Incidentally Diagnosed Low-Grade Primary Peritoneal Serous Carcinoma Within the Umbilical Hernia Sac in a Male: A Report of an Extremely Rare Case and Review of the Literature.

Primary peritoneal serous carcinoma (PPSC) is a rare tumor that develops in the peritoneum. PPSC originates from embryonic nests of Müllerian cells in the peritoneum, which are also present in the epithelium of the ovary. This similarity explains the histopathological resemblance between PPSC and low-grade serous ovarian carcinoma. While PPSC primarily affects women, it is an extremely rare occurrence in males, and it is believed that the significant difference in diagnosis rates between males and females is due to the inhibition of Müllerian system growth by substances produced by male Sertoli cells. These substances are present at higher levels in males, which may prevent the development of Müllerian system-derived tumors in men. We describe a 65-year-old male patient who presented for elective bariatric surgery and umbilical hernia repair, and an incidental finding of low-grade PPSC was made based on hernia sac pathology. The patient underwent further management, including tumor debulking and hyperthermic intraperitoneal chemotherapy (HIPEC), with positive outcomes. Long-term follow-up and oral letrozole treatment are planned.

Improvement in Hearing Loss Following Posterior Fossa Arachnoid Cyst Fenestration: A Case Study.

Arachnoid cysts are abnormal intradural collections of cerebrospinal fluid. For posterior fossa arachnoid cysts (PFACs), symptoms vary greatly, often relating to cranial nerve impingement and/or hydrocephalus. Literature on long-term symptomatic and radiographic follow-up of PFACs is lacking. This case study describes a 32-year-old man who presented with headaches and left-sided hearing loss and was found to have a large left-sided cerebellopontine angle arachnoid cyst with syrinx and ventriculomegaly. After PFAC fenestration and excision, his headaches resolved and his hearing markedly improved. At the one-year postoperative evaluation, symptom improvement persisted, and MRI demonstrated a stable decreased cyst and near-complete resolution of his syrinx.

Recent Advances in Genitourinary Tumors Updates From the 5th Edition of the World Health Organization Blue Book Series.

CONTEXT.­: Urinary and Male Genital Tumours is the 8th volume of the World Health Organization Classification of Tumours series, 5th edition. Released in hard copy in September 2022, it presents an update to the classification of male genital and urinary tumors in the molecular age. Building upon previous volumes in this series, significant effort has been made to harmonize terminology across organ systems for biologically similar tumors (eg, neuroendocrine tumors). Genomic terminology has been standardized and genetic syndromes covered more comprehensively. This review presents a concise summary of this volume highlighting new entities, notable modifications relative to the 4th edition, and elements of relevance to routine clinical practice. OBJECTIVE.­: To provide a comprehensive update on the World Health Organization classification of urinary and male genital tumors, highlighting updated diagnostic criteria and terminology. DATA SOURCES.­: The 4th and 5th editions of the World Health Organization Classification of Tumours: Urinary and Male Genital Tumours. CONCLUSIONS.­: The World Health Organization has made several changes in the 5th edition of the update on urinary and male genital tumors that pathologists need to be aware of for up-to-date clinical practice.

Multilineage Pituitary Neuroendocrine Tumors (PitNETs) Expressing PIT1 and SF1.

