Neoadjuvant therapy with doxorubicin-cyclophosphamide followed by weekly paclitaxel in early breast cancer: a retrospective analysis of 200 consecutive patients treated in a single center with a median follow-up of 9.5 years.

PURPOSE: We analyzed outcomes of doxorubicin-cyclophosphamide (AC) followed by weekly paclitaxel as neoadjuvant chemotherapy (NAC) for breast cancer (BC), in an everyday practice with long-term follow-up of patients. METHODS: All patients (n = 200) who received the AC-paclitaxel combination as NAC for BC at the Soroka University Medical Center from 2003 to 2012 were included in this retrospective cohort study. AC was administered on an every 3-week schedule (standard dose) until May, 2007 (n = 99); and subsequently every 2-week dose dense (dd) (n = 101). Clinical pathologic features, treatment course, and outcome information were recorded. Complete pathologic response (pCR) was analyzed according to BC subtype, dose regimen, and stage. RESULTS: Median age was 49 years; 55.5% and 44.5% of patients were clinically stage 2 and 3, respectively. Standard dose patients had more T3 tumors. Subtypes were human epidermal growth factor receptor-2 (HER2)-positive 32.5% (of whom 82% received trastuzumab), hormone receptor-positive/HER2-negative 53%, and triple negative 14.5%. Breast-conserving surgery (BCS) was performed in 48.5% of patients; only 9.5% were deemed suitable for BCS prior to NAC. Toxicity was acceptable. The overall pCR rate was 26.0% and was significantly higher in the dd group and HER2-positive patients. With a median follow-up of 9.51 years median event-free survival (EFS) and overall survival (OS) are 10.85 years and 12.61 years, respectively. Patients achieving pCR had significantly longer EFS and OS. CONCLUSION: NAC for BC with AC-paclitaxel can be safely administered in the "real-world' setting with high efficacy. Current efforts are aimed at increasing rates of pCR and identifying patients who may benefit from additional therapy or conversely, de-escalated treatment.

P16, Ki67, P53, and WT1 Expression in Uterine Smooth Muscle Tumors: An Adjunct in Confirming the Diagnosis of Malignancy in Ambiguous Cases.

The diagnosis of uterine smooth muscle tumors is sometimes difficult, as these tumors may show worrisome features, suspicious for but not diagnostic of malignancy. The recommended immunohistochemical panel in this setting is currently under debate. In this study, we aimed to find a panel of immunohistochemical stains that would be helpful in determining the correct diagnosis in ambiguous uterine smooth muscle tumors, with an emphasis on investigating the possible usefulness of the WT1 antibody. Uterine leiomyomas were found to be immunoreactive with WT1. Since a previous study reported on the lack of immunoreactivity of uterine leiomyosarcomas with WT1, we speculated that WT1 might be useful in this setting. We retrospectively reviewed the medical charts and slides of 91 patients: 22 with leiomyosarcoma, 15 with smooth muscle tumor of uncertain malignant potential, and 54 with leiomyoma. Immunohistochemical stains for WT1, p16, p53, and Ki67 were performed on each case. We found that immunoreactivity with p16 and Ki67 (>40% and >10% of the tumor cells, respectively) and loss of nuclear expression of WT1 (<10% of the tumor cells) were significantly more common in leiomyosarcomas (all P<0.001). Mutated p53 immunohistochemical staining pattern was significantly more prevalent in leiomyosarcomas than in leiomyomas (P<0.001). Thus, in diagnostically challenging uterine smooth muscle tumors, we recommend using an immunohistochemical panel composed of Ki67, p16, p53, and WT1. A positive result in either of the former 2 (p16 >40% and/or Ki67 >10%) has the strongest association with leiomyosarcoma (sensitivity: 95.5%, specificity=88.9%, positive predictive value=77.8%, negative predictive value=98.0%).

Malignant Peritoneal Mesothelioma in an Infant With Familial ATM Mutations.

