Gynecologic Pathology Journal Club: A 2-year, Worldwide Virtual Learning Experience With a Focus on Mentorship and Inclusion.

Journal clubs (JCs) are a common format used in teaching institutions to promote trainee engagement and develop skills in seeking out evidence-based medicine and critically evaluating literature. Digital technology has made JC accessible to worldwide audiences, which allows for increased inclusion of globally diverse presenters and attendees. Herein we describe the experience of the first 2 years of a virtual gynecologic pathology JC designed with the goal of providing mentorship and increasing inclusivity. JC began in a virtual format in April 2020 in response to the need for remote learning during the coronavirus disease 2019 pandemic. Each JC had 1 moderator, lasted 1 hour, featured up to 3 trainees/early-career pathologists, and covered articles on gynecologic surgical pathology/cytopathology. Trainees were recruited through direct contact with moderators and advertising through social media (eg, Twitter). A template was used for all presentations, and before presenting, live practice sessions were conducted with the moderator providing constructive feedback and evaluations were provided to presenters and attendees for feedback. Recordings of the meetings were made publicly available after the event through YouTube, a society website, and emails to registrants. Fifty-nine presenters participated, covering 71 articles. Most were trainees (53/59; 89%) from North America (33/59; 56%), with additional presenters from Asia (14/59; 24%), Australia/Oceania (5/59; 8%), Africa (4/59; 7%), and Europe (3/59; 5%). An average of 20 hours were spent per month by moderators on the selection of papers, meeting preparation, and provision of mentorship/feedback. Live events had a total of 827 attendees, and 16,138 interactions with the recordings were noted. Among those who self-identified on provided surveys, the attendees were most commonly from Europe (107/290; 37%) and were overwhelmingly practicing pathologists (275/341; 81%). The experience, including mentorship, format, and content, was positively reviewed by attendees and presenters. Virtual JC is an inclusive educational opportunity to engage trainees and early-career pathologists from around the world. The format allowed for the JC to be widely viewed by attendees from multiple countries, most being practicing pathologists. Based on feedback received, virtual JC appears to expand the medical knowledge of the attendees and empower presenters to develop their expertise and communication skills.

Transcriptome profiling and network enrichment analyses identify subtype-specific therapeutic gene targets for breast cancer and their microRNA regulatory networks.

Previous studies have suggested that breast cancer (BC) from the Middle East and North Africa (MENA) is presented at younger age with advanced tumor stage, indicating underlying biological differences. Given the scant transcriptomic data on BC from the MENA region and to better understand the biology of this disease, we performed mRNA and microRNA (miRNA) transcriptomic profiling on a local cohort of BC (n = 96) from Qatar. Our data revealed the differentially expressed genes and miRNAs as function of BC molecular subtypes (HR+, HER2+, HER2+HR+, and TNBC), tumor grade (GIII vs GI-II), patients' age (young (≤40) vs old (>40)), and ethnicity (MENA vs non-MENA). Our profiling data revealed close similarity between TNBC and HER2+, while the transcriptome of HER2+HR+ tumor was resemblant of that from HR+ tumors. Network analysis identified complex miRNA-mRNA regulatory networks in each BC molecular subtype, in high vs low grade tumors, in tumors from young vs old patients, and in tumors from MENA vs non-MENA, thus implicating miRNA-mediated gene regulation as an essential mechanism in shaping the transcriptome of BC. Integration of our transcriptomic data with CRISPR-Cas9 functional screen data and the OncoKB database identified numerous dependencies and therapeutic vulnerabilities in each BC molecular subtype, while CDC123 was functionally validated as potential therapeutic target for TNBC. Cox regression survival analyses identified mRNA and miRNA-based signatures predicative of worse and better relapse free survival (RFS), which were validated in larger BC cohorts. Our data provides comprehensive transcriptomic profiling and unraveled the miRNA-mRNA regulatory networks in BC patients from the region and identified novel actionable gene targets, employing integrated approach. Findings from the current study have potential implications to improve the current standard-of-care for BC from the MENA as well as patients from other ethnicities.

Uterine Adenosarcoma with Sarcomatous Overgrowth and Rhabdoid Features: A Rare Case.

