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Background Differentiated vulvar intraepithelial neoplasia (dVIN), the precursor lesion to human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC), can be difficult to distinguish from vulvar inflammatory dermatoses. p53 has been suggested to be a useful biomarker for dVIN, but the percentage, intensity and patterns of staining have not been well characterized in dVIN and its histologic mimics. Method We studied p53 immunohistochemical staining patterns in 16 dVIN cases and 46 vulvar non-neoplastic squamous lesions (12 lichen sclerosus (LS); 7 lichen simplex chronicus (LSC); 3 lichen planus (LP); 6 psoriasis (PSO); 13 spongiotic dermatitis (SPO); 5 candidiasis (CAN)). dVIN cases were adjacent to a p16-negative invasive VSCC in resection specimens. Results All dVIN cases demonstrated null-type or moderate-strong uniform p53 staining in over 70% of basal cells, with moderate to strong continuous parabasal staining extending to two-thirds of the epidermis. This was in contrast to weak or weak-moderate patchy p53 staining in the majority of other lesions. Moderate-strong and increased basal p53 staining (≥70%) was also observed in a subset of lichen sclerosus (5/12, 42%), lichen planus (1/3, 33%) and spongiotic dermatitis (36%, 4/11), however in all categories, this was limited to the basal layer and any staining in the parabasal layers was patchy. Conclusion Strong and uniform p53 staining of basal cells, extending into the parabasal layers, and a complete absence of staining (null-type) is useful in distinguishing dVIN from other mimics in the vulva. p53 staining of lesser intensity or quantity, particularly basal-overexpression only, overlaps with vulvar inflammatory lesions.

We measured the variation in practice across all aspects of endometrial cancer (EC) management and assessed the potential impact of implementation of molecular classification.Centers from across Canada provided representative tumor samples and clinical data, including preoperative workup, operative management, hereditary cancer program (HCP) referrals, adjuvant therapy, surveillance and outcomes, for all EC patients diagnosed in 2016. Tumors were classified into the four ProMisE molecular subtypes.A total of 1336 fully evaluable EC patients were identified from 10 tertiary cancer centers (TC; n = 1022) and 19 community centers (CC; n = 314). Variation of surgical practice across TCs was profound (14-100%) for lymphadenectomy (LND) (mean 57% Gr1/2, 82% Gr3) and omental sampling (20% Gr1/2, 79% Gr3). Preoperative CT scans were inconsistently obtained (mean 32% Gr1/2, 51% Gr3) and use of adjuvant chemo or chemoRT in high risk EC ranged from 0-55% and 64-100%, respectively. Molecular subtyping was performed retrospectively and identified 6% POLEmut, 28% MMRd, 48% NSMP and 18% p53abn ECs, and was significantly associated with survival. Within patients retrospectively diagnosed with MMRd EC only 22% had been referred to HCP. Of patients with p53abn EC, LND and omental sampling was not performed in 21% and 23% respectively, and 41% received no chemotherapy. Comparison of management in 2016 with current 2020 ESGO/ESTRO/ESP guidelines identified at least 26 and 95 patients that would have been directed to less or more adjuvant therapy, respectively (10% of cohort).Molecular classification has the potential to mitigate the profound variation in practice demonstrated in current EC care, enabling reproducible risk assessment, guiding treatment and reducing health care disparities.

Immunostaining for p53 is widely but variably used when diagnosing endometrial carcinoma (EC). Mutant-pattern p53 staining can support a diagnosis of serous carcinoma, and also serve as a surrogate test for identifying the "serous-like" subset of aggressive EC identified by The Cancer Genome Atlas characterized by high numbers of somatic copy number abnormalities. We, retrospectively, assessed WHO histotype, usage of p53 immunostaining, and p53 status in a consecutive series of biopsies showing EC from a single hospital. Of 79 ECs, 59 (75%) were low-grade EC (LGEC), 13 (16%) high-grade EC (HGEC), and 7 (9%) were serous. p53 immunostaining was performed at the time of diagnosis in 27/79 (34%) biopsies; 6/7 of serous histotype, 11/13 HGEC, and 10/59 LGEC. Mutant-pattern p53 staining was present in 6/6 serous, 2/11 HGEC, and 2/10 LGEC. The remaining 53 tumors subsequently had p53 immunostaining done; all 49 LGEC showed wild-type staining and the serous carcinoma and 1/2 HGEC showed mutant pattern staining. While there are no guidelines on using p53 in endometrial biopsies, this study shows consistent usage in high-grade histotypes and variable usage in LGEC. As 100% (7/7) of serous EC and 3% (2/59) of the LGECs showed mutant-pattern p53 staining, histotype may serve as a surrogate for p53 assessment, such that only HGEC or ambiguous carcinomas should be routinely subjected to p53 immunostaining.