Ataxia-telangiectasia (A-T), an autosomal recessive disorder characterized by progressive neurologic dysfunction, oculocutaneous telangiectasia, immunodeficiency, and cancer susceptibility, is caused by mutations in the ATM gene. A previous study of 4 A-T patients identified 2 rare homozygous missense mutations residing on the same allele of the ATM gene: c.1514T>C and c.1547T>C, which were shown to decrease ATM levels and increase T-cell acute lymphoblastic leukemia predisposition. We studied 5 patients from 2 consanguineous Bedouin families of the same tribe, presenting with A-T. Whole-exome sequencing data identified the 2 aforementioned mutations in ATM, which segregated within all family members as expected of autosomal recessive heredity. Interestingly, one individual was diagnosed with malignant peritoneal mesothelioma (MPM), an extremely rare neoplasm in pediatric patients. Here, we describe a case of a 4-month-old infant homozygous for the 2 ATM mutations, who developed MPM and died by the age of 2 years. To the best of our knowledge, this is the first case of peritoneal mesothelioma in an infant bearing ATM mutations, and one of the youngest pediatric mesotheliomas described. Thus, the risk of MPM might be considered in the follow-up of A-T patients, and ATM mutations sought in cases of early-onset MPM.

CDC174, a novel component of the exon junction complex whose mutation underlies a syndrome of hypotonia and psychomotor developmental delay.

Siblings of non-consanguineous Jewish-Ethiopian ancestry presented with congenital axial hypotonia, weakness of the abducens nerve, psychomotor developmental delay with brain ventriculomegaly, variable thinning of corpus callosum and cardiac septal defects. Homozygosity mapping identified a single disease-associated locus of 3.5 Mb on chromosome 3. Studies of a Bedouin consanguineous kindred affected with a similar recessive phenotype identified a single disease-associated 18 Mb homozygosity locus encompassing the entire 3.5 Mb locus. Whole exome sequencing demonstrated only two homozygous mutations within a shared identical haplotype of 0.6 Mb, common to both Bedouin and Ethiopian affected individuals, suggesting an ancient common founder. Only one of the mutations segregated as expected in both kindreds and was not found in Bedouin and Jewish-Ethiopian controls: c.1404A>G, p.[*468Trpext*6] in CCDC174. We showed that CCDC174 is ubiquitous, restricted to the cell nucleus and co-localized with EIF4A3. In fact, yeast-two-hybrid assay demonstrated interaction of CCDC174 with EIF4A3, a component of exon junction complex. Knockdown of the CCDC174 ortholog in Xenopus laevis embryos resulted in poor neural fold closure at the neurula stage with later embryonic lethality. Knockdown embryos exhibited a sharp reduction in expression of n-tubulin, a marker for differentiating primary neurons, and of hindbrain markers krox20 and hoxb3. The Xenopus phenotype could be rescued by the human normal, yet not the mutant CCDC174 transcripts. Moreover, overexpression of mutant but not normal CCDC174 in neuroblastoma cells caused rapid apoptosis. In line with the hypotonia phenotype, the CCDC174 mutation caused depletion of RYR1 and marked myopathic changes in skeletal muscle of affected individuals.

Gastrointestinal Polyposis in Cowden Syndrome.

