Primary adenocarcinomas of the vulva and related structures: An enigmatic and diverse group of tumors✰.

Approximately half of adenocarcinomas that involve the vulva are secondary, either through direct extension or metastases from elsewhere. Primary vulvar adenocarcinomas are rare and encompass a diverse array of neoplasms that are nominally classified based on the presumed tissue or organ of origin, the tumoral phenotype, or both. In this review, we summarize the clinicopathologic features of adenocarcinomas that originate from the vulva and related structures, including the terminal urethra. Adenocarcinomas of this region encompass lesions that are defined by their primary site (such as adenocarcinomas of the Bartholin gland, which by definition must be in the region of the Bartholin gland), histomorphology and immunophenotype (such as clear cell carcinoma and adenocarcinoma of intestinal [cloacogenic] type), or both (such as adenocarcinoma of skene gland origin, which is associated with that specific organ but which also displays a distinctive phenotype that is similar to the phenotype of high grade prostatic adenocarcinoma). Other types, such as mammary-type adenocarcinomas, are presumed to originate from the putative mammary-like glands of the vulva and display a spectrum of pathologic features that are similar to their mammary counterparts. Similarly, vulvar carcinomas of sweat gland origin are pathologically similar to their counterparts in the non-vulvar skin and include a variety of cutaneous adnexal-type malignancies such as apocrine adenocarcinoma and eccrine adenocarcinoma. Some tumors, such as adenoid cystic carcinoma, may represent a Bartholin gland adenocarcinoma, a carcinoma of sweat gland origin, or a carcinoma arising from extramammary Paget disease (EMPD), depending on the context. Invasive carcinomas of various types have been reported in 7-12.7% of EMPD, and these are likely the most common primary glandular malignancy of the vulva. Occasional vulvar adenocarcinomas have been reported to be HPV-associated, although this association has not been established for the broader group of vulvar adenocarcinomas. Rare adenocarcinomas are not classifiable by the aforementioned nosologic scheme, and are designated as vulvar adenocarcinoma NOS.

Correlation between invasive mammary carcinoma grade and size in ultrasound-guided core needle biopsy and subsequent surgical excision.

The purpose of this study was to correlate the histologic grade, mitotic rate and size of invasive mammary carcinomas (IMC) on ultrasound (US) core needle biopsy (CNB) and the follow-up excision (FUE). The underestimation and overestimation of the grades by CNB were 11% and 8%. CNBs were more specific for grade 3 tumors. Tumors >10 mm by US examination showed greater concordance in grades. The size in the FUE was the best determinant of pT followed by US examination. The extent of IMC on CNB was larger than FUE in 8% resulting in pT upstaging in 3% of cases.

Utility of a standardized protocol for submitting clinically suspected endometrial polyps to the pathology laboratory.

The purpose of the study is to assess whether a protocol for submitting clinically suspected endometrial polyps will improve the detection rate of polyps and evaluation of the background endometrium. A retrospective review from 1999 to 2015 was performed. Cases were divided into (1) polyps and curettings placed in 2 containers (separate, n=61) and (2) polyps and curettings placed in 1 container (combined, n=80). Polyps were identified in 100% of cases in the separate compared with 95% in the combined group (P=.62). The background endometrium was evaluable in 79% of cases in the combined compared to 90% in the separate group (P=.07). The frequency of hyperplasia without atypia, atypical hyperplasia, and carcinoma was 4.4%, 3.6%, and 1.5%, respectively. In conclusion, the enhanced rate of polyp detection and evaluation of the background endometrium in the separate group is minimal. This supports the recommendation of submitting endometrial polyps and curettings combined in 1 container.

The role of immunohistochemistry in the evaluation of gynecologic pathology part 2: a comparative study between two academic institutes.