Endometrial clear cell carcinoma (ECCC) is an uncommon histotype without unique identified molecular alterations. Recently, The Cancer Genome Atlas molecular subtypes have been reported in ECCC. ECCC cases were collected from 11 institutions with diagnoses confirmed by morphologic review and immunohistochemistry. DNA mismatch repair (MMR) proteins, p53 expression, and ARID1A expression was assessed by immunohistochemistry on tissue microarrays. Targeted next-generation sequencing was completed for POLE, TP53, KRAS, and PIK3CA. Pathogenicity of mutations was determined using MutationTaster and PolyPhen databases. For p53, immunohistochemistry and sequencing were complimentarily used to assess the p53 status. Of 57 cases, 46 were considered prototypical ECCC by morphology and immunohistochemical profile (Napsin A-positive and ER-negative). Three cases were excluded because of insufficient sample for complete immunohistochemical analysis, and 6 had failed sequencing, resulting in 37 cases. Of the 37 remaining cases, 6/37 (16%) had predicted pathogenic mutations in the exonuclease domain of POLE with an allelic frequency >10%; however, no hot-spot mutations were identified. No cases were MMR-deficient. The gene most commonly affected was TP53 (59%, 22/37), followed by KRAS (13%, 2/15) and PIK3CA (13%, 2/15). The current study is the largest molecular analysis of pure ECCC reported to date. When strict classification criteria are applied, MMR-deficient and POLE mutated subtypes are not represented. Further consensus on what represents a deleterious POLE mutations is needed. The findings support separately studying histologically/immunohistochemically defined ECCC to identify characteristic molecular alterations in future studies.

Background: Endometriosis affects one in ten women of reproductive age but it is diagnosed at advanced stages. Our objective was to develop a domestic animal model that would permit sequential assessment of endometriotic changes. Materials and methods: Surgical transplantation of endometrial tissue and fat (n = 4 grafts/tissue/animal) was done in dogs (n = 5), pigs (n = 4), and sheep (n = 5). Autologous grafts were sutured to the visceral (urinary bladder in dogs and pigs and uterus in sheep) and parietal peritoneum. Sham surgeries were performed (dogs and sheep n = 5 and pigs n = 3) by placing fat grafts alone. Plasma estrogen and progesterone concentration was performed prior to surgery and weekly following surgery until euthanasia. Animals were euthanized between 80 and 110 days after surgery. Gross and histopathologic features of endometriotic lesions were recorded. Results: A variety of lesions from transplanted endometrial grafts included endometriotic cysts, vesicles, solid lesions, or absence of lesions. The proportion of cysts was greater (p < 0.01) in dogs (18/20 grafts) than in pigs (5/16) and sheep (5/20). The area of endometriotic lesions at the time of euthanasia was greater than at the time of surgery in dogs (0.89 ± 0.11 cm2 vs 0.50 ± 0.09 cm2; p < 0.05), whereas, the size of lesions decreased (p < 0.05) by half or more in pigs and sheep. In dogs, endometrial cysts were characterized by simple cuboidal/columnar epithelium, endometrial glands, stromal tissue with hemorrhage and/or hemosiderin-laden macrophages, and smooth muscle cells. Conclusion: The development of endometriotic cysts was apparent in dogs than in sheep and pigs. Therefore, dog is a better domestic animal model for endometriosis.

