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Despite the current classification of high-grade serous carcinoma (HGSCA) and low-grade serous carcinoma (LGSCA) as mutually exclusive diseases based on morphology and molecular pathogenesis, cases with mixed morphologic features of HGSCA and LGSCA have been reported. Herein we assess the clinicopathologic, immunohistochemical (IHC), and molecular genetic characteristics of a group of these cases, which we termed indeterminate grade serous carcinoma (IGSCA) in comparison with groups of HGSCA and LGSCA. Using the World Health Organization (WHO) classification criteria, we selected 27 LGSCA and 19 IGSCA for detailed morphologic study. Thirteen classic HGSCA, 19 classic LGSCA, and 19 IGSCA were selected for p53 and BRAF V600E IHC and molecular genetic testing by next-generation sequencing. IGSCA showed the architectural patterns of invasion of LGSCA, but with higher grade nuclear features focally and a mitotic index intermediate between LGSCA and HGSCA. Few cases in the IGSCA group showed mutant TP53 by IHC or sequencing (4/18, 22.2%), 1 case had mutant BRAF non-V600E by sequencing, and 1 had an NRAS mutation. When present, the mutations were identical in the low-grade and high-grade areas. The IGSCA group had a long-term survival similar to the classic HGSCA group. IGSCA with mixed morphologic features of HGSCA and LGSCA is a rare and potentially clinically aggressive variant of serous carcinoma. Their distinct morphologic, but heterogenous molecular features, including low frequency of TP53 and BRAF mutations suggest that these rare tumors may have a different pathogenesis pathway compared with classic HGSCA and classic LGSCA.

The existence of a "high-grade endometrial stromal sarcoma" category of tumors has been a controversial subject owing to, among other things, the difficulty in establishing consistent diagnostic criteria. Currently, the recommended classification for such tumors is undifferentiated uterine/endometrial sarcoma. Interest in this subject has recently increased markedly with the identification of recurrent molecular genetic abnormalities. At Mayo Clinic, a group of neoplasms has been observed that morphologically resemble, either cytologically or architecturally, classic "low-grade" endometrial stromal sarcoma but feature obvious deviations, specifically, 17 tumors with unequivocally high-grade morphology. These high-grade tumors displayed 3 morphologic themes: (1) tumors with a component that is identical to low-grade ESS that transitions abruptly into an obviously higher-grade component; (2) tumors composed exclusively of high-grade cells with uniform nuclear features but with a permeative pattern of infiltration; (3) tumors similar to the second group but with a different, yet characteristic, cytomorphology featuring enlarged round to ovoid cells (larger than those found in low-grade ESS) with smooth nuclear membranes and distinct chromatin clearing but lacking prominent nucleoli. We collected clinicopathologic data, applied immunohistochemical studies, and also tested tumors by fluorescence in situ hybridization for abnormalities in JAZF1, PHF1, YWHAE, and CCND1. Tumors from these 3 groups were found to be immunohistochemically and genetically distinct from one another. Most notable was the fact that category 3 contained all the cases that tested positive for YWHAE rearrangement, did not show any classic translocations for JAZF1, PHF1, or CCND1, often presented at a high stage, and behaved aggressively. This study demonstrates the morphologic, immunophenotypic, and molecular genetic heterogeneity that exists within "undifferentiated endometrial sarcomas" as currently defined and lends credence to the effort of subclassifying some tumors as truly "high-grade endometrial stromal sarcomas." Our study also shows that, in the context of undifferentiated endometrial sarcomas, recognition of cytomorphologic features on routine hematoxylin and eosin-stained sections may be used to select tumors with specific molecular genetic changes-that is, translocations involving YWHAE. Our conclusions will help further efforts towards proper sub-classification of these tumors which will aid in diagnosis and potentially affect clinical management.