PitNETs are usually restricted in their cytodifferentiation to only one of 3 lineages dictated by expression of the pituitary transcription factors (TFs) PIT1, TPIT, or SF1. Tumors that show lineage infidelity and express multiple TFs are rare. We searched the pathology files of 4 institutions for PitNETs with coexpression of PIT1 and SF1. We identified 38 tumors in 21 women and 17 men, average age 53 (range 21-79) years. They represented 1.3 to 2.5% of PitNETs at each center. Acromegaly was the presentation in 26 patients; 2 had central hyperthyroidism associated with growth hormone (GH) excess and one had significantly elevated prolactin (PRL). The remainder had mass lesions with visual deficits, hypopituitarism, and/or headaches. Tumor size ranged from 0.9 to 5 cm; all 7 lesions smaller than 1 cm were associated with acromegaly. Larger lesions frequently invaded the cavernous sinuses. Four cases represented a second attempt at surgical resection. PIT1 was usually diffusely positive but 5 cases had variable (patchy or focal) staining. SF1 reactivity was variable in intensity but diffuse in all but 2 cases. GATA3 data, available in 14 cases, identified diffuse positivity in 5 and focal staining in 1. GH was expressed in all but 5 tumors, PRL and thyrotropin (TSH) were expressed in 14 and 13, respectively, follicle-stimulating hormone (FSH) in 11 of 18, and luteinizing hormone (LH) in 4 of 17. Keratin staining patterns were diffuse perinuclear/membranous in 27, variable perinuclear in 4, and negative in 3; scattered fibrous bodies were seen in 5 and diffuse fibrous bodies in 1. Ki67 labeling index ranged from < 1 to 7.9%. In 3 cases, these tumors represented one of multiple synchronous PitNETs; a separate corticotroph tumor was seen in 2 patients and one patient had 2 additional discrete lesions, a sparsely granulated lactotroph, and a pure gonadotroph tumor comprising a triple tumor. PitNETs expressing PIT1 and SF1 represent multilineage PitNETs. These rare tumors have variable clinical and morphological features, most often presenting as large tumors with GH excess and occasionally as one of multiple synchronous PitNETs of distinct lineages.

The Mucosal Manifestations of Syphilis in the Head and Neck.

Objectives: Syphilis is a resurging disease which can present itself in many ways, including lesions within the head and neck mucosa. Some of these lesions may clinically mimic oral malignancies. This literature review aims to better characterize the mucosal presentations of syphilis. Methods: PubMed, EMBASE, and clinicaltrials.gov were searched for full-text, English articles published from 1950 to 2022 that reported patients with head and neck mucosal manifestations of syphilis. Articles were screened according to PRISMA guidelines. Results: One hundred forty-three manuscripts documenting 236 individual patients were included in the review. Patients with secondary syphilis accounted for 62% of patients presenting with head and neck mucosal lesions. The most common lesions found in primary and secondary syphilis were ulcerations, primarily found on the tongue, lips, and palate. While serologic studies are the gold standard for diagnosing syphilis, biopsy of these lesions have characteristic syphilitic changes. Conclusions: Syphilis' nickname of "The great imitator" remains to be true, and the head and neck mucosal manifestations of this disease can resemble commonly seen malignancies. Awareness of this disease and its lesions is prudent given the rising incidence of syphilis within the United States.

Modeling collective cell behavior in cancer: Perspectives from an interdisciplinary conversation.

Collective cell behavior contributes to all stages of cancer progression. Understanding how collective behavior emerges through cell-cell interactions and decision-making will advance our understanding of cancer biology and provide new therapeutic approaches. Here, we summarize an interdisciplinary discussion on multicellular behavior in cancer, draw lessons from other scientific disciplines, and identify future directions.

Recent Advances in the Classification of Gynecological Tract Tumors: Updates From the 5th Edition of the World Health Organization "Blue Book".

CONTEXT.­: The World Health Organization Classification of Tumours: Female Genital Tract Tumors, 5th edition, published in September 2020, comes 6 years after the 4th edition, and reflects the monumental leaps made in knowledge about the biology of gynecological tumors. Major changes include revised criteria for the assignment of the site of origin of ovarian and fallopian tube tumors, a revision in the classification of squamous and glandular lesions of the lower genital tract based on human papillomavirus association, and an entire chapter devoted to genetic tumor syndromes. This article highlights the changes in the 5th edition relative to the 4th edition, with a focus on areas of value to routine clinical practice. OBJECTIVE.­: To provide a comprehensive update on the World Health Organization classification of gynecological tumors, highlighting in particular updated diagnostic criteria and terminology. DATA SOURCES.­: The 4th and 5th editions of the World Health Organization Classification of Tumours. CONCLUSIONS.­: The World Health Organization has made several changes in the 5th edition of the update on female genital tumors. Awareness of the changes is needed for pathologists' translation into contemporary practice.

A Case of Retroperitoneal Synovial Sarcoma in Pregnancy Treated with Antepartum Doxorubicin plus Ifosfamide Chemotherapy.