Uterine adenosarcoma is usually a low-grade neoplasm with a mixed benign epithelial component and malignant stroma, commonly found in postmenopausal women. In the presence of sarcomatous overgrowth, it has been shown to have poor prognosis. Uterine adenosarcoma with sarcomatous overgrowth and rhabdoid features is extremely rare. We report here a case of a 28-year-old female who was found to have adenosarcoma with sarcomatous overgrowth with extensive rhabdoid features. The tumor had metastasized to the pelvis, omentum, iliac, and obturator lymph nodes. She was lost to follow-up for 10 months, after which she presented with recurrent tumor at the hysterectomy site. She was started on palliative chemoradiotherapy, on which she progressed but later experienced drug toxicity, became cachectic, and was unwilling to continue chemotherapy. There are a few cases of adenosarcoma with sarcomatous overgrowth reported in young women and only two cases with rhabdoid features. Based on this report, adenosarcoma with sarcomatous overgrowth and rhabdoid features appears to be an extremely aggressive tumor with poor prognosis.

The Many Faces of Serous Neoplasms and Related Lesions of the Female Pelvis: A Review.

Ovarian serous tumors and related lesions are one of the most common conditions of the female genital tract. While ovarian high-grade serous carcinoma carries high mortality and adverse prognosis, most other serous lesions have better clinical behavior. In recent years, significant progress has been made in understanding the nature and histogenesis of these lesions that has contributed to better and more precise clinical management. Most of the high-grade serous carcinomas involve the ovaries and/or peritoneum, although in most cases, their origin seems to be in the fallopian tube. This view is supported by the recognition of precursor lesions in the fallopian tube, such as p53 signature and serous tubular in situ carcinoma. This paper presents salient morphologic, immunohistochemical, and molecular data related to serous tumors and related lesions of the female pelvis and discusses the histogenetic interrelationship among these lesions in light of current knowledge.

PD-L1 immunostaining: what pathologists need to know.

BACKGROUND: Immune checkpoint proteins, especially PD-L1 and PD-1, play a crucial role in controlling the intensity and duration of the immune response, thus preventing the development of autoimmunity. These proteins play a vital role in enabling cancer cells to escape immunity, proliferate and progress. METHODS: This brief review highlights essential points related to testing for immune checkpoint therapy that histopathologists need to know. RESULTS: In recent years, several inhibitors of these proteins have been used to reactivate the immune system to fight cancer. Selection of patients for such therapy requires demonstration of PD-L1 activation on the tumor cells, best done by immunohistochemical staining of the tumor and immune cells using various antibodies with predetermined thresholds. CONCLUSIONS: Immune checkpoint therapy appears to be promising and is rapidly expanding to include a large variety of cancers.

Ciliated Cell Variant of Endometrial Carcinoma in an Adenomyoma in Uterus.

Ciliated cell variant of endometrioid adenocarcinoma (CCVEA) is an extremely rare tumor that has been seldom reported in the literature as low-grade endometrioid carcinoma with a favorable prognosis. CCVEA is characterized by neoplastic glands composed predominantly of ciliated cells with relatively little nuclear atypia. Recognition of the ciliated component is the key to the diagnosis of CCVEA but it can lead to diagnostic confusion with tubal metaplasia especially on endometrial biopsies. Herein, we report the case of a 56-year-old woman who presented with post-menopausal vaginal bleeding. Endometrial biopsy revealed extensive atypical complex endometrial hyperplasia composed predominantly of ciliated cells. The patient subsequently had a hysterectomy and bilateral salpingo-oophorectomy that revealed a large adenomyoma, adherent to the right ovary. The adenomyoma was extensively involved by CCVEA with some extension to the endometrial cavity. To the best of our knowledge, this is the first report of CCVEA that appears to arise in an adenomyoma.

Carcinomas of the Uterine Cervix: Comprehensive Review With An Update on Pathogenesis, Nomenclature of Precursor and Invasive Lesions, and Differential Diagnostic Considerations.