GOALS: To further characterize the gastrointestinal manifestations of Cowden syndrome in clinically well-annotated patients to improve the diagnosis of this syndrome. BACKGROUND: The gastrointestinal manifestations of Cowden Syndrome, an important heritable and multiorgan cancer syndrome, are not well defined. Proper diagnosis is essential for effective cancer surveillance and prevention in these patients. STUDY: Cowden patients with gastrointestinal polyps were selected for medical record and pathologic slide review. RESULTS: Of 19 total patients, genetic testing revealed pathogenic PTEN mutations in 12. Pan-colonic (11-patients, 58%) and pan-gastrointestinal (8-patients, 42%) polyp distributions were common. Inflammatory (juvenile) polyps were the most common of the hamartomatous polyp (18 patients, 95%), along with expansive lymphoid follicle polyps (12 patients, 63%), ganglioneuromatous polyps (10 patients, 53%), and intramucosal lipomas (5 patients, 26%). The findings of 2 or more hamartomatous polyp types per patient emerged as a newly described and highly prevalent (79%) feature of Cowden syndrome. Ganglioneuromatous polyps, rare in the general population, and intramucosal lipomas, which may be unique to Cowden syndrome, should both prompt further evaluation. Colonic adenomas and adenocarcinomas were common; 10 patients (53%) had single and 3 (16%) had ≥3 adenomas, whereas 2 (11%) had colonic adenocarcinoma, strengthening the emerging association of colorectal cancer with Cowden syndrome. CONCLUSIONS: The clinical phenotypes and gastrointestinal manifestations in Cowden syndrome are quite variable but this series adds the following new considerations for this syndromic diagnosis: multiple gastrointestinal hamartomas, especially 2 or more hamartoma types, and any intramucosal lipomas or ganglioneuromas. These features should warrant consideration of Cowden syndrome.

Oral Mucoceles in Children--Analysis of 56 New Cases.

BACKGROUND: Mucoceles are common cystic lesions of the oral mucosa. Extravasation mucoceles (EMs) are mainly found in the lower lip of young patients, whereas retention mucoceles (RMs) are usually located in the cheek or palate of older patients. This study was undertaken to more fully characterize the clinicopathologic features of mucoceles in pediatric patients. METHODS: The records of 56 pediatric patients with mucoceles were included in the study. Age, sex, history of trauma, intraoral site, size, and method of treatment were evaluated. Histopathologically the lesions were classified as being EMs or RMs. RESULTS: The age range was 1.5 to 16 years (mean age 11.2 yrs). Of the 56 patients, 24 (43%) were males and 32 (57%) were females, with a male:female ratio of 1:1.33. A history of trauma was recorded in 32 (57%) patients of the lower lip. The intraoral sites were the lower lip (38 [68%]), tongue (10 [18%]), and floor of the mouth (8 [14%]). Of the 56 patients, 44 (79%) were EM and 12 (21%) were ranulas. No RMs were found. Mucoceles ranged from 0.3 to 3.8 cm in diameter (mean 0.9 cm). The treatment of EMs was surgical excision. Cryosurgey, electrosurgery, and carbon dioxide laser were also used. CONCLUSION: In contrast to adults, where EM and RM types can be found, among children all cases are of the EM type. The disparate site and age incidences of EMs and RMs of the oral mucosa suggest that these two types are not related and possibly have a different etiopathogenesis.

Positive margin status in uterine cervix cone specimens is associated with persistent/recurrent high-grade dysplasia.

The frequency of positive cone margins and its significance in cervical intraepithelial neoplasia are under controversy. The purpose of the current study was to identify factors associated with positive cone margin status and to evaluate its clinical significance in high-grade cervical intraepithelial neoplasia. Medical records of women who underwent loop electrosurgical excision procedure at the Soroka Medical Center (January 2001-July 2011) were reviewed retrospectively. Patient age, extent of dysplasia, endocervical glands involvement, positive margin status, type of margin involved, degree of margin involvement, and postcone endocervical curettage results were evaluated as possible factors associated with persistent/recurrent disease. A total of 376 women were included in the study. Cone margin involvement was observed in 33% (endocervical-22%, ectocervical-8%, both margins-3%). Factors significantly associated with cone margin involvement were older age (older than 35 y), widespread dysplasia in the cone specimen (≥4 sections) (P<0.001 for each), and endocervical glands involvement (P=0.003). Fifty patients (13%) had persistent/recurrent disease. Involvement of the cone margins (focal: hazard ratio=17, P<0.001; extensive: hazard ratio=28, P<0.001) and older age (hazard ratio=1.18 for every 5 additional years, P=0.03) were associated with persistent/recurrent disease. We conclude that women older than 35 yr with widespread high-grade dysplasia in the cone specimen and involvement of endocervical glands are more likely to have positive cone margins. Positive cone margins, particularly when extensively involved, and increased patient age are associated with persistent/recurrent disease. These factors should be considered while planning for further management.

