Atypical Placental Site Nodule Arising in a Postcesarean Section Scar: Case Report and Review of the Literature.

The distinction between benign and malignant trophoblastic lesions often presents a diagnostic challenge, even in entities with defined morphologic and immunohistochemical criteria. Lesions arising from chorionic-type intermediate trophoblast, namely placental site nodule (PSN) and epithelioid trophoblastic tumor (ETT), can be distinguished by existing criteria. However, a putative intermediate lesion termed "atypical placental site nodule" (APSN) has been described in the literature but is not well-classified. We present a case of APSN, along with a brief literature review, and we propose more definitive morphologic and immunohistochemical criteria for this entity, in order to facilitate easier diagnosis and gather more information regarding outcomes.

Nodular Hyperplasia of the Bartholin Gland, A Benign Mimicker of Aggressive Angiomyxoma: A Case Series and Literature Review.

Nodular hyperplasia (NH) of the Bartholin gland is an exceedingly rare benign solid lesion of the female genital tract that can mimic the Bartholin gland cyst clinically. The histologic criteria for NH were established in 1998 by Koenig and Tavassoli. In this case series, we describe 4 cases of NH from Women and Infants Hospital in Rhode Island. All cases have microscopic features of lobular proliferation of acini and inspissated mucin. One case especially has extensive mucin extravasation mimicking an aggressive angiomyxoma. In this case series, we call attention to NH as another entity to consider in the differential diagnosis of an enlarged Bartholin gland. We also discuss ways to distinguish it from other benign and malignant solid lesions of the vulvar vestibule.

Primary Ovarian Solid Pseudopapillary Neoplasm With CTNNB1 c.98C>G (p.S33C) Point Mutation.

Ovary is one of the extrapancreatic sites of origin of solid pseudopapillary neoplasm (SPN). Only 9 cases of primary ovarian SPN, 1 with CTNNB1 mutation similar to pancreatic SPN, have been reported in the English literature. We describe the second case of ovarian SPN with confirmed CTNNB1 mutation. A 49-year-old postmenopausal woman presented with a 4.5 cm right ovarian mass. Ovarian mass showed histologic and immunohistochemical features of pancreatic SPN. The ovarian surface was intact and uninvolved. Ki-67 index was low (1%-5%). DNA sequencing of CTNNB1 exon 3 revealed c.98C>G (p.S33C), a well-characterized activating mutation. Our case adds to the growing body of evidence that primary ovarian SPN are phenotypically and genotypically similar to pancreatic SPN.

Endometrial Adenocarcinomas With Significant Mucinous Differentiation: A Characterization of Intratumoral Heterogeneity of KRAS Mutations in Mucinous and Endometrioid Histologic Components.

OBJECTIVE: KRAS mutations are frequently seen in malignancies with mucinous morphology. In our previous study, mucinous endometrial carcinomas were associated with a significantly higher frequency of KRAS mutations as compared with matched conventional endometrioid carcinomas. This study expands our previous report by exploring possible intratumoral heterogeneity for KRAS gene mutations in the mucinous components of mucinous carcinomas (MCs) and endometrioid carcinomas with significant mucinous differentiation (ECSMD) versus their associated "usual" endometrioid components. MATERIALS AND METHODS: KRAS-positive cases from our previous report were studied, including 10 MCs and 10 ECSMDs. The specimens were microscopically dissected to separately isolate morphologically mucinous and endometrioid components. Direct DNA sequencing for KRAS mutations at codons 12 and 13 using capillary electrophoresis were performed. RESULTS: KRAS mutations were detected in the endometrioid components of 8 (80%) of 10 MCs and 3 (30%) of 10 ECSMDs. The endometrioid component of the ECSMD group was less frequently associated with KRAS mutation than the endometrioid component of the MC group, even when the mucinous component of the same tumor contained a mutation; the difference is statistically significant (P < 0.05). CONCLUSIONS: Our current study shows that intratumoral heterogeneity for KRAS gene mutation was associated with ECSMD, but less frequently with MC. It is possible that when the mucinous component predominates, qualifying for an MC, KRAS mutations appear to be widespread, irrespective of the mucinous or nonmucinous differentiation of the tumor cells. The findings suggest that multiple samples for KRAS tests may be useful, especially in endometrioid carcinoma with significant mucinous differentiation.

