognosis and was often noted in tumours with rhabdoid morphology within this small cohort. CONCLUSIONS: Our report adds to the growing list of female genital tract malignancies with loss of SWI/SNF proteins, underlining their broad differential diagnosis and the importance of careful, context-dependent interpretation of SWI/SNF protein loss.

The history of urologic pathology: an overview.

This article begins with the testis and a legendary figure, Sir Astley Cooper, who wrote an early text on the organ. The early 20th century saw the first major development, the description of the seminoma by the French investigator Maurice Chevassu, but the pace of knowledge did not accelerate until after World War II with a major article from the Armed Forces Institute of Pathology (AFIP) by Nathan B. Friedman and Robert A. Moore, soon followed by the first series testis fascicle by Frank J. Dixon and Moore. Other noteworthy contributions were made by two masters of gonadal pathology, Gunnar Teilum and Robert E. Scully. In the 1970s, Niels E. Skakkebaek played a seminal role in elaborating in-situ neoplasia of the testis. The school of British testicular tumour authored, in the mid-1970s, under the editorship of Roger C. B. Pugh, one of the best texts on testicular pathology. Advances in more recent years have been largely spearheaded by Thomas M. Ulbright of the Indiana University School of Medicine. Observations on the prostate gland date back to Andreas Vesalius and William Cheselden, the latter appearing to have introduced the word for the gland. Note is made of contributions on the anatomy and histology of the gland by Oswald Lowsley, L. M. Franks, and John McNeal. Diagnosing carcinoma of the prostate was brought into the modern age in a landmark 1953 article by Robert S. Totten et al. In the 1960s, Donald F. Gleason introduced a grading system that is now in use worldwide. The topic of premalignant lesions has been well established only for approximately three decades, based initially on the work of Dr McNeal and David G. Bostwick. One of the first to write a book on the bladder was the remarkable British surgeon-pathologist Sir Henry Thompson. Workers at the AFIP, including Colonel James E. Ash and Fatallah K. Mostofi, wrote many outstanding articles on bladder pathology. The roles of other institutions, such as Johns Hopkins University, the Mayo Clinic, and St Peter's Hospital Institute of Urology, London, and those who worked there are noted. Knowledge of the pathology of the urachus dates largely back to the remarkable book on the topic in 1916 by the Hopkins investigator Thomas S. Cullen. Information on renal tumours dates largely to the work of Paul Grawitz, but awareness of the many variants of renal cell carcinoma in general was slow to evolve, and has only accelerated in recent years. The AFIP group of Dr Mostofi, ably assisted by Colonel Charles J. Davis and Isabell A. Sesterhenn, has contributed to knowledge of renal neoplasia with articles of note on oncocytoma, metanephric adenoma, and medullary carcinoma. In the mid-1980s, the German workers Wolfgang Thoenes and Stephan Störkel recognised the distinctive tumour known as chromophobe renal cell carcinoma. Work on renal tumours in the young owes much to J. Bruce Beckwith. The observational talents of numerous investigators have, in just over a century, advanced our knowledge of diseases of the urinary tract and testis remarkably.

Granulosa Cell Tumors of the Ovary With Prominent Thecoma-like Foci: A Report of 16 Cases Emphasizing the Ongoing Utility of the Reticulin Stain in the Modern Era.

Sixteen adult granulosa cell tumors which had conspicuous zones of cells with pale cytoplasm imparting a resemblance to thecoma are reported. The neoplasms occurred in patients from 38 to 86 yr of age, the majority being over 55 yr of age. Ten tumors were incidental findings, the remainder being associated with symptoms or signs related to an adnexal mass. All the tumors were unilateral, typically small, usually under 5 cm, with only 3 being larger. With 1 exception they were uniformly solid and were typically entirely or focally yellow on sectioning. Microscopic examination typically showed a nodular pattern of growth constituted by cells with moderate to abundant pale cytoplasm; the cells resembled those seen in most thecomas. The nodules occasionally became confluent and focally a diffuse pattern was seen. Typical foci of adult granulosa cell neoplasia in the form of foci of conspicuous epithelial differentiation were absent or rare in most cases but were seen in subtle form in 6 cases and overtly in 3. A few tumors had other features seen in some thecomas, hyaline plaques, sclerosis, and calcification. Reticulin stains were examined in 13 cases and showed that the thecoma-like foci exhibited a dearth of reticulum indicating that those areas were predominantly of granulosa cell nature. Most adult granulosa cell tumors have cells with scant cytoplasm; occasional tumors have abundant eosinophilic cytoplasm, so-called luteinized adult granulosa cell tumors. That some granulosa cell tumors have the cytoplasmic features described herein has occasionally been noted but the resemblance to thecoma has not been emphasized to the best of our knowledge and in the past such tumors may have been misdiagnosed as thecoma, the referral diagnosis in 6 of our cases. A reticulin stain is of crucial aid in indicating the epithelial nature of the thecoma-like foci in these cases. Given the small size of the majority of the tumors the distinction between a small adult granulosa cell tumor and thecoma does not have significant prognostic or therapeutic implications in most cases but awareness of this feature of a small subset of adult granulosa cell tumors is warranted. Our findings have import to the diagnosis of thecoma which is uncommon if strict criteria, including exclusion of granulosa tumors of the type described, are used.

