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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.

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.

Magnetic resonance (MR) relaxometry is a quantitative imaging method that measures tissue relaxation properties. This review discusses the state of the art of clinical proton MR relaxometry for glial brain tumors. Current MR relaxometry technology also includes MR fingerprinting and synthetic MRI, which solve the inefficiencies and challenges of earlier techniques. Despite mixed results regarding its capability for brain tumor differential diagnosis, there is growing evidence that MR relaxometry can differentiate between gliomas and metastases and between glioma grades. Studies of the peritumoral zones have demonstrated their heterogeneity and possible directions of tumor infiltration. In addition, relaxometry offers T2* mapping that can define areas of tissue hypoxia not discriminated by perfusion assessment. Studies of tumor therapy response have demonstrated an association between survival and progression terms and dynamics of native and contrast-enhanced tumor relaxometric profiles. In conclusion, MR relaxometry is a promising technique for glial tumor diagnosis, particularly in association with neuropathological studies and other imaging techniques.

Corneal dystrophies are phenotypically and genetically heterogeneous, often resulting in visual impairment caused by corneal opacification. We investigated the genetic cause of an autosomal dominant corneal stromal dystrophy in a pedigree with eight affected individuals in three generations. Affected individuals had diffuse central stromal opacity, with reduced visual acuity in older family members. Histopathology of affected cornea tissue removed during surgery revealed mild stromal textural alterations with alcianophilic deposits. Whole genome sequence data were generated for four affected individuals. No rare variants (MAF < 0.001) were identified in established corneal dystrophy genes. However, a novel heterozygous missense variant in exon 4 of SPARCL1, NM_004684: c.334G > A; p.(Glu112Lys), which is predicted to be damaging, segregated with disease. SPARC-like protein 1 (SPARCL1) is a secreted matricellular protein involved in cell migration, cell adhesion, tissue repair, and remodelling. Interestingly, SPARCL1 has been shown to regulate decorin. Heterozygous variants in DCN, encoding decorin, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway. Therefore, we performed immunohistochemistry to compare SPARCL1 and decorin localisation in corneal tissue from an affected family member and an unaffected control. Strikingly, the level of decorin was significantly decreased in the corneal stroma of the affected tissue, and SPARCL1 appeared to be retained in the epithelium. In summary, we describe a novel autosomal dominant corneal stromal dystrophy associated with a missense variant in SPARCL1, extending the phenotypic and genetic heterogeneity of inherited corneal disease.

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 BCORL1rearrangements. 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-BCORL1rearrangement 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 BCORL1fusion and highlights the utility of immunohistochemical and molecular techniques in the diagnosis of these tumors, not all of which are high grade.

One hundred malignant mixed germ cell tumors of the ovary that occurred in patients 3 to 55 years (mean: 20 y) of age are described. The clinical presentation was usually that of any highly malignant tumor of the ovary (abdominal pain and distension), but rarely (3 cases) endocrine manifestations were present. The tumors were usually unilateral (96%), ranged from 4 to 38 cm (mean: 16 cm), and were uniformly solid or, more often, solid and cystic; occasionally the typical appearance of dysgerminoma could be appreciated. The most common tumor type was yolk sac tumor (91%), followed by dysgerminoma (61%), immature teratoma (58%), embryonal carcinoma (38%), and choriocarcinoma (11%). A variety of admixtures were encountered; dysgerminoma and yolk sac tumor was the most common combination (25% of the tumors) with the 2 components often being sharply demarcated. Immature teratoma and yolk sac tumor was the next most common pairing (20%) followed by yolk sac tumor and embryonal carcinoma, with or without immature teratoma (16%). Tumors with a choriocarcinoma component had the most varied combinations of tumor types. Embryoid bodies were seen in 21% of the tumors, most often as fragmented forms arranged in a nodular manner with yolk sac tumor and/or embryonal carcinoma; uncommonly they occurred singly or in clusters. Numerous confluent well-formed embryoid bodies (polyembryoma) were prominent in 2 tumors. Three tumors had a focal diffuse embryoma pattern. The specific tumor types showed the known diverse spectrum of microscopic appearances, but the frequent haphazard arrangement of 2 or more subtypes often resulted in complex morphology. Overgrowth of another neoplastic component, most often primitive neuroectodermal tumor, occurred in 10% of the tumors further complicating the histologic picture. This is the largest series of ovarian malignant mixed germ cell tumors reported and details their characteristics including associations of their subtypes and the frequent apparent role of embryoid bodies in giving rise to yolk sac tumor and embryonal carcinoma components.

Throughout the 19th and 20th centuries, aided by advances in medical imaging, discoveries in physiology and medicine have added nearly 25 years to the average life expectancy. This resounding success brings with it a need to understand a broad range of age-related health conditions, such as dementia. Today, mathematics, neuroimaging and scientific computing are being combined with fresh insights, from animal models, to study the brain and to better understand the etiology and progression of Alzheimer’s disease, the most common cause of age-related dementia in humans. In this manuscript, we offer a brief primer to the reader interested in engaging with the exciting field of mathematical modeling and scientific computing to advance the study of the brain and, in particular, human AD research.

Published compounds from ChEMBL version 32 are used to seek evidence for the occurrence of “natural selection” in drug discovery. Three measures of natural product (NP) character were applied, to compare time- and target-matched compounds reaching the clinic (clinical compounds in phase 1–3 development and approved drugs) with background compounds (reference compounds). Pseudo-NPs (PNPs), containing NP fragments combined in ways inaccessible by nature, are increasing over time, reaching 67% of clinical compounds first disclosed since 2010. PNPs are 54% more likely to be found in post-2008 clinical versus reference compounds. The majority of target classes show increased clinical compound NP character versus their reference compounds. Only 176 NP fragments appear in >1000 clinical compounds published since 2008, yet these make up on average 63% of the clinical compound’s core scaffolds. There is untapped potential awaiting exploitation, by applying nature’s building blocks─“natural intelligence”─to drug design.

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.

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.

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.