Testosterone-induced "Virilization" of Mesonephric Duct Remnants and Cervical Squamous Epithelium in Female-to-Male Transgenders: A Report of 3 Cases.

Mesonephric ducts regress in genotypic females, leaving behind few remnants. These vestigial structures are often recognized in the mesosalpinx and paracervical regions. We report here 3 cases of female-to-male transgenders who underwent hysterectomy following testosterone treatment. Both female and male genital structures were identified on histologic examination. Although the morphologic appearances of the specimens were unremarkable, histologically 1 case revealed a well-formed fallopian tube as well as an epididymis and 2 cases showed prostate glands to be present in the cervical squamous epithelium.

The clinical significance of K-ras mutation in endometrial "surface epithelial changes" and their associated endometrial adenocarcinoma.

OBJECTIVES: The entity of 'surface epithelial changes' (SECs) was first described in 1995 [1]. Morphologically, SECs usually arise from malignant glands at the superficial aspect of well differentiated (WD) endometrioid carcinomas (ECs) and impart the appearance of a 'maturational' phenomenon at the surface of the cancer. Exhibiting a paradoxically bland histologic appearance, SECs typically show morphologic features that mimic benign entities, particularly endocervical microglandular hyperplasia (MGH). SECs have been associated with approximately half of WD endometrioid carcinomas many of which showed focal mucinous differentiation. Despite their morphologically benign histology, some have questioned whether the presence of SECs represents a 'marker' for an underlying malignancy, especially in postmenopausal women with endocervical or MGH-type SECs in their endometrial sampling. Since the biologic nature of SECs is unknown, we aimed to study the prevalence of KRAS gene mutations in SECs and the underlying WD endometrioid adenocarcinomas (EC) from which they directly arise. METHODS: 24 cases with biopsy proven SECs and ECs in their subsequent hysterectomy were retrieved. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue. PCR amplification for KRAS codons 12 and 13 was performed, followed by sequencing using capillary electrophoresis. RESULTS: KRAS codons 12 and 13 mutations were detected in 19 of 24 (79%) SECs, and 19 of 24 (79%) ECs. All SECs had the same KRAS mutation as the underlying EC. CONCLUSIONS: Our results suggest that SECs are of neoplastic origin and that KRAS mutations play an important role in the tumorigenesis of ECs and SECs.

An Isolated Metastasis From Clear Cell Renal Cell Carcinoma to the Uterus: A Case Report and Review of Literature.

Ovaries are a favored site for metastatic tumors arising in the female genital tract. Other organs of the mullerian system, that is, the uterine corpus as well as the fallopian tubes, cervix, and the vagina are less commonly involved by metastases. If there is no clinical history of a known extramullerian primary tumor, suspicion that a uterine mass represents metastatic disease is low. We report the case of a renal clear cell carcinoma presenting as an isolated uterine mass and morphologically mimicking a primary endometrial clear cell adenocarcinoma. A review of the English literature yielded only a recent abstract describing 3 cases of renal clear cell carcinoma metastasizing to the endometrium.

Pathology of endometrial ablation failures: a clinicopathologic study of 164 cases.

Endometrial ablation is a minimally invasive alternative to hysterectomy for abnormal uterine bleeding. Although the failure rate is low, continued bleeding or development of pelvic pain after ablation does occur. We analyzed the clinicopathologic features of 164 hysterectomy specimens after endometrial ablation, 19 of which were performed for indications other than failed ablation (control cases). Pathologic findings included: dense fibrosis and hyalinization of the endometrial surface ablative necrosis within the uterine cavity and adherent to the endometrial surface, persistent months after ablation; uterine cavity lined by superficial, large, congested, patent blood vessels with atherosis; ablation changes present only in the lower uterine segment; and residual endometrium present in the cornual regions. Patients with ablative necrosis underwent subsequent hysterectomy sooner than those without such debris (median of 5 vs. 23 mo, respectively). Patients with superficial abnormal vessels were also more likely to have a shorter ablation-hysterectomy interval than those without (median of 2 vs. 18 mo, respectively). Patients with associated adenomyosis or prior tubal ligation were significantly more likely to have continued bleeding. Possible sources of continued abnormal bleeding or pelvic pain include: the presence of ablative necrosis or superficial abnormal blood vessels, although the association did not reach statistical significance in this study; incomplete ablation, affecting only the lower uterine segment or sparing the cornual region; tubal endometriosis after ligation; and endometrial regeneration via adenomyosis.