Use of specific immunohistochemistry (IHC) marker, singly or in panels, differs and is influenced by practice setting, individual experience beside other factors. This is a part 2 study where we surveyed the application of IHC in gynecologic (gyn) pathology. Our specific aim in this part was to identify what specific stains are preferentially used. A retrospective chart review on all cases accessioned to the gyn pathology specialty sign out service during a 1-year period was performed at two academic pathology departments. Outside referral and consult as well as gyn cytology cases were excluded from the study. The most commonly ordered markers in diagnostic gyn pathology in descending order of frequency were as follows: P16, ki-67, p53, estrogen receptor (ER), progesterone receptor (PR), and CK7. P16 was used mainly in establishing the diagnosis/grading of squamous intraepithelial lesions (SIL) and differentiating serous from endometrioid carcinomas (ECs). P53 was used particularly in the diagnosis of serous carcinomas and establishing the diagnosis of differentiated vulvar intraepithelial neoplasia. Positive p16 was documented in all high-grade SIL, endocervical carcinomas, and serous carcinomas. In contrast, p16 was negative in all benign, low-grade SIL, and ECs. ER and PR were used in panels with p16, p53, vimentin, and carcinoembryonic antigen to assign tumors to specific site, in differentiating EC from serous carcinomas and in establishing the diagnosis of endocervical adenocarcinomas. Immunohistochemistry was used in 4.7% and 8.7% of gyn surgical path cases at two institutions. P16, ki-67, and p53 were the most commonly used markers especially in grading SIL. This study documents the most commonly used IHC biomarkers at two tertiary care academic centers for defining benchmarks for IHC use.

The role of immunohistochemistry in the evaluation of gynecologic pathology: a single institutional experience.

Although morphology is the cornerstone of diagnostic pathology, it may be necessary to apply ancillary techniques, including immunohistochemistry (IHC) to resolve diagnostic problems. To provide some insights into IHC use in gynecologic (gyn) surgical pathology, we reviewed our institutional experience in using IHC during a 1-year period. A total number of 487 markers were ordered on 203 cases (2.4 markers/case). These 203 represented 4.8% of the 4216 gyn cases that were accessioned during the study period. Immunohistochemistry was used in 22 (9.3%) of 236 vulvar, 13 (9.2%) of 142 vaginal, 92 (5.9%) of 1557 cervical, 59 (3.5%) of 1698 uterine, 1 (0.3%) of 311 fallopian tube, and 16 (6.9%) of 232 ovarian specimens. The most common markers were p16 (n = 125), Ki-67 (n = 69), and p53 (n = 59). Immunohistochemistry proved to be a valuable tool in separating benign from dysplastic or malignant categories, or to increase diagnostic certainty in the latter category, in 131 (65%) of the 203 cases where IHC was requested, and 3.1% of all 4216 gyn cases examined. In the other 72 cases, IHC was utilized to histotype carcinomas, to define a site of origin for an established malignancy, or to assess the expression of predictive markers. Among 6 pathologists, years of practice and time spent on gyn service significantly affected IHC use, with less use with more than 10 years of practice and more than 10 weeks/year of service. This study documents IHC use at a tertiary care academic center and contributes data to define benchmarks for expected IHC use.

Malignancy associated with ovarian teratomas: frequency, histotypes, and diagnostic accuracy of intraoperative consultation.

Mature cystic teratomas are common ovarian germ cell tumors that rarely undergo malignant transformation, and intraoperative consultation is generally not warranted. The aims of this study were to review a large number of ovarian teratomas (OTs), to document the rate and histotypes of associated malignancy, and to identify parameters that may be associated with malignancy. In this study, a retrospective medical record review of patients diagnosed as having OTs from 2002 to 2011 was performed. Patient age, tumor size, type, and laterality were obtained from pathology reports and operative notes. A total of 956 OTs that ranged in size from 0.3 to 45 cm were identified. Intraoperative consultation was requested in a total of 316 (33.1%) of 956. Intraoperative gross evaluation only was performed on 211 (66.8%) of 316, of which 4 cases were malignant on final diagnosis. Frozen section was performed on 105 (33.2%) of 316, of which 12 were malignant on final diagnosis. The final diagnoses of all OT cases were as follows: 26 (2.7%) of 956 were associated with malignant tumors. The latter were larger than benign cases (average sizes, 11.2 cm vs 6.5 cm; P < .001), and patients with malignant tumors were significantly older than those with benign mature cystic teratoma (48.7 years vs 38.8 years, P < .001). The sensitivity and positive predictive value of frozen section examination during the intraoperative consultation for the detection of malignancy in OTs are 80% and 100%, respectively. In conclusion, patient age and large tumor size were associated with malignancy in this data set. Mucinous and serous borderline tumors were more common than squamous cell carcinoma in our cohort.

Selective breast/gynecologic pathology fellowship training in the United States: Experience of program directors.