The tissue derivation of mucinous ovarian carcinoma remains a mystery; however, rare tumors are associated with mature teratoma. Two decades ago, studies of chromosomal heteromorphisms and DNA polymorphisms proved that ovarian teratomas arise during female gametogenesis. We sought to exploit the relationship between mucinous carcinoma and associated teratoma to provide molecular evidence for tissue of origin. Seventeen cases of mucinous ovarian carcinoma were studied, 6 of which had associated mature teratoma. DNA was extracted from the mucinous carcinoma, teratoma, and normal dissected tissue from formalin-fixed, paraffin-embedded sections. Twelve polymorphic microsatellite markers were used to allelotype each sample. Alleles from the teratomas and carcinomas were scored as homozygous (1 allele present in the tumor when normal tissue was heterozygous), heterozygous (2 alleles present matching normal tissue), or noninformative (normal tissue was homozygous). Of the 6 carcinoma/teratoma pairs, 2 showed complete matching homozygosity for informative markers (isodisomy), whereas 2 showed matching heterozygosity. One case did not have the corresponding teratoma available for comparison but demonstrated complete homozygosity and was presumed to be isodisomic. The remaining case had a teratoma homozygous for 7 of 10 informative markers, whereas the matching carcinoma was homozygous for only 2 of these markers. Carcinomas without associated teratoma demonstrated variable zygosity. Microsatellite polymorphism analysis demonstrates that mucinous ovarian carcinomas usually clonally match associated teratomas when present and often show evidence of complete isodisomy, indicating that at least some mucinous carcinomas arise from female gametes and thus are of germ cell origin. The zygosity patterns in mucinous carcinomas without teratoma suggest that these tumors may arise through a different mechanism.

The clinical and pathologic features of serous borderline tumors (SBTs) with autoimplants (AIs) were studied with emphasis on their relation to survival, ovarian SBT with a micropapillary pattern, and their distinction from serous adenocarcinoma. The 30 patients ranged in age from 17 to 70 years (mean, 35.8 years). Two had stage I disease, 10 had stage II disease, and 18 had stage III disease. Twenty-five patients had bilateral ovarian tumors. In 28 cases, AIs were present on the surface of the neoplasm or between exophytic surface tumor papillae; in 2 cases, AIs were between papillae within intracystic tumor. The AIs consisted of single cells or glands and clusters of cells with mild to moderate nuclear atypia within a fibroblastic stroma; the stroma dominated over the epithelium in extent within the AI. In many cases, the epithelial cells in the AI had abundant eosinophilic cytoplasm. All but 2 of the patients had coexisting noninvasive peritoneal implants; 3 of them also had invasive peritoneal implants. Six of the SBTs had a micropapillary pattern; 3 of these were stage III and 3 stage II tumors. Clinical follow-up was available for 11 patients. Eight were alive and well after 4 to 7 years (mean, 5 years); 3 of these patients had stage II disease and 5 had stage III disease. Three were dead of disease after 7 to 12 years (mean, 9 years). Two patients who died of disease had stage III disease, and 1 of them had invasive implants. The third patient had stage II disease, invasive implants, and the tumor was of the micropapillary type. Our study indicates that the majority of patients with SBT with AI have stage II or III disease and abundant exophytic tumor. SBTs with AI had a micropapillary pattern in 20% of the cases. AIs do not appear to have an adverse impact on survival when controlled for peritoneal implant type and for this reason must be distinguished from true stromal invasion in serous carcinoma, a misdiagnosis sometimes made, or seriously entertained, initially in these cases. Features that favor AI over carcinoma arising in an SBT are 1) a location between tumor papillae or on the ovarian surface 2) a predominance of stroma over epithelial cells, and 3) the "borderline" cytologic appearance of epithelial cells.

Eight endocervical adenocarcinomas with a prominent cystic component that resulted in a resemblance, in part, to certain benign lesions are described. The patients ranged in age from 34 to 78 years (average age, 48.6 years), and three women were postmenopausal. Presentations included abnormal cervical cytology smears (n = 4) and vaginal bleeding (n = 3). One patient was pregnant at the time of diagnosis. Six tumors were typical endocervical-type and two tumors were intestinal-type adenocarcinomas. The cysts occupied 50% to approximately 90% of the tumor and ranged from 1 to 8 mm in diameter. They were lined by flattened to low cuboidal to pseudostratified epithelium with focal goblet cells and Paneth cells in the two intestinal-type tumors, and the epithelial lining of the cysts was denuded occasionally. Seven tumors contained luminal mucin, which was brightly eosinophilic in one patient and resembled the contents of mesonephric tubules, but was mucin positive on special stains. A desmoplastic stroma was identified in two patients; the remainder had no stromal reaction. The features that resulted in mimicry of benign lesions were the cystic glands, their sometimes orderly distribution, and focal, deceptively bland cytology. All tumors contained, at least focally however, architecturally abnormal glands lined by cytologically malignant cells.