A small organ takes center stage: selected topics in fallopian tube pathology.

In this paper we consider a number of non-neoplastic and neoplastic lesions of the fallopian tube. Emphasis has been placed on diagnostically difficult entities, some of which result in misdiagnosis and consequent alteration of treatment, including "pseudocarcinomas" that represent a florid epithelial response to acute and/or chronic salpingitis. Endometriosis-related lesions may cause infertility, or undergo malignant transformation to a Mullerian carcinoma, most frequently endometrioid and clear cell types. Pregnancy-related tubal lesions include the easily misdiagnosed metaplastic papillary tumor as well as several manifestations of ectopic pregnancy. Covered briefly are familial conditions such as the Peutz-Jeghers syndrome and its association with tubal mucinous metaplasia, clear cell papillary cystadenoma associated with von Hippel-Lindau syndrome, and the Li Fraumeni syndrome's germline p53 mutation and its association with distal tubal p53 signatures. Miscellaneous tumors discussed include the common adenomatoid tumor and the uncommon female adnexal tumor of probable Wolffian origin. Important issues including the updated staging of fallopian tube carcinomas, and the histopathologic variants of endometrioid carcinomas and their sometimes unusual patterns that engender the potential for confusion with other tumors are briefly noted. The final section covers the relatively recent and novel concept of the fallopian tube as the predominant site of origin of ovarian and peritoneal carcinomas. Discussed are the histologic, immunohistochemical, and molecular biologic evidence that support the tubal fimbria as the site of serous tubal intraepithelial carcinoma, possibly the immediate precursor to high-grade ovarian and peritoneal serous carcinoma.

Endometrial carcinomas with significant mucinous differentiation associated with higher frequency of k-ras mutations: a morphologic and molecular correlation study.

OBJECTIVES: K-ras gene product in the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway is critical in the development of certain types of malignancies. K-ras mutation-associated pancreatic and ovarian carcinomas often display mucinous differentiation. Previous studies have shown that k-ras mutation is found in 10% to 30% of endometrial carcinomas. We investigated k-ras mutations in several morphologic subtypes of endometrial carcinomas with particular emphasis on various degrees of mucinous differentiation. METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue sections. Polymerase chain reaction amplification for k-ras codons 12 and 13 were performed, followed by sequencing using capillary electrophoresis. The Fisher exact test is used to compare the prevalent difference of k-ras mutation among the groups. P < 0.05 was considered significant. RESULTS: K-ras mutations were detected in 8 (80%) of 10 mucinous carcinomas, 12 (67%) of 18 endometrioid carcinomas (ECs) with significant mucinous differentiation (ECMD), 4 (25%) of 16 ECs, and 1 (9%) of 11 serous carcinomas. The differences were statistically significant between mucinous carcinomas versus EC (P < 0.01) and ECMD versus EC (P < 0.05). CONCLUSION: The findings suggest that mucinous carcinoma and endometrioid carcinoma with significant mucinous component are more likely to be associated with k-ras mutation. Potential clinical implications of k-ras mutation lies in the management of recurrent or higher-stage endometrial mucinous tumors, which would not be responsive to treatment protocols containing epidermal growth factor receptor inhibitors.

Unilateral pelvic mass presenting in postmenopausal patients: report of two unusual cases.

We encountered 2 unusual cases of polypoid endometriosis presenting as unilateral ovarian masses. The first was benign and was found in a 57-year-old postmenopausal patient; the second case gave rise to well-differentiated endometrioid carcinoma in an 80-year-old patient. The second patient also had a superficially invasive endometrioid adenocarcinoma of the endometrium arising in a background of complex atypical hyperplasia. Intraoperative evaluation was requested in both cases.

Vestibular papillomatosis: a benign condition mimicking genital warts.

Vestibular papillomatosis (VP) is a benign condition of the female genitalia that may be mistaken for condyloma acuminatum (genital warts). In contrast to condylomata, lesions of VP each grow from a distinct mucosal insertion; match the color of the surrounding mucosa; and are symmetrically distributed, limited to the inner labia minora and vaginal introitus. Recognition of this entity will help to prevent unnecessary stress, testing, and discomfort.

Tubal metaplasia of the endometrium with cytologic atypia: analysis of p53, Ki-67, TERT, and long-term follow-up.