We report a case of a 25-year-old pregnant woman diagnosed with a large, unresectable retroperitoneal synovial sarcoma. Successful neoadjuvant treatment with doxorubicin plus ifosfamide prepartum and continuing postpartum resulted in significant disease response allowing for later tumor resection. Following the first prepartum chemotherapy cycle, a decreased amniotic fluid index was noted, representing a potential complication of chemotherapy. Induction of labor was performed at 33 weeks gestation with excellent outcome in the newborn. This case highlights the complex medical decision-making process in the setting of cancer diagnosed during pregnancy, balancing oncologic and obstetric concerns, and to our knowledge is only the second reported case of synovial sarcoma treated with neoadjuvant cytotoxic chemotherapy in the antepartum period.

Plasma Cell Myeloma Within a Renal Cell Carcinoma, an Intimate Histologic Relationship: A Case Report and Literature Review.

The coexistence of two separate malignancies in a patient is a rare occurrence. Even more infrequent is the coexistence of a hematologic malignancy and a solid tumor. However, the relationship between renal cell carcinoma (RCC) and plasma cell myeloma (PCM) has been reported in previous studies. These studies described synchronous cases of RCC and PCM and demonstrated that this situation occurs more frequently than expected by probability calculations. We present, what we believe to be, the first reported case of RCC directly and physically involved by PCM and, we review the literature on the association between these malignancies and explore possible mechanisms for their higher than expected association. In describing this case, emphasis is made to describe unique histologic findings that could further support a more direct and intimate association between these tumors.

Primary Cutaneous Gamma/Delta T-cell Lymphoma and Hemophagocytic Lymphohistiocytosis Associated With AIDS.

Primary cutaneous gamma delta T-cell lymphoma (PCGD-TCL) is a rare lymphoma that makes up less than 1% of all cutaneous T-cell lymphomas. Patients with PCGD-TCL typically present with rapidly progressing plaques and ulceronecrotic nodules most frequently located on extremities without lymph node or bone marrow involvement. The overall prognosis is poor with a median overall survival of approximately 15 months. This case highlights a patient with concomitant PCGD-TCL, hemophagocytic lymphohistiocytosis, and human immunodeficiency virus-1-acquired immunodeficiency syndrome. There is a paucity of case reports describing PCGD-TCL and there are no evidence-based treatment recommendations. Further studies are needed to optimize strategies to treat patients with these diseases.

Gene fusion characterisation of rare aggressive prostate cancer variants-adenosquamous carcinoma, pleomorphic giant-cell carcinoma, and sarcomatoid carcinoma: an analysis of 19 cases.

AIMS: To evaluate the molecular underpinnings of the rare aggressive prostate cancer variants adenosquamous carcinoma, pleomorphic giant-cell carcinoma, and sarcomatoid carcinoma. METHODS AND RESULTS: We retrieved 19 tumours with one or more variant(s), and performed ERG immunohistochemistry, a next-generation sequencing assay targeting recurrent gene fusions, and fluorescence in-situ hybridisation (FISH) for ERG and BRAF. Divergent differentiation included: sarcomatoid carcinoma (n = 10), adenosquamous carcinoma (n = 7), and pleomorphic giant-cell carcinoma (n = 7). Five patients had more than one variant. Four had variants only in metastases. ERG rearrangement was detected in nine (47%, seven via sequencing, showing TMPRSS2-ERG fusions and one GRHL2-ERG fusion, and two via FISH, showing rearrangement via deletion). ERG was immunohistochemically positive in the adenocarcinoma in eight of nine (89%) patients, but was immunohistochemically positive in the variant in only five of nine patients (56%, typically decreased). One patient had a false-positive ERG immunohistochemical result in the sarcomatoid component despite a negative FISH result. Two (11%) harboured BRAF fusions (FAM131A-BRAF and SND1-BRAF). CONCLUSIONS: ERG fusions are present in these rare prostate cancer variants with a frequency close to that in conventional prostate cancer (9/19, 47%). ERG immunohistochemistry usually detects rearrangement in the adenocarcinoma, but is less sensitive for the variant histology, with weak to negative staining. Adenosquamous and sarcomatoid variants can, particularly, occur together. Molecular assessment may be an additional tool in selected cases to confirm the prostatic origin of unusual tumours. The presence of two BRAF rearrangements suggests that this gene fusion may be enriched in this setting, as RAF kinase fusions have been previously reported in 1-2% of prostate cancers.

Epigenetics and genome stability.