The Cancer Genome Atlas recently identified a genomic-based molecular classification of endometrial carcinomas, with 4 molecular categories: (1) ultramutated (polymerase epsilon [POLE] mutated), (2) hypermutated (microsatellite instability), (3) copy number abnormalities-low, and (4) copy number abnormalities-high. Two studies have since proposed models to classify endometrial carcinomas into 4 molecular subgroups, modeled after The Cancer Genome Atlas, using simplified and more clinically applicable surrogate methodologies. In our study, 151 endometrial carcinomas were molecularly categorized using sequencing for the exonuclease domain mutations (EDM) of POLE, and immunohistochemistry for p53 and mismatch repair (MMR) proteins. This separated cases into 1 of 4 groups: (1) POLE EDM, (2) MMR-D, (3) p53 wildtype (p53 wt), or (4) p53 abnormal (p53 abn). Seven gynecologic pathologists were asked to assign each case to one of the following categories: grade 1 to 2 endometrioid carcinoma (EC), grade 3 EC, mucinous, serous carcinoma (SC), clear cell, dedifferentiated, carcinosarcoma, mixed, and other. Consensus diagnosis among all 7 pathologists was highest in the p53 wt group (37/41, 90%), lowest in the p53 abn group (14/36, 39%), and intermediate in the POLE EDM (22/34, 65%) and MMR-D groups (23/40, 58%). Although the majority of p53 wt endometrial carcinomas are grade 1 to 2 EC (sensitivity: 90%), fewer than half of grade 1 to 2 EC fell into the p53 wt category (positive predictive value: 42%). Pure SC almost always resided in the p53 abn group (positive predictive value: 96%), but it was insensitive as a marker of p53 abn (sensitivity 64%) and the reproducibility of diagnosing SC was suboptimal. The limitations in the precise histologic classification of endometrial carcinomas highlights the importance of an ancillary molecular-based classification scheme.

The placenta is unique among surgical pathology specimens in that it reflects the (patho)physiologies of two patients: the mother and the fetus. Placental examination may offer diagnostic, prognostic, and therapeutic information of clinical relevance to both neonates and their mothers. Pathological processes of relevance to future pregnancies may also be identified, facilitating preconception counseling as well as suggesting monitoring and potential intervention in subsequent gestations. In the setting of intrauterine or neonatal demise, the placenta may be the only, and often most useful, source of information regarding a potential cause of death. The following chapter describes the clinical and pathologic features of both common placental pathologies and uncommon lesions with important clinical implications with which the pathologist should be familiar.

Mesonephric carcinomas of the gynecologic tract are neoplasms that are often under-recognized due to their varied morphologic appearances. Recently, GATA3 and TTF1 have been reported to be useful immunohistochemical markers for distinguishing mesonephric carcinomas from its morphologic mimics. Herein, we compared the performance of GATA3 and TTF1 to the traditional markers used for mesonephric carcinomas, CD10 and calretinin. We studied 694 cases: 8 mesonephric carcinomas (7 cervical [includes 3 mesonephric carcinosarcomas], 1 vaginal), 5 mesonephric-like carcinomas (4 uterine corpus, 1 ovarian), 585 endometrial adenocarcinomas, and 96 cervical adenocarcinomas. Mesonephric-like carcinomas were defined as tumors exhibiting the classic morphologic features of mesonephric carcinoma, but occurring outside of the cervix and without convincing mesonephric remnants. GATA3 had the highest sensitivity and specificity (91% and 94%) compared with TTF1 (45% and 99%), CD10 (73% and 83%), and calretinin (36% and 89%). GATA3, however, also stained a substantial number of uterine carcinosarcomas (23/113, 20%). TTF1 was positive in 5/5 (100%) mesonephric-like carcinomas and only 1/8 (13%) mesonephric carcinomas. In 4/6 (67%) TTF1 positive cases, GATA3 exhibited an inverse staining pattern with TTF1. In summary, GATA3 was the best overall marker for mesonephric and mesonephric-like carcinomas, but cannot be used to distinguish mesonephric carcinosarcomas from Mullerian carcinosarcomas. The inverse staining pattern between GATA3 and TTF1, suggests that TTF1 may be useful when GATA3 is negative in small biopsies where mesonephric or mesonephric-like carcinoma is suspected. The greater TTF1 positivity in mesonephric-like carcinomas suggests they may be biologically different from prototypical mesonephric carcinomas.