Uterine cervix conization based on Pap smear results: the "see and treat" approach.

BACKGROUND: The "see and treat" approach, proceeding without a biopsy directly to uterine cervix conization in women diagnosed with high grade squamous intraepithelial lesion (HGSIL) on Pap smear, shortens the treatment duration, lessens patient anxiety, and reduces health care costs. OBJECTIVES: To evaluate the level of diagnostic accuracy and the over-treatment rate in the "see and treat" versus conventional management of women diagnosed with HGSIL. METHODS: We retrospectively reviewed all women with HGSIL who had undergone the "see and treat" approach during 2001-2011 at Soroka University Medical Center. Similar cohorts, who were managed conventionally with a cervical biopsy prior to the conization, served as a comparison group. RESULTS: The study population consisted of 403 women: 72 (18%) had undergone the "see and treat" approach and 331 (82%) conventional management. The false positive rate was 11% for the "see and treat" group, compared to 6% for the conventional management group (P = 0.162). Similarly, no statistically significant difference was observed when comparing the positive predictive value (PPV) of high grade dysplasia diagnosed on Pap smear (PPV 88.9%) versus cervical biopsy (PPV 93.8%) (P = 0.204). Moreover, both the false positive rate and PPV remained similar in subgroups of patients, according to age, menopausal status, number of births, and colposcopy findings. CONCLUSIONS: The accuracy level of HGSIL diagnosis on Pap smear is similar to that of high grade dysplasia on a cervical biopsy. We therefore recommend referring patients with HGSIL directly to conization. Skipping the biopsy step was not associated with significant over-treatment or other adverse effects.

The significance of lower uterine segment involvement in endometrial cancer.

BACKGROUND: Limited data suggests lower uterine segment involvement (LUSI) in endometrial cancer may be associated with other poor prognostic factors. We assessed the unclear impact of LUSI on prognosis in endometrial cancer. METHOD: ology: A revision of pathological samples following surgical staging between the years 2002-2022 was performed and clinical data collected from patients' records. Characteristics and outcomes of women with and without LUSI were compared and analysed. Kaplan Meyer survival curves compared overall survival (OS) and progression-free survival (PFS). RESULTS: 429 women were included, of which 45 (10.5%) had LUSI. No differences were found between the groups regarding demographic or clinical characteristics. LUSI was significantly associated with lympho-vascular space invasion (40% vs. 22% p = 0.01), lymph node involvement (6.4% vs. 9.1%, p = 0.05), shorter PFS (4 vs. 5.5 years, p = 0.01) and OS (5.6 vs. 11.5 years, p = 0.03). Multivariate analysis showed higher hazard ratios for OS and PFS (1.55 95%CI 0.79-3.04 and 1.29 95%CI 0.66-2.53, respectively) but these were insignificant even in a sub-analysis of endometrioid histology (1.76 95%CI 0.89-3.46 and 1.35 95%CI 0.69-2.65, respectively). A trend towards decreased PFS and OS was demonstrated in the Kaplan Meyer survival curves for all cases (log rank test p = 0.5 and 0.29 respectively), endometrioid histology (log rank test p = 0.06 and 0.51 respectively) and early-stage disease (log rank test p = 0.63 and 0.3 respectively). CONCLUSION: LUSI may be related to poorer outcome of endometrial cancer and may represent an additional factor to consider when contemplating adjuvant treatment, especially in endometrioid-type and early-stage disease.

Complete digital pathology transition: A large multi-center experience.