Published data on combined breast and gynecologic [breast/gyn] surgical pathology fellowship training programs are limited. Our study aimed to survey the landscape of such fellowships in the United States (US), including specific information about their characteristics and the educational activities therein. Using web searches, we identified programs offering combined breast/gyn surgical pathology fellowship training. We developed a 26-item questionnaire asking program directors to report on the characteristics of their fellowship training structure. The search revealed 25 academic based programs offering one-year combined breast/gyn fellowship training, predominantly located (40 %) in the Northeast area. The following data was obtained: 44 % of the programs were accredited by the ACGME, 82 % required >19 weeks of breast and gyn service, and 69.6 % accepted the common application, 54.5 % of programs require completion of a research project for graduation. An annual average of 3000 breast and 3000 gyn cases appears to be the usual volume of cases. Interestingly, only 36 % of the program directors are graduates of a combined breast/gyn fellowship program. In conclusion, we present the most comprehensive and up-to-date census of combined breast/gyn pathology fellowships in the US. Our study provides valuable information on the current state of combined breast/gyn pathology fellowship training. The information will be helpful to current and prospective trainees, as well as program leaders.

The Malignant Potential of Ovarian Steroid Cell Tumors Revisited: A Multi-institutional Clinicopathologic Analysis of 115 Cases.

Steroid cell tumors (SCTs) of the ovary are rare and understudied, and as such, uncertainties remain about their malignant potential, as well as clinicopathologic predictors of patient outcome. Based on a multi-institutional cohort of cases, we present findings from the largest study of SCT reported to date. Clinicopathologic data were documented on 115 cases of SCT that were assembled from 17 institutions. The median patient age was 55 years (range: 9 to 84). When measured, preoperative androgen levels were elevated in 84.2% (48/57) of patients. A total of 111 (96.5%) cases were classified as stage I (103 stage IA; 2 stage IB; 6 stage IC). The stage distribution for the remaining 4 patients was as follows: stage II (n = 1), III (n = 3; 1 IIIA, 1 IIIB, 1 IIIC). The median tumor size was 3 cm (range: 0.2 to 22). Cytologic atypia, microscopic tumor necrosis, microscopic tumor hemorrhage, and a mitotic index of >1 mitotic figure/10 high-power fields were present in 52% (60/115), 9.6% (11/115), 37% (43/115), and 19% (22/115) of cases, respectively. Of 115 patients, 7 (6.1%) recurred postexcision, 4 (3.5%) ultimately died of disease, and 10 (8.7%) either recurred, died of disease, or were advanced stage at presentation. The median duration to recurrence postresection was 33 months (range: 23 to 180). Four of the 7 recurrences were stage IA at baseline. Tumor size >4 cm, International Federation of Gynecology and Obstetrics (FIGO) stage ≥IB, tumor necrosis, and tumor hemorrhage were each significantly associated with reduced recurrence-free survival in log-rank tests and univariable Cox models, with age older than 65 years being of marginal significance (hazard ratio [HR]: 5.4, 95% CI: 1.0-30.0, P = 0.05). Multivariable analyses suggested that FIGO stage ≥IB (HR: 27.5, 95% CI: 2.6-290.5), and age older than >65 years (HR: 21.8, 95% CI: 1.6-303.9) were the only parameters that were independently associated with recurrence. Cross-section analyses showed that tumor necrosis, tumor hemorrhage, and larger tumor size were significantly associated with a FIGO stage ≥IB status, which bolstered the conclusion that they are not independent predictors of recurrence. In summary, <10% of SCTs are clinically malignant, a substantially lower frequency than has previously been reported in the literature. Clinicopathologic predictors of patient outcomes that are prospectively applicable in practice could not be definitively established. Recurrences may occur many years (up to 15 y in this study) after primary resection, even in stage IA cases.

The Clinical Utility and Impact of Next Generation Sequencing in Gynecologic Cancers.