Most cervical carcinomas and their related lesions are attributed to an infection by human papillomavirus (HPV). The infection usually starts in the basal cells at the squamocolumnar junction. It causes cell proliferation and maturation abnormalities along with nuclear abnormalities resulting in low-grade squamous intraepithelial lesions. An overwhelming majority of these lesions spontaneously disappear, and the infection is cleared. In a small subset of high-risk HPV infection cases, the lesions may persist and progress to high-grade squamous intraepithelial lesions. These are associated with the incorporation of the viral genome into the human genome. Some of the high-grade squamous intraepithelial lesions, over several years, progress to invasive carcinoma. Carcinomas of the cervix are usually squamous cell carcinomas (SCCs), but 20% to 25% of the cases may manifest as adenocarcinomas. Similar to SCC, adenocarcinomas may initially manifest as adenocarcinomas in situ and may progress to invasive carcinomas after a variable period of time. In the recently published World Health Organization classification of female genital tumors, SCCs, and adenocarcinomas of the cervix are divided into HPV-associated and HPV-independent tumors. This review draws on the latest terminology and the several morphologic subtypes recognized for each category.

Endometriosis: A Comprehensive Review.

Endometriosis is a relatively common condition in which endometrial tissue is established in locations outside the uterus where, like the eutopic endometrium, it responds to hormonal stimuli and develops internal bleeding, inflammation, and fibrosis. These changes are associated with chronic and often debilitating cyclic pain and infertility. The pathogenesis of endometriosis is multifactorial, and several theories have been proposed to explain it. These include retrograde menstruation, celomic metaplasia, embryologic rests, and lymphovascular spread. Hormones, immunologic status, and genetic factors may also play a role. In most patients, the disease involves pelvic organs, but rarely it may also extend to a large variety of distant locations in the body. Patients with ovarian endometriosis are at higher risk for developing ovarian carcinomas including endometrioid and clear cell carcinomas. Some of these carcinomas may arise in a background of structural and/or nuclear atypia within the endometriotic foci. There is no known cure for endometriosis and treatment mostly consists of managing chronic pain or infertility.

Incidental low grade mucinous neoplasm of appendix in pregnancy: A case report & literature review.

INTRODUCTION: Mucinous neoplasms of appendix account for 0.2-0.4% of all the appendix specimens. The occurrence of this neoplasm in pregnancy is extremely rare. We describe a case of a pregnant lady who was diagnosed as acute appendicitis and found to have Low-Grade Mucinous neoplasm on histopathology. In the existent literature, there are only a few such cases reported and none from our Middle East region. CASE PRESENTATION: 42-year-old pregnant lady at 24 weeks of gestation presented with classical symptoms of acute appendicitis. She had leukocytosis but the Ultrasound was equivocal. She underwent laparoscopic appendectomy and found to have an inflamed appendix. Postoperative recovery was satisfactory and was discharged home. The histopathology report showed low-grade mucinous neoplasm of the appendix and she was detailed about it on follow up. DISCUSSION: The incidence of appendiceal neoplasm is rare in routine appendectomy and carcinoid is the most common tumor of the appendix. Low-Grade mucinous neoplasm is a rare entity and its presence in pregnancy is further rarer. CONCLUSION: Since this neoplasm does not manifest with a characteristic clinical profile it is difficult to diagnose, even with extensive preoperative evaluation. Although surgical treatment is straight forward, the management of the appendiceal neoplasm during pregnancy necessitates full knowledge of the natural history of the disease to attain equilibrium of concern for maternal survival and fetal health.

Locally Aggressive Giant Cell Tumor of Bone With Pulmonary Distant Metastasis and Extrapulmonary Seeding in Pregnancy.

Giant cell tumor of bone (GCTB) is a locally aggressive benign neoplasm that is associated with a large biological spectrum ranging from latent benign to highly recurrent and occasionally metastatic tumor. In this article, we present a case of a 26-year-old woman who presented with swelling at the left lower ribs during pregnancy. Surgical excision was done, and histopathology showed tumor with features consistent with GCTB. MRI preformed after delivery revealed recurrence of the mass with extensive growth reaching 17 cm with two subcutaneous satellite nodules in the adjacent abdominal wall. positron emission tomography-computed tomography (PET-CT) scan revealed bilateral fluorodeoxyglucose (FDG)-avid lung nodules. Surgical resection was done, and histopathology showed no evidence of malignant transformation. Few months later, the tumor recurred again, with peritoneal deposits. The patient underwent wide massive resection of the recurrent mass and then started on denosumab therapy. Molecular analysis of the tumor detected H3F3A G34W mutation with no copy number alterations. We are presenting this case of GCTB with pulmonary distant metastasis and extrapulmonary seeding to upsurge awareness among clinicians about the possible extreme aggressive biological behavior of GCTB that can mimic the presentation of malignant bone tumor and also to discuss the possible predictive factors of such aggressive behavior.