INTRODUCTION: Transitioning from glass slide pathology to digital pathology for primary diagnostics requires an appropriate laboratory information system, an image management system, and slide scanners; it also reinforces the need for sophisticated pathology informatics including synoptic reporting. Previous reports have discussed the transition itself and relevant considerations for it, but not the selection criteria and considerations for the infrastructure. OBJECTIVE: To describe the process used to evaluate slide scanners, image management systems, and synoptic reporting systems for a large multisite institution. METHODS: Six network hospitals evaluated six slide scanners, three image management systems, and three synoptic reporting systems. Scanners were evaluated based on the quality of image, speed, ease of operation, and special capabilities (including z-stacking, fluorescence and others). Image management and synoptic reporting systems were evaluated for their ease of use and capacity. RESULTS: Among the scanners evaluated, the Leica GT450 produced the highest quality images, while the 3DHistech Pannoramic provided fluorescence and superior z-stacking. The newest generation of scanners, released relatively recently, performed better than slightly older scanners from major manufacturers Although the Olympus VS200 was not fully vetted due to not meeting all inclusion criteria, it is discussed herein due to its exceptional versatility. For Image Management Software, the authors believe that Sectra is, at the time of writing the best developed option, but this could change in the very near future as other systems improve their capabilities. All synoptic reporting systems performed impressively. CONCLUSIONS: Specifics regarding quality and abilities of different components will change rapidly with time, but large pathology practices considering such a transition should be aware of the issues discussed and evaluate the most current generation to arrive at appropriate conclusions.

Vaginal brenner tumor.

Extraovarian Brenner tumors are extremely rare. We report a case of vaginal Brenner tumor occurring in an 84-year-old woman. The tumor presented with vulvar irritation and soreness and consisted of a 1.8-cm polypoid mass arising from the lower third of the vagina. Microscopically, it had all the 3 components--urothelial islands, glands, and fibrous stroma--characteristic of a Brenner tumor. We suggest that vaginal Brenner tumors arise from a metaplastic process within the mullerian epithelium.

Is radical hysterectomy necessary in early cervical cancer?

AIMS: To estimate the prevalence of tumor spread to the parametrium, vagina and uterine corpus in radical hysterectomy specimens and define a subgroup of patients with low-risk of extracervical involvement, who may benefit from less radical surgery. METHODS: We retrospectively reviewed 96 patients with stage IA1-IIA cervical cancer who had undergone radical hysterectomy and pelvic lymphadenectomy. RESULTS: Tumor spread beyond the uterine cervix was evident in 45 (47%) patients. Thirteen (13%) of the 96 patients had parametrial tumor spread, 12 (13%) had vaginal tumor extension, and 23 (24%) had uterine corpus involvement. Tumor size >2 cm, stromal invasion to a depth of ≥8 mm, and lymph vascular space invasion (LVSI) were significantly associated with extracervical invasion. Twenty-five patients had stromal invasion of <8 mm and no LVSI, of which only 1 (4%) had extracervical involvement. On the contrary, extracervical involvement was evident in 44 patients (63%) among those who had stromal invasion of ≥8 mm and/or LVSI (p < 0.001). Among women with LVSI, extracervical tumor spread was seen with any tumor size and any depth of stromal invasion. All patients with stromal invasion to a depth of >15 mm had extracervical invasion. CONCLUSION: Patients with tumor size <2 cm, depth of invasion of <8 mm and no LVSI could be considered for less radical surgery.

Positive pathological margins after loop electrosurgical excision procedure - Management and outcome.

OBJECTIVE: Pathological involvement of cervical conization margins is a risk factor for recurrence, although management of these patients is controversial. We aimed to define risk factors for positive margins and compare recurrence following additional surgical intervention compared to conservative management. METHODS: A retrospective study of all conizations at our center between 2010 and 2019. Univariate analysis identified characteristics associated with positive margins. Women were stratified by mode of management comparing three groups (surveillance, repeat conization or hysterectomy) then two groups (surveillance vs. additional surgery). Kaplan Meyer survival curves compared cumulative recurrence stratified by mode of management. Pathological results of subsequent surgical procedures were examined for residual disease. RESULTS: Of 448 conizations performed, 131 (29.2%) had positive margins which were associated with menopause, high-grade cytology and endocervical gland involvement. Women who underwent surveillance (n = 45) were more likely to be nulliparous, with low-grade histology and less endocervical gland involvement. Women who underwent hysterectomy (n = 61) were more likely to be postmenopausal and parous. Recurrence did not differ significantly in the three-group (p = 0.073) or two-group model (6.4% vs. 7.1% p = 0.869). Kaplan Meyer survival curves depicting cumulative recurrence did not differ significantly in either model (log rank test p = 0.642 for the three-group model, and p = 0.868 for the two-group model). Residual disease was found in 51.6% of hysterectomy specimens and 52.6% of repeat conizations. CONCLUSION: Surveillance is non-inferior to additional surgery in cases with positive conization margins and constitutes a valid option specifically for younger women at risk of future obstetric complications and those susceptible post-hysterectomy complications.