Next generation sequencing (NGS) has facilitated the identification of molecularly targeted therapies. However, clinical utility is an emerging challenge. Our objective was to identify the clinical utility of NGS testing in gynecologic cancers. A retrospective review of clinico-pathologic data was performed on 299 gynecological cancers where NGS testing had been performed to identify (1) recognition of actionable targets for therapy, (2) whether the therapy changed based on the findings, and (3) the impact on survival. High grade serous carcinoma was the most common tumor (52.5%). The number of genetic alterations ranged from 0 to 25 with a mean of 2.8/case. The most altered genes were TP53, PIK3CA, BRCA1 and BRCA2. Among 299 patients, 100 had actionable alterations (79 received a targeted treatment (Group1), 29 did not receive treatment (Group 2), and there were no actionable alterations in 199 (Group3). The death rate in groups 1, 2 and 3 was 54.4%, 42.8% and 50.2%, with an average survival of 18.6, 6.6 and 10.8 months, respectively (p = 0.002). In summary, NGS testing for gynecologic cancers detected 33.4% of actionable alterations with a high clinical action rate. Along with the high clinical utility of NGS, testing also seemed to improve survival for patients who received targeted treatment.

Preclinical use of longitudinal MRI for screening the efficacy of S-nitrosoglutathione in treating spinal cord injury.

PURPOSE: To evaluate the therapeutic efficacy of S-nitrosoglutathione (GSNO) in spinal cord injury (SCI) using in vivo MRI in combination with neuorobehavioral testing and postmortem tissue analysis. MATERIALS AND METHODS: Sixteen female rats were mildly injured at the vertebral T10 level and randomized into control (n = 8) and GSNO-treatment (n = 8) groups. GSNO was delivered at 0.05 mg/kg dose in saline by means of tail vein at 1 hr postinjury and then given orally on the following days. On postinjury days 1, 3, 7, and 28, the rats were tested behaviorally, then scanned using sagittal T2-weighted MRI for the quantification of lesion, edema, and hemorrhagic regions at the injury site. Excised cords were analyzed using histology and immunohistochemistry. RESULTS: Treatment with GSNO was feasible in rats with SCI. On the average, the GSNO group at each scan day 1, 3, 7, and 28 exhibited better functional recovery as indicated by the behavioral performance of 52%, 33%, 19%, and 18%, and had smaller lesions of -4%, -16%, -20%, and -17% compared with the controls, respectively. Edema trend was parallel to the lesion volumes in both groups. Ex vivo data demonstrated that GSNO plays a role in neuronal tissue preservation and sparing. CONCLUSION: The data collectively provided the preliminary evidence that the injured rats responded favorably to GSNO treatment. Longitudinal MRI provides critical quantitative information regarding the changes in lesion properties, which helps evaluating the efficacy of an exogenous intervention in SCI.

Grossly unremarkable cervix in endometrial carcinomas: lymphovascular space invasion and microcystic elongated and fragmented pattern may be associated with high incidence of cervical stromal involvement.

Accurate staging of endometrial carcinoma is crucial to optimize patients' care. A pivotal parameter that pathologists evaluate to guide staging is the presence of cervical stromal involvement. However, the standard protocol for adequate sampling of the cervix is lacking. A total of 71 grossly unremarkable cervices in hysterectomy specimens with endometrial carcinomas have been studied. Sixty-three (89.7%), five (7.0%), and three (4.2%) were FIGO stage I, II, and III, respectively. Of 71 (8.5%) cases, 6 cases had cervical stromal involvement, among which, 4 (67%) showed endometrioid carcinoma (EC), 1 case of serous carcinoma, and 1 carcinosarcoma. Microcystic elongated and fragmented (MELF) pattern was identified in 12 (16.9%) cases, among which 11 were EC. The presence of MELF pattern was associated with advanced age, deeper myometrial invasion, and advanced FIGO stage. Tumors with lower uterine segment involvement (5/6; 80%), lymphovascular space invasion (4/6; 67%), and MELF pattern (3/6; 50.0%) tended to have cervical stromal involvement. Thus, we provide evidence that the presence of these features in hysterectomy specimens from patients with endometrial carcinoma may warrant extended sampling of the cervix while submitting four representative sections (one section from each quadrant) seems adequate to evaluate for occult cervical stromal involvement in grossly unremarkable cervices in the absence of these features.

Diagnostic Utility and Significance of Performing Multistep Level Sections in Breast and Gynecologic Biopsy Specimens.