CK20 and CK5/6 Immunohistochemical Staining of Urothelial Neoplasms: A Perspective.

Cytokeratins belong to the family of intermediate filaments. They are expressed in a highly specific manner in epithelial cells where they play a crucial role in the integrity and mechanical stability of the cells. Several types of cytokeratins have been described in normal as well as neoplastic urothelium. In the case of urothelial neoplasms expression of CK20 and CK5/6 has been shown in several studies to have diagnostic and prognostic implications. Thus, low-grade urothelial carcinoma manifests CK expression limited to the umbrella cells, while high-grade tumors usually have an expression in the entire thickness of the urothelium except for the basal layer. CK5/6 expression on the other hand is expressed in the basal cells in all low-grade and some high-grade urothelial carcinomas. Diffuse CK20 staining accompanied by loss of CK5/6-positive basal layer is usually associated with aggressive clinical behavior. Double staining of the slides for these cytokeratins may facilitate proper interpretation and correlation.

Fatal renal mucormycosis with Apophysomyces elegans in an apparently healthy male.

Mucor is an angioinvasive fungus that was reported mainly in immunocompromised patients. It usually presents as rhino-orbital, pulmonary, gastrointestinal, and disseminated disease. Isolated renal mucormycosis is an extremely rare infection in immunocompetent patients and is associated with high fatality rate. Early diagnosis, prompt antifungal treatment, and surgery give the patient the best chance for cure and survival. We describe herein a case of renal zygomycosis caused by Apophysomyces elegans (A. elegans) in an immunocompetent host. To the best of our knowledge, this is the first case of renal A. elegans to be reported from Qatar and the Middle East.

Classification of Endometrial Carcinoma: New Perspectives Beyond Morphology.

Endometrial carcinoma has been traditionally divided into type 1 or endometrioid type that is usually moderate to well differentiated and type 2 that is usually poorly differentiated with high histologic grade and aggressive clinical behavior. However, interobserver diagnostic agreement is suboptimal, particularly among the high-grade histotypes. Furthermore, recent data indicate that this histotype assignment does not independently correlate with survival. In recent years, there has been remarkable progress in our understanding of the molecular basis of endometrial carcinoma and extensive molecular studies have been performed under The Cancer Genome Atlas Program (TCGA) leading to molecular classification of endometrial carcinoma that has been shown to be significantly prognostic. This classification system divides the tumors into 4 subgroups namely, polymerase ε exonuclease (POLE) ultramutated, hypermutated microsatellite instability, copy number low, and copy number high (serous-like). Carcinomas with POLE domain hotspot mutations are highly prognostically favorable; those with copy number alterations and TP53 mutations are highly aggressive; and microsatellite unstable and "copy number low" endometrioid are associated with intermediate prognoses. The TCGA applied methods that are too costly and cumbersome for widespread implementation into routine clinical practice. Several other groups have attempted to identify these categories by using immunohistochemical biomarkers rather than molecular studies. Immunohistochemical biomarkers have been used successfully to identify all the subgroups except for POLE ultramutated, which requires sequencing for proper categorization. It is hoped that future studies will identify a suitable biomarker for POLE mutation so that this classification can be routinely used in all medical centers.

Urothelial Carcinoma In Situ (CIS): New Insights.