A group of investigators have proposed that the presence of micropapillary or cribriform patterns within ovarian serous tumors diagnosed as borderline according to World Health Organization (WHO) criteria identifies a subset of these neoplasms that are apt to be associated with invasive peritoneal implants and therefore should be designated as "micropapillary carcinoma." The authors of the current article identified 40 serous borderline tumors that showed one or both of these patterns, using the earlier investigators' published criteria for so-called micropapillary carcinoma, and compared them with 44 tumors that lacked these patterns (controls). Twenty-six patients with micropapillary tumors were aged 21 to 76 years (mean 38); 11 with cribriform tumors were aged 34 to 79 years (mean 60); and 3 with tumors having both patterns were aged 21 to 58 years (mean 38); the control patients were aged 22 to 83 years (mean 54). An advanced stage, bilaterality, and ovarian surface growth were features of the "micropapillary" tumors more often than of the control tumors. Except for a postoperative death related to sepsis, all 11 patients with Stage I tumors with either or both patterns who were followed until their death, or for at least 5 years (mean 7.9 years), survived without evidence of disease; a twelfth patient had a recent removal of recurrent pelvic tumor at 2.8 years and was alive at 3.3 years. Six of the eight patients with Stage II or III tumors with either or both patterns who were followed for at least 5 years (mean 7.5 years) survived disease-free. No deaths from tumor or progressive recurrences occurred in 27 control cases with 5-14 (mean 7.9) years of follow-up data. The two tumor-related deaths in the entire series, one from a micropapillary tumor and one from a cribriform tumor, occurred in patients who had Stage III tumors with invasive peritoneal implants. No patient with "micropapillary" tumors and noninvasive implants had progressive disease. Two women with "micropapillary" tumors and two control subjects had stable recurrent tumor or a newly developed tumor in a contralateral ovary that had been spared during the initial operation. Our findings confirm those of previous investigators that noninvasive serous tumors with a micropapillary or cribriform pattern or both patterns may be accompanied by invasive peritoneal implants more often than tumors without such patterns and that in such cases the disease is likely to be progressive and fatal. Since so-called micropapillary carcinomas lack obvious stromal invasion within the ovary, and their prognosis when they spread to the peritoneum is much closer to that associated with typical Stage II and III serous borderline tumors than to that associated with similarly staged serous carcinomas, the authors believe that this newly described category of tumors should remain as a subset within the borderline category, with a notation that their prognosis is poor if they are associated with invasive peritoneal implants.

Low-grade peritoneal serous carcinomas have been the subject of limited study, and their distinction from peritoneal serous psammocarcinomas and serous borderline tumors is not always easy. The clinicopathologic features of 14 low-grade serous carcinomas, 7 psammocarcinomas, and 19 serous borderline tumors of peritoneal origin were compared. Average ages were 58 years (low-grade serous carcinomas), 48 years (borderline tumors), and 40 years (psammocarcinomas). Typical clinical presentations were abdominal pain, abdominal mass, or both, with the tumors incidental in 37% (borderline tumors), 43% (psammocarcinomas), and 36% (low-grade serous carcinoma). Operative and gross findings varied from nodules to adhesions to a dominant mass. Treatment was surgical debulking in most cases, with biopsy alone for eight borderline tumors. Seven patients with low-grade serous carcinoma were alive when last seen, but follow-up duration is short (average, 1.2 years): five were without disease, one had recurrent disease and one persistent disease. One patient with serous carcinoma died of disease at 3.5 years, and two patients died of other causes. Three patients with psammocarcinoma were alive without disease (average 3.3 years). Fourteen patients with borderline tumors were alive (average 3 years): 10 were without disease, 2 had persistent disease, and serous carcinoma developed in 2. The low-grade serous carcinomas resembled the invasive implants of ovarian serous borderline tumors. lacked high-grade nuclear atypia, showed tissue, lymphovascular space invasion, or both and had appreciable solid epithelial proliferation. Some serous carcinomas showed abundant psammomatous calcification suggesting psammocarcinoma but had too much epithelial proliferation for that diagnosis. The psammocarcinomas showed at least 75% psammoma bodies, no more than moderate cytological atypia, tissue or lymphovascular space invasion, or both, and rare epithelial proliferation less than 15 cells across. Adequate sampling was necessary to identify invasion, with highest yields of invasive foci in omental samples; individual foci in some cases of carcinoma resembled borderline tumor. The serous borderline tumors resembled the noninvasive implants of ovarian serous borderline tumors, lacked invasion, and did not show nuclear atypia of the degree seen in grade 2 or grade 3 serous carcinoma. Low-grade serous carcinoma, psammocarcinoma, and serous borderline tumors of peritoneal origin share some clinicopathologic features and may be underrecognized at surgery and gross examination. Because of overlapping microscopic patterns, adequate sampling is mandatory to identify small foci of invasion that exclude a borderline tumor and identify significant cellularity that excludes a psammocarcinoma. Conservative therapy is merited for younger women with borderline tumors. Maximum debulking is recommended for bulky symptomatic borderline tumors, low-grade serous carcinoma, and psammocarcinoma. Although short-term outcomes for the carcinomas appear favorable, follow-up is too limited to determine long-term outcomes.