OBJECTIVES: The significance of performing multistep level sections, including preparation of unstained sections in breast and gynecologic biopsy specimens, has been studied. METHODS: Consecutive H&E-stained level sections of 785 atypical and malignant biopsy specimens were included. The diagnostic material was categorized into present, absent, increased in size, or depleted. If the multistep level sections helped in establishing the diagnosis after a nondiagnostic material or the tissue significantly increased in size, this was considered a positive impact. RESULTS: No effect and positive impact of performing multistep level sections were obtained in 84.8% and 15.2% by preparing a second level and 97.2% and 2.8% by preparing a third level, respectively. Eighteen (2.3%) of the diagnoses could have been missed without performing a second level, while 8 (1%) could have been missed without performing a third level. The intervening unstained sections were used in 27 of 785 (3.4%) of the cases. CONCLUSIONS: Staining two level sections with H&E significantly affected the diagnosis. However, preparing a third level did not improve the diagnosis. A universal protocol should be considered to standardize the handling of biopsy specimens among laboratories.

Evaluating regional blood spinal cord barrier dysfunction following spinal cord injury using longitudinal dynamic contrast-enhanced MRI.

BACKGROUND: In vivo preclinical imaging of spinal cord injury (SCI) in rodent models provides clinically relevant information in translational research. This paper uses multimodal magnetic resonance imaging (MRI) to investigate neurovascular pathology and changes in blood spinal cord barrier (BSCB) permeability following SCI in a mouse model of SCI. METHODS: C57BL/6 female mice (n = 5) were subjected to contusive injury at the thoracic T11 level and scanned on post injury days 1 and 3 using anatomical, dynamic contrast-enhanced (DCE-MRI) and diffusion tensor imaging (DTI). The injured cords were evaluated postmortem with histopathological stains specific to neurovascular changes. A computational model was implemented to map local changes in barrier function from the contrast enhancement. The area and volume of spinal cord tissue with dysfunctional barrier were determined using semi-automatic segmentation. RESULTS: Quantitative maps derived from the acquired DCE-MRI data depicted the degree of BSCB permeability variations in injured spinal cords. At the injury sites, the damaged barriers occupied about 70% of the total cross section and 48% of the total volume on day 1, but the corresponding measurements were reduced to 55% and 25%, respectively on day 3. These changes implied spatio-temporal remodeling of microvasculature and its architecture in injured SC. Diffusion computations included longitudinal and transverse diffusivities and fractional anisotropy index. Comparison of permeability and diffusion measurements indicated regions of injured cords with dysfunctional barriers had structural changes in the form of greater axonal loss and demyelination, as supported by histopathologic assessments. CONCLUSION: The results from this study collectively demonstrated the feasibility of quantitatively mapping regional BSCB dysfunction in injured cord in mouse and obtaining complementary information about its structural integrity using in vivo DCE-MRI and DTI protocols. This capability is expected to play an important role in characterizing the neurovascular changes and reorganization following SCI in longitudinal preclinical experiments, but with potential clinical implications.

Differential expression of metallothioneins (MTs) 1, 2, and 3 in response to zinc treatment in human prostate normal and malignant cells and tissues.

BACKGROUND: The disturbance of zinc homeostasis featured with a significant decrease of cellular zinc level was well documented to associate with the development and progression of human prostate malignancy. We have previously reported that zinc treatment induces prostate malignant cell apoptosis through mitochondrial pathway. Metallothionein (MT) is a major receptor/donor of zinc in the cells. However, the studies on the expression of MT in association with the prostate pathological and malignant status are very limited, and the zinc regulation of MT isoform expression in prostate cells remains elusive. The goals of this study were to define the expression of endogenous MTs, the isoforms of MT 1, 2, 3 at both messenger ribonucleic acid (mRNA) and protein levels; and to investigate the zinc effect on MT expression in normal prostate, benign prostatic hyperplasia (BPH) and malignant PC-3 cells, and in relevant human tissues. Cellular MT proteins were detected by immunohistochemistry, fluorescence staining and Western blot analysis; reverse transcription polymerase chain reaction (RT-PCR) was used to determine the MT isoform-specific mRNAs. RESULTS: Our results demonstrated a significant suppression of endogenous levels of MT1/2 in malignant PC-3 cells (95% reduction compared to the normal prostate cells) and in human adenocarcinoma tissues (73% MT1/2 negative). A moderate reduction of MT1/2 expression was observed in BPH. Zinc treatment remarkably induced MT1/2 expression in PC-3 and BPH cells, which was accordant with the restored cellular zinc level. MT 3, as a growth inhibitory factor, was detected and up-regulated by zinc mainly in BPH cells. CONCLUSION: This study provided evidence of the association of attenuated MT1/2 with prostate tumor progression, and the zinc induction of MT1/2 expression resulting in cellular zinc restoration. The results suggest the potential of MT1/2 as a candidate biomarker for prostate cancer and the utilization of zinc in prostate cancer prevention and treatment.