Aims To characterize the histomorphological features of endometrial carcinomas (ECs) harbouring polymerase e (POLE) mutations. Methods and results Forty-three ECs with POLE mutations were compared with a cohort of 202 ECs. Most POLE-mutated ECs were endometrioid [34/43 (79%)]; the remaining tumours were mixed [6/43 (14%)], serous [2/43 (5%)], and clear cell [1/43 (2%)]. The endometrioid carcinomas were predominantly International Federation of Gynecology and Obstetrics grade 3 (27/43, 63%). The histotype distribution did not differ from that of control ECs (P = 0.69), but the grade of the EC was higher (P < 0.0005). Both nuclear grade and mitotic index were significantly higher in POLE-mutated ECs than in the comparison cohort. POLE-mutated ECs were associated with peritumoral lymphocytes and numerous tumour-infiltrating lymphocytes. Lymphovascular invasion was present in 20 of 43 tumours. Adjuvant radiotherapy and adjuvant chemotherapy would be offered in up to 80% and 40% of patients, respectively, on the basis of stage, grade, lymphovascular invasion, and histotype. Conclusions POLE-mutated ECs are typically of high grade, with prominent lymphocytic infiltration, but they are not sufficiently distinctive to allow accurate diagnosis based on routine haematoxylin and eosin staining. Even though POLE-mutated tumours are associated with an excellent prognosis, current guidelines for giving adjuvant treatment for EC result in most patients receiving adjuvant therapy.

Standardized terminology has proven benefits in cancer reporting; in contrast, reporting of benign diagnoses in endometrial biopsy currently lacks such standardization. Unification and update on the lexicon can provide the structure and consistency needed for optimal patient care and quality assurance purposes. The Special Interest Group in Gynecologic Pathology of the Canadian Association of Pathologists-Association Canadienne des Pathologistes (CAP-ACP) embarked in an initiative to address the current need for consensus terminology in benign endometrial biopsy pathology reporting. Nine members of the Special Interest Group developed a guideline for structured diagnosis of benign endometrial pathology through critical appraisal of the available peer-reviewed literature and joint discussions. The first version of the document was circulated for feedback to a group of professionals in akin fields, the CAP-ACP Executive Committee and the CAP-ACP general membership. The final 1-page document included 17 diagnostic terms comprising the most common benign endometrial entities, as well as explanatory notes for pathologists. The proposed terminology was implemented in the practice of 5 pathologists from the group, who applied the guideline to all benign endometrial biopsies over a 2-wk period. A total of 212 benign endometrial biopsies were evaluated in this implementation step; the recommended terminology adequately covered the diagnosis in 203 cases (95.8%). A list of terminology for benign endometrial biopsy reporting, based on expert consensus and critical appraisal of the available literature, is presented. On the basis of our results of implementation at multiple centers, the proposed guideline can successfully cover the large majority of diagnostic scenarios. The document has the potential to positively impact patient care, promote quality assurance, and facilitate research initiatives aimed at improving histopathologic assessment of benign endometrium.