Tubal metaplasia of the endometrium may occasionally display cytologic atypia (atypical tubal metaplasia) resembling serous carcinoma or endometrial intraepithelial carcinoma. Although atypical tubal metaplasia is presumed to be reactive or degenerative in etiology, its clinical significance is unknown. In this study, we investigated atypical tubal metaplasia in regard to its immunoexpression of p53, Ki-67, and human telomerase reverse transcriptase (TERT), and its long-term clinical outcome. A total of 63 cases of atypical tubal metaplasia and 200 cases of endometrial samples with typical tubal metaplasia were followed for a mean of 64 and 61 months, respectively. Of the 63 atypical tubal metaplasia cases, formalin-fixed, paraffin-embedded tissue sections from 16 cases were immunostained with antibodies to p53, Ki-67, and TERT. Sections from 13 cases of uterine serous carcinoma were also stained for TERT as control. After long-term follow-up, 5% of patients in the atypical tubal metaplasia group developed hyperplasia without atypia compared with 4% of patients in the control group (P=0.44), whereas 3% in the atypical tubal metaplasia group developed atypical hyperplasia or carcinoma compared with 2% in the control group (P=0.44). p53 immunoreactivity was either focal and weak or negative in all cases of both atypical and typical tubal metaplasia (P>0.05). Ki-67 immunoreactivity was present in 0-5% of cells in 94% of both atypical and typical tubal metaplasia (P>0.05). TERT immunoexpression was absent in all 16 cases of atypical tubal metaplasia, but present in all 13 cases of uterine serous carcinoma (P<0.0001). Our study indicates that atypical tubal metaplasia displays an immunostaining pattern similar to otherwise typical tubal metaplasia of the endometrium, and distinct from uterine serous neoplasms. The presence of atypical tubal metaplasia in endometrial samplings does not increase the risk of developing endometrial hyperplasia or malignancy.

Vascular plexiform leiomyoma mimicking uterine tumor resembling ovarian sex cord tumor.

Leiomyomata are common benign smooth muscle neoplasms with a usually easily recognizable histologic pattern. However, there is a wide variety of subtypes described in the literature, characterized by predominance of a particular distinct histologic pattern. Here we describe a case of a highly vascular leiomyoma with a prominent plexiform pattern and cords and tubules of epithelioid cells that mimics a uterine tumor resembling an ovarian sex cord tumor.

Atypical melanocytic nevi of genital type: a distinctive pigmented lesion of the genital tract often confused with malignant melanoma.

A 30-year-old female presented with a 0.3 cm slightly raised tan-brown papule with somewhat irregular borders on her right labia minora. The papule was detected by her gynecologist during an annual gynecologic visit. Excision of the lesion revealed an atypical melanocytic nevus of genital type (AMNGT). This nevus is often confused with other pigmented lesions especially dysplastic nevus or even malignant melanoma. This distinctive melanocytic nevus often causes significant concern to pathologists and dermatologists. The diagnostic criteria and differentiating features from dysplastic nevi and malignant melanoma are discussed.

Utility of PTEN expression of endometrial "surface epithelial changes" and underlying atypical endometrial hyperplasia.

Surface epithelial changes (SECs) have been reported to be associated with endometrial carcinoma in about 49% of cases. They have also been seen to be associated with endometrial hyperplasia. Although morphologically benign, these lesions are considered a marker for underlying malignancy. Their true biologic nature, however, is not known. PTEN has been reported to be altered in endometrial carcinomas and endometrial precancers where no morphologic changes are appreciated. The current study aims to investigate PTEN status in the endometrial SECs. Thirty-two cases of endometrial biopsy are divided into 2 groups: group 1 had 18 cases of SEC and underlying endometrial atypical hyperplasia and group 2 had 14 cases of SEC alone. Four-micron sections were cut from each block and stained with antibodies to PTEN. One section was stained with hematoxylin and eosin to confirm the presence of the area of interest. Positive and negative control slides were run with each batch of staining. All 32 cases were followed for a median period of 54 (range, 21 to 84) months. Overall, PTEN alteration (NULL) was found in 12 of the 32 cases of endometrial samples (37.5%) examined. In group 1, 10 of the 18 cases (56%) of atypical endometrial hyperplasia with "SECs" showed PTEN NULL. Of these 10 cases, 6 (60%) cases showed FIGO grade 1 endometrioid carcinoma in subsequent hysterectomy specimens. Two other cases (20%) had atypical endometrial hyperplasia only. In group 2, two of the 14 (14%) cases of SECs alone showed PTEN NULL phenotype. These 2 patients were followed for 26 and 63 months, respectively, and subsequent endometrial biopsies and pap smears were negative. Of the remaining 12 cases that retained PTEN, 9 cases (75%) were negative when followed for a median of 54 months (range, 21 to 84 mo). SECs seem to be a heterogeneous entity. Presence of PTEN NULL phenotype in SECs and associated endometrial hyperplasia does not necessarily predict an increased incidence of endometrioid carcinoma in subsequent follow-up. However, absence of PTEN NULL phenotype in SECs alone may predict a benign follow-up.