Intraoperative Pathologic Consultation on Hysterectomy Specimens for Endometrial Cancer: An Assessment of the Accuracy of Frozen Sections, "Gross-Only" Evaluations, and Obtaining Random Sections of a Grossly "Normal" Endometrium.

OBJECTIVES: Pathologic intraoperative consultation (IOC) is a common approach for segregating the subset of patients with endometrial cancer who likely require a lymphadenectomy. METHODS: We evaluate factors related to the performance and value of IOC, including the accuracy of frozen sections, "gross-only examinations," and obtaining random sections when a gross lesion is not apparent. RESULTS: IOC was performed by gross examination only in 17 (8%) of 250 cases, the specificity and negative predictive value of which in diagnosing cancer were 100% and 85%, respectively. Among the 64 cases wherein a gross lesion was not apparent and random sections were examined, a final diagnosis of carcinoma was rendered in 20, of which only three (15%) had a diagnosable malignancy on the random section. The frozen-section/final diagnosis concordance was 80% for tumor grade. Determining the depth of myometrial invasion was problematic, with 36% underestimation and 2.6% overestimation. CONCLUSIONS: Obtaining random sections in the absence of a gross lesion has no significant benefit, and a negative result is likely to provide inaccurate data to the surgeon. Frozen-section analyses are a generally reliable tool to determine "low-risk" pathologic parameters that were evaluated herein when a gross lesion is present.

Proteomic analysis of mitochondria-to-nucleus retrograde response in human cancer.

All tumors examined to date contain mutations in mitochondrial DNA (mtDNA). In addition, depletion of mtDNA is reported in a variety of tumors. Mitochondrial dysfunction resulting from changes in mtDNA invokes mitochondria-to-nucleus retrograde response in human cells. To identify proteins involved in retrograde response and their potential role in tumorigenesis, we carried out a comparative proteomic analysis using a cell line in which the mitochondrial genome was completely depleted (rho(0) cells lacking all mtDNA-encoded protein subunits), a cybrid cell line in which mtDNA was restored, and the parental cell line. Our comparative proteomic approach revealed marked changes in the cellular proteome and led us to identify quantitative changes in expression of several proteins. We found that subunits of complex I and complex III, molecular chaperones, and a protein involved in cell cycle control were downregulated and Inosine 5'-monophosphate dehydrogenase type 2 (IMPDH2) involved in nucleotide biosynthesis was upregulated in rho(0) cells. Our findings demonstrate that the expression of proteins is restored to wild type level by transfer of wild type mitochondria to rho(0) cells, suggesting that these proteins play key roles in retrograde response. To determine a potential role for identified retrograde responsive proteins in tumorigenesis, we analyzed the expression of UQCRC1 gene (encoding ubiquinol cytochrome-c reductase core protein I) in breast and ovarian tumors. We found that (1) UQCRC1 was highly expressed in breast (74%) and ovarian tumors (34%) and (2) the expression positively correlated with cytochrome c-oxidase (COXII) encoded by mtDNA. Our study opens an avenue for identification of retrograde proteins as potential tumor suppressors or oncogenes involved in carcinogenesis.

Metastatic Breast Carcinoma to the Prostate Gland.

Cancer of the male breast is an uncommon event with metastases to the breast occurring even less frequently. Prostate carcinoma has been reported as the most frequent primary to metastasize to the breast; however, the reverse has not been previously reported. Herein, we present, for the first time, a case of breast carcinoma metastasizing to the prostate gland. Prostate needle core biopsy revealed infiltrative nests of neoplastic epithelioid cells, demonstrated by immunohistochemistry (IHC) to be positive for GATA3 and ER and negative for PSA and P501S. A prostate cocktail by IHC study demonstrated lack of basal cells (p63 and CK903) and no expression of P501S. The patient's previous breast needle core biopsy showed strong ER positivity and negative staining for PR and HER2. Similar to the prostate, the breast was negative for CK5/6, p63, and p40. This case demonstrates the importance of considering a broad differential diagnosis and comparing histology and IHC to prior known malignancies in the setting of atypical presentation or rare tumors.