Endometriosis is a common disease characterized by the presence of ectopic endometrial tissue. Although the pathogenesis of endometriosis remains unclear, several factors have been implicated, including the dysregulation of homeobox ( HOX) genes. Our objective was to investigate the localization and immunoreactivity of HOXB4 in endometrial tissues from women with or without endometriosis. We studied samples of eutopic endometrium (EE), endometriomas (Eoma), superficial endometriosis (SE), and deep infiltrating endometriosis (DIE) from 34 women with endometriosis, as well as eutopic endometrium from 38 women without endometriosis (EC). HOXB4 localization and immunoreactivity was assessed using immunohistochemistry and histoscore analysis. Data were analyzed with and without stratification by menstrual cycle phase. HOXB4 protein was present in the nuclei of endometrial glandular epithelial cells but not in stromal cells. HOXB4 immunoreactivity was reduced in DIE samples compared to all other groups. A smaller reduction in HOXB4 immunoreactivity was observed in SE samples compared to EC samples. HOXB4 immunoreactivity was significantly greater in proliferative compared to secretory phase samples in the EC group but not in EE, Eoma, or DIE groups. Among only proliferative phase samples, HOXB4 immunoreactivity was reduced in EE, Eoma, and DIE groups compared to EC. Based on these data, we suggest that an impaired capacity of eutopic and ectopic endometrial tissue to upregulate levels of HOXB4 during the proliferative phase may play a role in the pathogenesis of endometriosis and that further downregulation of HOXB4 may enhance ectopic implant invasiveness.

Background and Objectives Controversy continues over the extent of surgical resection margin required to minimize the risk of local recurrence (LR) in breast-conserving therapy (BCT) for early stage breast cancer. This study explores whether or not a narrow (≤2 mm) but negative resection margin affects LR. Methods All patients registered at the Saskatoon Cancer Center between January 1, 1991 and December 31, 2000 with a diagnosis of early stage invasive duct carcinoma treated with BCT were examined. All charts and pathology reports were reviewed with a review of the pathology for all cases where the resection margin was unclear in the original report. Other factors known or thought to effect LR (age, radiation boost, grade, extensive DCIS, ER/PR receptor status) were considered in the statistical analysis. Results Amongst the 200 narrow margin cases 19 LR were detected (19/201 = 9.5%) while 52 LR were detected in the 491 wide margin cases (52/491 = 10.6%). This difference was not statistically significant. Conclusions A narrow (≤2 mm) surgical resection margin does not result in an increase in LR compared to a surgical resection margin >2 mm in BCT for early stage duct carcinoma and does not warrant re-excision. J. Surg. Oncol. 2011; 103:212–216. © 2011 Wiley-Liss, Inc.

Burkitt’s lymphoma is the most frequent subtype of non-Hodgkin’s lymphoma in childhood. Radiographic findings are protean and can often overlap with other neoplastic and nonneoplastic processes. We present an unusual case of Burkitt’s lymphoma in a 12-year-old boy presenting with a one-week history of urinary retention, dysuria, and “tailbone pain,” as well as a 4-week history of jaw pain, initially treated as a dental abscess. On dental radiography, the patient was found to have resorption of alveolar bone adjacent to the lower first molars bilaterally, in keeping with “floating teeth,” classically associated with Langerhans cell histiocytosis. Additionally, a large, eccentric, prostatic mass was noted, prompting the inclusion of rhabdomyosarcoma on the differential diagnosis, with subsequent definitive diagnosis of Burkitt’s lymphoma on tissue and bone marrow biopsy. This case highlights the imaging overlap of these childhood neoplasms with an unusual lymphomatous prostate mass. It is important that the radiologists and pediatricians be aware of this potential overlap and the unusual presentation of Burkitt’s lymphoma.

Controversy continues over the extent of surgical resection margin required to minimize the risk of local recurrence (LR) in breast-conserving therapy (BCT) for early stage breast cancer. This study explores whether or not a narrow (≤ 2 mm) but negative resection margin affects LR.All patients registered at the Saskatoon Cancer Center between January 1, 1991 and December 31, 2000 with a diagnosis of early stage invasive duct carcinoma treated with BCT were examined. All charts and pathology reports were reviewed with a review of the pathology for all cases where the resection margin was unclear in the original report. Other factors known or thought to effect LR (age, radiation boost, grade, extensive DCIS, ER/PR receptor status) were considered in the statistical analysis.Amongst the 200 narrow margin cases 19 LR were detected (19/201 = 9.5%) while 52 LR were detected in the 491 wide margin cases (52/491 =10.6%). This difference was not statistically significant.A narrow (≤ 2 mm) surgical resection margin does not result in an increase in LR compared to a surgical resection margin 2 mm in BCT for early stage duct carcinoma and does not warrant re-excision.