Sixty-three examples of transitional cell metaplasia of the cervix or vagina from patients 50 to 84 (average 67.6) years of age are described. Fifty-seven of the 59 patients were postmenopausal and two perimenopausal. Only four patients were documented to have received hormonal therapy. The lesion was an incidental microscopic finding in all patients and was found in 29 hysterectomy specimens, 18 endocervical or endometrial curettage specimens, 11 cervical biopsy or cone biopsy specimens, and five vaginal biopsy specimens. The sites involved by transitional cell metaplasia were the exocervix (n = 14), transformation zone (n = 33), vagina (n = 10), or a combination (n = 4). The cervical and vaginal specimens most commonly showed involvement of the surface epithelium by transitional cell metaplasia. Other transitional cell patterns were isolated stromal nests (n = 9) and invagination of surface epithelium into the underlying stroma (n = 2). The typical appearance of transitional cell metaplasia was a hyperplastic epithelium with lack of maturation, consisting of spindled nuclei with tapered ends and frequent longitudinal nuclear grooves. The nuclei were typically oriented vertically in the deeper layers, and horizontally with a streaming pattern superficially. The cells had low nuclear to cytoplasmic ratios, perinuclear halos, and absent to rare mitotic figures. Mild to moderate atypia was seen in only two cases. Many of the cases could have been confused with squamous dysplasia due to the lack of apparent maturation. However, in most cases, attention to cytologic detail disclosed the typical features of transitional cell metaplasia. This process, usually seen in older women, has not been emphasized and can be overdiagnosed as dysplasia, leading to unnecessary treatment.

Mucinous epithelium is the most uncommon type identified in ovarian adenofibromas. Because of the rarity of mucinous adenofibromas and the presence of cytologic atypia in some, these neoplasms may be mistaken for low-grade metastatic adenocarcinoma. The clinicopathologic features of 10 mucinous adenofibromas are reviewed. They occurred in women 24 to 76 (mean, 51) years of age, were unilateral, and ranged in diameter from 1 to 25 cm. Seven tumors were classified as benign, containing glands lined by a single layer of mucin-containing columnar cells. Three tumors that contained crowded glands lined by mucin-containing cells with mild to moderate nuclear atypia, nuclear stratification of up to three cells in thickness, and focal tufting were classified as benign with epithelial atypia. Most women had a hysterectomy and bilateral salpingo-oophorectomy. Follow-up information was available on six women, who were alive and well from 6 to 126 (mean 41) months after diagnosis. The identification of mucinous glands in typical fibromatous stroma should allow the distinction of these benign neoplasms from metastatic carcinomas.