Acquired vulvar lymphangioma circumscriptum after cervical cancer treatment: Case report.

Vulvar lymphangioma circumscriptum (LC) is a rare entity which may present as a painful, warty lesion. In contrast to the congenital form, which occurs in children, the acquired form arises in older adults and may be associated with infection, Crohn's disease, or prior pelvic/regional surgery. We present a case of acquired LC of the vulva in a 55-year-old woman who presented with a 3-4 year history of vulvar pain following chemotherapy, radiation, and brachytherapy for cervical cancer. Vulvar shave biopsies followed by excision revealed a thickened dermis with epidermal hyperkeratosis, parakeratosis, elongated rete ridges and dilated lymphatic channels containing eosinophilic material and scattered thrombi. The differential diagnosis for this unusual lesion includes more common conditions such as condyloma acuminatum, fungating squamous cell carcinoma and molluscum contagiosum. It is important to recognize the clinical presentation as well as the distinct histological appearance of this rare benign entity.

Comparison Between HER2, Estrogen Receptors and Progesterone Receptors in Primary Breast Carcinomas and Matched Lymph Node Metastases.

OBJECTIVE: In the current work, we compared HER2 by fluorescence in situ hybridization and estrogen and progesterone receptors by immunohistochemistry in matched primary breast carcinomas and their lymph node metastases. MATERIAL AND METHOD: Thirty-nine cases of primary and lymph node metastases were assessed for HER2. Primary tumors of the cases selected were known to be HER2 negative. Also, immunohistochemistry for estrogen and progesterone receptors was performed on 36 cases from the same cohort to assess any discrepancy between the primary tumor and the lymph node metastases. RESULTS: Out of 39 cases, one case was HER2 amplified in lymph node metastasis compared to non-amplified primary tumor. Approximately eight percent of cases (3/36) were estrogen receptor-negative in LN metastasis and 5.55% (2/36) were less strongly positive compared to the positive primary tumors. Nineteen percent (7/36) were progesterone receptor-negative in lymph node metastasis in contrast to the matched positive primary tumors, and 5.55% (2/36) were progesterone receptor-positive in lymph node as compared to their corresponding negative primary tumors. CONCLUSION: While most matched primary breast tumors and lymph node metastases show concordance in HER2, estrogen and progesterone receptor status, we confirmed the multiple reports that identified discordant results in a subset of cases. These results support the newly adopted guidelines that require testing for HER2 on metastatic lesions.

Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors.

Reactive oxygen species (ROS) signal cascades involved in cell growth, cell death, mitogenesis, angiogenesis and carcinogenesis. ROS are produced as a byproduct of oxidative phosphorylation (OXPHOS) in the mitochondria. It is estimated that 2-4% of the oxygen consumed during OXPHOS is converted to ROS. Besides mitochondria, NADPH-oxidase 1 (Nox1) also generates a significant amount of ROS in the cell. In this paper, we tested the hypothesis that mitochondria control Nox 1 redox signaling and the loss of control of this signaling contributes to tumorigenesis. We analyzed Nox1 expression in a mitochondrial gene knockout (rho(0)) cell line and in the isogenic cybrid cell line in which mitochondrial genes were restored by transfer of wild type mitochondria into rho(0) cells. Our study revealed, for the first time, that the inactivation of mitochondrial genes leads to down-regulation of Nox1 and that the transfer of wild type mitochondrial genes restored the Nox1 expression to a level comparable to that in the parental cell line. Consistent with Nox1 down-regulation, we found that rho(0) cells contained low levels of superoxide anion and that superoxide levels reversed to parental levels in cybrid cells when Nox1 expression was restored by transfer of wild type mitochondria. Increasing mitochondrial superoxide levels also increased the expression of Nox1 in parental cells. Confocal microscopy studies revealed that Nox1 localizes in the mitochondria. Nox1 was highly expressed in breast (86%) and ovarian (71%) tumors and that its expression positively correlated with expression of cytochrome C oxidase encoded by mtDNA. Our study, described in this paper demonstrates the existence of cross talk between the mitochondria and NADPH oxidase. Furthermore, our studies suggest that mitochondria control Nox1 redox signaling and the loss of control of this signaling contributes to breast and ovarian tumorigenesis.