Multiple Luteinized Follicle Cysts of the Ovary in a Patient With a Pituitary Adenoma: Report of a Case and Review of the Literature.

The case of a 36-yr-old woman with a pituitary adenoma who was found to have bilateral ovarian masses is reported. The right ovary was removed, measured 15 cm in maximum dimension, and contained multiple cysts which on microscopic examination had the typical morphology of follicle cysts. The left ovary was grossly similar intraoperatively. Subsequent excision of the pituitary adenoma was followed ∼3 mo later by a return to normal size of the left ovary. The case represents an example of multiple luteinized follicle cysts, analogous to the phenomenon seen occasionally in pregnancy, but with a different clinical background. Periodic documentation of this phenomenon is present in the literature, predominantly the clinical literature with limited pathologic documentation of the nature of the process in many reports. As pertains to the evaluation of follicle cysts encountered during pregnancy the differential diagnosis is with a cystic granulosa cell tumor of either adult or juvenile types, more likely the latter. The cyst lining is identical to that of standard follicle cysts and contrasts with the immature mitotically active nuclei seen in a juvenile granulosa cell tumor. That neoplasm also usually shows follicular differentiation typically absent in follicle cysts. Pathologists should be aware of the rare occurrence of luteinized follicle cysts in patients with a pituitary adenoma to enable correct intraoperative and standard pathologic evaluation.

ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity.

High-grade endometrial stromal sarcoma likely encompasses underrecognized tumors harboring genetic abnormalities besides YWHAE-NUTM2 fusion. Triggered by three initial endometrial stromal sarcomas with ZC3H7B-BCOR fusion characterized by high-grade morphology and aggressive clinical behavior, we herein investigate the clinicopathologic features of this genetic subset by expanding the analysis to 17 such tumors. All of them occurred in adult women with a median age of 54 (range, 28-71) years. They were predominantly based in the endomyometrium and demonstrated tongue-like and/or pushing myometrial invasion. Most were uniformly cellular and displayed haphazard fascicles of spindle cells with mild to moderate nuclear atypia. Myxoid matrix was seen in 14 of 17 (82%) tumors, and collagen plaques were seen in 8 (47%). The mitotic index was ≥10 mitotic figures/10 high-power fields (HPFs) in 14 of 17 (82%) tumors with a median of 14.5 mitotic figures/10 HPFs. No foci of conventional or variant low-grade endometrial stromal sarcoma were seen. All tumors expressed CD10 with only limited or absent desmin, SMA and/or h-caldesmon staining. ER and PR expression in >5% of cells was seen in 4 of 12 (33%) tumors. Diffuse cyclin D1 and BCOR immunoreactivity was present in 7 of 8 (88%) and 7 of 14 (50%) tumors, respectively. Fluorescence in situ hybridization or targeted RNA sequencing confirmed ZC3H7B-BCOR fusion in all tumors, including four and two previously diagnosed as myxoid leiomyosarcoma and undifferentiated uterine sarcoma, respectively. Limited clinical data suggest that patients present at higher stage and have worse prognosis compared with published outcomes in low-grade endometrial stromal sarcoma. Tumors with ZC3H7B-BCOR fusion constitute a distinct group of endometrial stromal sarcomas with high-grade morphology that should be distinguished from other uterine mesenchymal neoplasms that may demonstrate myxoid morphology.