Urothelial carcinoma in situ (CIS) is a high-grade noninvasive malignancy with a high tendency of progression. Although it is typically grouped with other nonmuscle invasive bladder cancers, its higher grade and aggressiveness make it a unique clinical entity. Urothelial CIS is histologically characterized by replacement of the urothelium by cells which fulfill the morphologic criteria of malignancy including nuclear pleomorphism, hyperchromasia, prominent nucleoli, and increased numbers of normal and abnormal mitoses. Urothelial CIS may be categorized as primary when it is not associated with any past or present urothelial carcinoma. It is termed as secondary when there is concomitant or previous urothelial carcinoma in the patient. In recent years detailed molecular studies have provided valuable data for intrinsic molecular subclassification of urothelial carcinoma into 2 broad categories namely luminal and basal types with significant implications for prognosis and therapy. Similar studies on urothelial CIS are limited but have provided crucial insight into the molecular basis of CIS. These studies have revealed that urothelial CIS may also be divided into luminal and basal subtypes, but luminal subtype is much more common. It has also been shown that in many cases, luminal type of urothelial CIS may undergo a class switch to basal type during progression to an invasive carcinoma. Additional studies may be required to confirm and further elaborate these findings.

Heterotopic Gastric Mucosa Presenting as Lower Gastrointestinal Bleeding: An Unusual Case Report.

Heterotopic gastric mucosa (HGM) is gastric mucosal tissue outside the stomach. It can be discovered anywhere throughout the gastrointestinal tract and is mostly asymptomatic. HGM, although rare beyond the ligament of Treitz, should be included in the differential diagnosis in a young patient with a polyp causing obstructive symptoms or bleeding. Very few cases are published in literature. We describe a case of young male who presented with an episode of large amount of melena, from a bleeding jejunal lesion, diagnosed by endoscopy. Laparotomy and wedge resection of the jejunal lesion was done, and histopathology showed gastric heterotopia in a small jejunal diverticulum.

Paget's "Seed and Soil" Theory of Cancer Metastasis: An Idea Whose Time has Come.

The concept that the pattern of metastatic spread of cancer is not random and that cancer cells exhibit preferences when metastasizing to organs, dates back to 1889 when Steven Paget published his "seed and soil" hypothesis. He proposed that the spread of tumor cells is governed by interaction and cooperation between the cancer cells (seed) and the host organ (soil). Extensive studies during the last several decades have provided a better understanding of the process of metastatic spread of cancer and several stages such as intravasation, extravasation, tumor latency, and development of micrometastasis and macrometastasis have been defined. Furthermore, recent studies have shown that the target organs may be prepared for metastatic deposits by the development of premetastatic niches. This specialized microenvironment is involved in promoting tumor cell homing, colonization, and subsequent growth at the target organ. The premetastatic niche consists of accumulation of aberrant immune cells and extracellular matrix proteins in target organs. The primary tumor plays a key role in the development of premetastatic niches by producing tumor-derived soluble factors which mobilize bone marrow-derived hematopoietic cells to the premetastatic niche. Exosomes-derived from the primary tumor also contribute to cancer-favorable microenvironment in the premetastatic niches. These changes prime the initially healthy organ microenvironment and render it amenable for subsequent metastatic cell colonization.

Invasive rhinocerebral mucormycosis in a patient with liver cirrhosis leading to fatal massive stroke.

Immunocompromised status is associated with invasive fungal infections including mucormycosis. These infections are challenging to treat and associated with high overall mortality. Here we report a fatal case of invasive mucormycosis in a cirrhotic, diabetic patient. Despite the swift diagnosis and management; the fungal invasion of the right internal carotid artery lead to massive ischemic stroke. Timely diagnosis and management is crucial for management but it seems not always enough and new approaches for treatment must be sought.

Sarcomatoid Variant of Urothelial Carcinoma of the Renal Pelvis with Inferior Vena Cava Tumour Thrombus: A Case Report and Literature Review.

Sarcomatoid variant of urothelial carcinoma (SVUC) of the renal pelvis is a rare entity. To the best of our knowledge, around 25 cases of this neoplasm have been reported in the literature to date, most of which were of high stage. The inferior vena cava tumour thrombus, which is a hallmark of renal cell carcinoma (RCC), may rarely be found in urothelial carcinoma of renal pelvis. In this report, a case of SVUC associated with tumour extension to inferior vena cava is documented. This association has been encountered in only one previously reported case. The possibility of urothelial carcinoma of the renal pelvis should therefore be included in the differential diagnosis of tumour thrombus of the inferior vena cava.