Functional binding of PD1 ligands predicts response to anti-PD1 treatment in patients with cancer.

Accurate predictive biomarkers of response to immune checkpoint inhibitors (ICIs) are required for better stratifying patients with cancer to ICI treatments. Here, we present a new concept for a bioassay to predict the response to anti-PD1 therapies, which is based on measuring the binding functionality of PDL1 and PDL2 to their receptor, PD1. In detail, we developed a cell-based reporting system, called the immuno-checkpoint artificial reporter with overexpression of PD1 (IcAR-PD1) and evaluated the functionality of PDL1 and PDL2 binding in tumor cell lines, patient-derived xenografts, and fixed-tissue tumor samples obtained from patients with cancer. In a retrospective clinical study, we found that the functionality of PDL1 and PDL2 predicts response to anti-PD1 and that the functionality of PDL1 binding is a more effective predictor than PDL1 protein expression alone. Our findings suggest that assessing the functionality of ligand binding is superior to staining of protein expression for predicting response to ICIs.

Assessing Obesity-Related Adipose Tissue Disease (OrAD) to Improve Precision Medicine for Patients Living With Obesity.

Obesity is a heterogenous condition that affects the life and health of patients to different degrees and in different ways. Yet, most approaches to treat obesity are not currently prescribed, at least in a systematic manner, based on individual obesity sub-phenotypes or specifically-predicted health risks. Adipose tissue is one of the most evidently affected tissues in obesity. The degree of adipose tissue changes - "adiposopathy", or as we propose to relate to herein as Obesity-related Adipose tissue Disease (OrAD), correspond, at least cross-sectionally, to the extent of obesity-related complications inflicted on an individual patient. This potentially provides an opportunity to better personalize anti-obesity management by utilizing the information that can be retrieved by assessing OrAD. This review article will summarize current knowledge on histopathological OrAD features which, beyond cross-sectional analyses, had been shown to predict future obesity-related endpoints and/or the response to specific anti-obesity interventions. In particular, the review explores adipocyte cell size, adipose tissue inflammation, and fibrosis. Rather than highly-specialized methods, we emphasize standard pathology laboratory approaches to assess OrAD, which are readily-available in most clinical settings. We then discuss how OrAD assessment can be streamlined in the obesity/weight-management clinic. We propose that current studies provide sufficient evidence to inspire concerted efforts to better explore the possibility of predicting obesity related clinical endpoints and response to interventions by histological OrAD assessment, in the quest to improve precision medicine in obesity.

Natural history of biologically malignant struma ovarii: analysis of 27 cases with extraovarian spread.

The natural history of 27 cases of biologically malignant struma ovarii from a series of 88 cases of histologically malignant or histologically proliferative struma ovarii is described. The extraovarian spread was evident at presentation in 17 patients. The malignant nature of the other 10 tumors became apparent only after they recurred. The tumors measured 5 to 24.5 cm and were more than 50% thyroid tissue in all but 2 cases. The microscopic diagnosis of the thyroid tissue was follicular adenoma in 17 cases (63%), papillary carcinoma in 7 (26%), unremarkable in 2 (7%), and follicular carcinoma in 1 case (4%). Generally, the clinical course was protracted, with long-term survival documented in most patients. Clinical features predictive of biologic malignancy were the presence of adhesions, peritoneal fluid (> or = 1 L), or a serosal rent in the struma ovarii (including cystectomy). In addition, pathologic factors predictive of a poorer prognosis were large size (> or = 10 cm), strumal component more than 80%, and extensive papillary carcinoma, especially with solid areas, necrosis, and > or = 5 mitoses per 10 high-power fields. Follow-up for all patients was 1.5 to 33 years (mean=13.5 yr). On last follow-up 3 patients (11%) had no evidence of disease, 9 (33%) were alive with disease, 5 (19%) died of other causes, and 10 patients (37%) died of the disease. Death from disease occurred 1.5 to 32 years after diagnosis (mean=14 yr). Recurrence was seen as early as 2 months and as late as 29 years after initial surgery (mean=7 yr). Long-term follow-up is indicated in patients with any of the above-mentioned adverse indicators.

