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.

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.

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.

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.

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.

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.

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.

Rare subtype(s) and frequency of multi-viral subtype high-risk human papilloma virus infection in high-grade squamous intraepithelial lesion and squamous cell carcinoma in a cervical carcinoma prevalent developing country: a multiplex real-time polymerase chain reaction-based pilot study.

BACKGROUND: Bangladesh, with a population of 160 million and nearly half being women, has the 4th highest rate of cervical carcinoma deaths in the world. It is projected that ∼500,000 of these women would die of this entirely preventable cancer by 2030. HPV vaccination is not widely offered in Bangladesh. This pilot study is designed to find out the prevalence of rare and multi-viral high-risk HPV (hrHPV) subtype(s) infection which may help strategize a large scale vaccination program in tackling cervical carcinoma in the country. METHODS: Forty cases of cervical High-Grade squamous intraepithelial lesion (HSIL) and Squamous cell carcinoma (SqCa) were collected. DNA was extracted from tissue representing HSIL and SqCa and multiplex PCR was run to identify all 15 hrHPV subtypes along with known positive controls. RESULTS: Of the total, 27 cases were biopsies/cones and 13 were hysterectomies including 5 HSIL and 35 SqCa. Infection caused by rare subtypes, hrHPV 45 and 52, were found in only two cases. Multi-subtype infection, detected in 28 % cases, was limited to HPV16/18 in all cases but one; one case showed hrHPV16/52 combination. CONCLUSION: A remarkable homogeneity of hrHPV 16 infection is noted in women with HSIL & SqCa in this country in these limited samples. This finding is in sharp contrast to the reports from western countries of frequent multi-viral and rare subtype hrHPV infection. This pilot study suggests that a vaccination program may be highly effective in controlling cervical cancer there. A larger study, however, is required to ratify the findings.

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.

High-risk human papillomavirus infection involving multiple anatomic sites of the female lower genital tract: a multiplex real-time polymerase chain reaction-based study.

High-risk human papillomavirus infection usually is seen at one anatomic site in an individual. Rarely, infection at multiple anatomic sites of the female lower genital tract in the same individual is encountered either simultaneously and/or at a later date. The current study identifies the various subtypes of high-risk human papillomavirus infection in these scenarios and analyzes the potential significance of these findings. High-risk human papillomavirus infection involving 22 anatomic sites from 7 individuals was identified after institutional review board approval. Residual paraffin-embedded tissue samples were retrieved, and all 15 high-risk human papillomavirus were identified and viral load quantified using multiplex real-time polymerase chain reaction-based method. Multiple high-risk human papillomavirus subtypes were identified in 32% of the samples and as many as 5 different subtypes of high-risk human papillomavirus infection in a single anatomic site. In general, each anatomic site has unique combination of viral subtypes, although one individual showed overlapping subtypes in the vagina, cervix, and vulvar samples. Higher viral load and rare subtypes are more frequent in younger patients and in dysplasia compared with carcinoma. Follow-up ranging from 3 to 84 months revealed persistent high-risk human papillomavirus infection in 60% of cases.

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.

Incidental gynecologic neoplasms in morcellated uterine specimens: a case series with follow-up.

Laparoscopic hysterectomy with morcellation (LHM) is considered a safe and less invasive alternative to other hysterectomy techniques by shortening postoperative hospital stay and patient recovery. Sparse incidental gynecologic neoplasms after LHM have been reported; however, the frequency and subsequent follow-up have not been systematically investigated in a large case series. We aimed to determine the frequency and types of incidental findings after LHM with clinical outcomes. An electronic chart review was conducted searching all cases of LHM performed within 5 years to determine the incidence of unexpected gynecologic neoplasms and subsequent peritoneal disease. Patient demographics, prior preoperative investigation, and subsequent follow-up were investigated. For comparison, the overall frequency of pertinent uterine neoplasms was noted during the study period. Of the 352 cases of LHM identified, 3 harbored unsuspected malignancies, an incidence of 0.9%. Four variant smooth muscle tumors (1.1%) and 5 benign non-smooth muscle neoplasms (1.4%) were identified at the time of initial morcellation. Two cases of subsequent peritoneal "implanted" leiomyoma were identified (0.6%). Of malignant or atypical mesenchymal neoplasms diagnosed at our institution during the study period, 8.6% were diagnosed in a morcellated specimen. There is a clinically important risk of occult malignant or atypical neoplasms in morcellated uterine specimens. Proper pathologic evaluation of malignant or atypical uterine neoplasms is limited when a uterus is morcellated. Patients undergoing morcellation procedures are also potentially at risk for dissemination of disease. Clinicians and patients should be aware of these risks when discussing surgical options for hysterectomy.

Localized amyloidosis of the vulva with and without vulvar intraepithelial neoplasia: report of a series.

Localized primary cutaneous amyloidosis is uncommon in Europe and North America and is infrequently reported in the English literature. The constituents of such deposits have not been previously examined; this series characterizes amyloid deposits in localized vulvar amyloidosis and their association with vulvar intraepithelial neoplasia. All biopsies and excisions of vulva over 18 months were reviewed. Cases with suspected amyloidosis were retrieved after institutional review board approval. Twenty cases mimicking amyloidosis were selected as controls. All study and control cases were stained with Congo red. Four Congo red-positive study cases were studied by liquid chromatography-tandem mass spectrometry. Of 27 Congo red-positive study cases, 25 were then examined by immunohistochemical stains with antibodies to cytokeratin 5 (CK5) and cytokeratin 14 (CK14). Of 149 cases reviewed, 26 localized and 1 systemic vulvar amyloidosis were identified. Liquid chromatography-tandem mass spectrometry analysis of the deposits revealed unique peptide profile consistent with CK5 and CK14. Immunohistochemical staining with antibodies to CK5 and CK14 also detected these components in the deposits. The vulvar deposit of systemic amyloidosis consisted of amyloid light chain (λ)-type amyloid deposit. All control cases were negative for Congo red. Keratin-associated amyloid materials (CK5 and CK14) were found to be unique in localized vulvar amyloidosis. Leakage of keratins from the basal layer of the epithelium into the superficial dermis may have been the possible source of the deposits. It appears to be associated with both high-grade and low-grade vulvar intraepithelial neoplasias and, rarely, lichen sclerosus, seborrheic keratosis, and benign vulvar skin.

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.