The clinicopathological features of 25 cases of peritoneal serous neoplasms histologically identical to noninvasive implants of ovarian serous borderline tumors but with minimal or no ovarian surface involvement were reviewed. The patients ranged in age from 19 to 53 (mean, 31) years; 18 of them were under 35 years of age. Infertility and abdominal pain were the most common presenting complaints. An extraovarian mass was present in two patients; adhesions or granularity of peritoneal surfaces were described in 23 of them. In 21 cases only the pelvic peritoneum was involved; the upper abdominal peritoneum was involved additionally in four cases. Most of the women were treated by hysterectomy, bilateral salpingo-oophorectomy, and omentectomy; six of them received chemotherapy postoperatively and two received both chemotherapy and radiation therapy. Nine women had a more limited operation to preserve their fertility. The 25 patients were followed for 4 to 13.9 (mean, 8) years. There was no clinical evidence of recurrence in 21 women. Borderline tumor recurred in two patients, who remained well for 1.7 and 2 years after excision of the recurrent tumor. Invasive low-grade serous carcinoma of the peritoneum developed in one woman who was living with extensive intra-abdominal tumor at the last follow-up examination. One woman died of disseminated SBT, which was diagnosed cytologically but not confirmed by biopsy.

Three cases of giant cell arteritis involving the female genital tract of postmenopausal women are reported. The patients were 80, 64, and 57 years of age and presented with fatigue and anemia, fatigue and an abdominal mass, and fever and weight loss, respectively. Two of the patients had palpable pelvic masses; one had an ovarian mass visible on ultrasound examination. All three patients were anemic, and the erythrocyte sedimentation rate was elevated in the two women in whom it was tested. Exploratory laparotomy revealed ovarian tumors in two patients; one had a mucinous cystadenoma, and one had bilateral ovarian fibromas. The third patient had a cyst of the rete ovarii. Extensive giant cell arteritis of the small to medium-sized arteries was found unexpectedly in the ovaries and fallopian tubes of two patients who had prior hysterectomies and in the ovaries, fallopian tubes, and uterus of one patient. One patient was treated postoperatively with prednisone with improvement of symptoms and a decrease in the erythrocyte sedimentation rate. Of the two patients who received no therapy, one was found to have a thoracic aortic aneurysm 5 years postoperatively, and the other was alive without symptoms 17 years after the operation. Giant cell arteritis of the female genital tract is a rare finding in elderly women and may occur as an isolated finding or as part of generalized giant cell arteritis.

Recent ultrastructural studies have shown that tubular carcinoma of the breast lacks basal lamina. This study was undertaken to determine the usefulness of light-microscopic examination of PAS staining for basal lamina in the differentiation of tubular carcinoma and sclerosing adenosis. Ten cases of tubular carcinoma show no basal lamina except for an occasional short segment. Ten cases of sclerosing adenosis show intact basal lamina except for short focal discontinuities. It is concluded that the lack of basal lamina in tubular carcinoma and its presence in sclerosing adenosis is a useful differential feature.

The clinical and pathological features of two cases of ependymoma that originated in the broad ligament are reported. Metastases developed in both patients. The tumors had the distinctive features of ependymoma on light-microscopical examination, and the diagnosis was confirmed by ultrastructural study in one case and immunoperoxidase staining for glial fibrillary acidic protein in both cases. The tumors presented diagnostic difficulties because of their close resemblance to serous papillary carcinomas of the ovary and the absence of published reports of ependymoma occurring in the female genital tract.

The significance of varying degrees of epithelial atypicality was investigated in 27 endometrioid adenofibromas and cystadenofibromas of the ovary. The tumors were classified as atypical or borderline on the basis of the degree of atypicality of the epithelial element. All tumors were confined to the ovary at the initial operation and most of them were treated by a hysterectomy and bilateral salpingo-oophorectomy. Seven tumors with mild to severe cytologic and architectural atypicality similar to that encountered in atypical endometrial hyperplasia were classified as atypical adenofibromas. No recurrences or deaths from tumor occurred in patients with this type of tumor during 1-18.5 years of follow-up. Twenty tumors that contained closely packed glands or epithelial islands with a cribriform pattern composed of cells with low-grade malignant nuclear characteristics embedded in an abundant fibromatous stroma without evidence of invasion were classified as borderline. Nineteen patients with tumors of this type had no evidence of disease 1-13 years after initial therapy. One of these tumors was discovered at autopsy. These data, although based on a relatively small series of cases, suggest that atypical endometrioid adenofibromas and those of borderline malignancy have an excellent prognosis.