Routine histologic features in complex atypical hyperplasia can predict the presence of endometrial carcinoma: a clinicopathological study of 222 cases.

There is a wide range of finding endometrial adenocarcinoma (ADCA) in the uterus after a diagnosis of complex atypical hyperplasia (CAH), likely due to a poor diagnostic reproducibility and an inherent heterogeneity in CAH. We evaluated whether histologic subtyping of CAH would help predict ADCA. Our study consisted of 222 cases of CAH diagnosed by endometrial biopsy or curettage. ADCA was seen in 38.3% of these cases at hysterectomy. We divided CAH into 2 subtypes: type A was defined as back-to-back glands in a focus smaller than 2.1 mm, and type B as crowded glands with cytologic atypia but with still-intervening stroma regardless of lesional size. Type A was associated with a significantly higher frequency of ADCA (75.9%) compared with type B (26.2%). Lesions containing neutrophilic/cellular debris showed a higher association of ADCA (60.0%) compared with those without neutrophilic/cellular debris (35.5%). CAH present outside endometrial polyp was associated with a higher frequency of ADCA (42.5%) than that confined to endometrial polyp (19.5%). Within type B cases, lesions greater than 3 mm had a higher association of ADCA (34.3%) than did smaller ones (13.6%). Patients older than 50 years were more likely to have ADCA in the uterus compared with younger women with a preoperative diagnosis of CAH (43.2% versus 28.3%). CAH made on office biopsy showed a higher association of ADCA (46.6%) compared with a diagnosis made on curettage (31.1%). Recognition of these clinicopathological features in CAH may prove useful in predicting the likelihood of ADCA in the uterus.

Association of ovarian hyperthecosis with endometrial polyp, endometrial hyperplasia, and endometrioid adenocarcinoma in postmenopausal women: a clinicopathological study of 238 cases.

Ovarian hyperthecosis, a source of estrogen, may occur in postmenopausal women. In this study, we evaluated the possible association of ovarian hyperthecosis with endometrial polyp, endometrial hyperplasia, and endometrioid adenocarcinoma in postmenopausal women. Our study consisted of 238 postmenopausal women: 108 with endometrioid adenocarcinoma and 130 without endometrial carcinoma. The International Federation of Gynecology and Obstetrics system was used to grade endometrioid adenocarcinoma. Within the endometrioid adenocarcinoma cases, 48 (44.4%) were grade 1, 46 (42.6%) were grade 2, and 14 (13.0%) were grade 3. Among the noncancer cases, 71 (54.6%) had atrophic endometrium, 32 (24.6%) had endometrial polyp, and 27 (20.8%) had endometrial hyperplasia. The frequency of ovarian hyperthecosis in patients with endometrial polyp (46.9%), endometrial hyperplasia (55.6%), and grade 1 (43.8%), grade 2 (54.3%), and grade 3 (57.1%) endometrioid adenocarcinoma was each significantly higher than that in patients with atrophic endometrium (23.9%), supporting an association of these lesions with ovarian hyperthecosis in postmenopausal women. There was no statistically significant difference in the rate of ovarian hyperthecosis among patients with endometrial polyp, endometrial hyperplasia, and grade 1, grade 2, and grade 3 endometrioid adenocarcinoma. Our study indicates that ovarian hyperthecosis with its resultant risk factor of hyperestrinism may contribute to the pathogenesis of endometrial polyp, endometrial hyperplasia, and endometrioid adenocarcinoma in postmenopausal women. Although some studies show that grade 3 endometrioid adenocarcinoma has different genetic/molecular changes from its lower-grade counterparts, our study suggests that endometrioid adenocarcinoma of all grades may share the common risk factor of hyperestrinism.