Isolated and synchronous vulvar granular cell tumors: a clinicopathologic study of 17 cases in 13 patients.

Granular cell tumors (GCTs) are benign Schwann cell-derived neoplasms occurring throughout the body. Vulvar GCTs are usually isolated, but occasionally multifocal. On account of their anatomic location, surgical interventions aiming for negative resection margins can result in significant morbidity. We describe the clinicopathologic features of 17 vulvar GCTs in 13 patients followed for an average of 7 years. The average age at presentation was 46 years, and 84% of the patients were black. The tumors were multifocal in 3 (23%) patients, and all, either at presentation or subsequently also developed extravulvar foci. Patients with multifocal vulvar GCTs were nearly 10 years younger at presentation than patients in whom the disease was isolated. The most common complaint was a slow-enlarging mass occasionally associated with pruritus or overlying hyperpigmentation. Clinically, the tumors were subcutaneous, mobile, and nodular (2.1 cm on average), without overlying ulceration, and most often were found in the labia majora (6/17). The neoplasms were histologically heterogeneous, but exhibited either a predominantly nodular (3/17) or infiltrative (13/17) pattern of invasion. Cytologically, the tumors displayed round to polygonal cells with a granular cytoplasm, small hyperchromatic nuclei with minimal pleomorphism, and less than 2 mitoses per 10 high power fields. One tumor (1/17) consisted of cells with predominantly vesicular nuclei and prominent nucleoli and was classified as an atypical vulvar GCT. All tumors so examined were reactive for S-100 protein. Eight of 17 tumor excision specimens had positive margins. Of these, 5 tumors remained stable whereas the other 2 with follow-up progressed to require reexcisions after periods of 14 and 8.0 years, respectively. All patients with excisions with negative margins remained stable. Patients with multifocal tumors did not have a higher risk of recurrence per tumor, compared with patients with isolated disease, regardless of the margin status. No patient died from her disease. As granular cell neoplasms have such a low risk or recurrence and behave generally in an indolent manner, aggressive therapy is usually unwarranted.

Paget disease of the vulva: a histologic study of 56 cases correlating pathologic features and disease course.

The Duke experience with 56 vulvar Paget disease patients was analyzed emphasizing pathologic features and controversial issues. Nearly all patients were Caucasian, and their mean age was 69 years. The average length of follow-up was 5.6 years. For each case, the following histologic features were evaluated and their association with disease course was examined: pseudo-invasion, adnexal involvement, signet-ring cells, cytologic atypia, glands formation, epidermal acantholysis, parakeratosis, hyperkeratosis, and chronic inflammation. The recurrence rate after surgical management was 32%, with epidermal acantholysis being the only statistically significant risk factor. Stromal invasion occurred in 10 patients (18%), and was not a statistically significant adverse prognostic indicator, although the single patient who died of the disease had the deepest stromal invasion. Recurrence was more common after resections with positive surgical margins, but this correlation was not statistically significant. Intraoperative frozen section analysis of the margins did not reduce recurrence rate, nor was it useful in attaining permanent free margins. The Paget cells were consistently reactive with cytokeratin-7 and carcinoembryonic antigen and unreactive with S-100 protein, HMB-45, and Mart-1. In addition, the tumor cells were usually positive for mucin stains. This profile helps distinguish vulvar Paget disease from its mimics, Pagetoid squamous cell carcinoma and malignant melanoma.