Maintaining genome stability is essential to an organism's health and survival. Breakdown of the mechanisms protecting the genome and the resulting genome instability are an important aspect of the aging process and have been linked to diseases such as cancer. Thus, a large network of interconnected pathways is responsible for ensuring genome integrity in the face of the continuous challenges that induce DNA damage. While these pathways are diverse, epigenetic mechanisms play a central role in many of them. DNA modifications, histone variants and modifications, chromatin structure, and non-coding RNAs all carry out a variety of functions to ensure that genome stability is maintained. Epigenetic mechanisms ensure the functions of centromeres and telomeres that are essential for genome stability. Epigenetic mechanisms also protect the genome from the invasion by transposable elements and contribute to various DNA repair pathways. In this review, we highlight the integral role of epigenetic mechanisms in the maintenance of genome stability and draw attention to issues in need of further study.

Multi-organ involvement secondary to varicella zoster virus, herpes simplex virus and cytomegalovirus in an immunocompromised patient.

The use of immunosuppressing agents can act as a catalyst for viral reactivation, promoting systemic infection with organ involvement. Current literature remains sparse on this topic but does provide individual case reports involving single viruses. We present the case of an immunocompromised patient with skin lesions, pancreatitis, colitis and hepatitis. Work-up revealed varicella zoster virus, which likely put the patient at risk for multi-organ involvement, as well as clinical suspicion of other implicated viruses, specifically herpes simplex virus and cytomegalovirus. A high clinical index of suspicion along with biopsy guidance for viral involvement in immunocompromised patients is crucial for early diagnosis and treatment of these conditions.

Giant Tricuspid Valve Fibroelastoma Incidentally Diagnosed During Routine Stress Testing.

Papillary fibroelastomas (PFEs) are the most common valvular tumor, typically occurring on left-sided valves. We describe the evaluation and treatment of a giant tricuspid PFE in a healthy 43-year-old police officer who was referred for evaluation of frequent premature ventricular contractions during job-related treadmill stress testing. (Level of Difficulty: Beginner.).

Hamartomas of skin and soft tissue.

Hamartomas are benign lesions composed of aberrant disorganized growth of mature tissues. Choristomas are similar, except that they are composed of tissues not normally found at the anatomic site in which the lesion is arising. A wide range of hamartomas and choristomas can arise in the skin and soft tissue. Some of these may cause diagnostic difficulty and potentially be mistaken for neoplasms. Some neoplasms may resemble hamaratomas. Here we review the current clinical and pathologic features of these lesions, both common and rare, and discuss how to distinguish them from other entities in the differential diagnosis.

Extraskeletal Mesenchymal Chondrosarcoma.

Extraskeletal mesenchymal chondrosarcoma is a rare soft tissue sarcoma arising from soft tissues, mainly of the lower extremities, meninges, and orbits. It usually presents during the second to third decades of life, and has a slight predominance in females. Histologically, it has a typical biphasic pattern comprising small cells and islands of hyaline cartilage. It can pose a diagnostic challenge in small biopsy specimens where 1 of the 2 components can be absent. The prognosis is extremely variable; survival varies depending on the location of the tumor.

Syndrome-Associated Tumors by Organ System.

Certain tumors suggest the possibility of a patient harboring a genetic syndrome, particularly in children. Syndrome-associated tumors of the gastrointestinal tract, genitourinary tract, gynecologic tract, heart, lungs, brain, eye, endocrine organs, and hematopoietic system will be briefly discussed.

Clinical and Pathologic Features of Hispanic Endometrial Cancer Patients With Loss of Mismatch Repair Expression.

OBJECTIVES: Approximately 3% to 5% of endometrial cancers (EC) are associated with Lynch syndrome (LS). The clinical characteristics and prevalence of LS have not been well studied in the US Hispanic population. Hispanics are the largest and fastest growing ethnic minority group in the United States. We sought to characterize the demographics, tumor characteristics, and prevalence of loss of mismatch repair (MMR) protein expression in a large Hispanic population with EC. METHODS: From January 1, 2005, to August 1, 2012, 83 women of Hispanic ethnicity diagnosed with EC 50 years and younger were identified. Clinical and pathologic data were abstracted from the electronic medical record. Tumor studies included immunohistochemistry of MLH1, MSH2, MSH6, and PMS2 and methylation of the MLH1 promoter. RESULTS: Ninety-five percent of patients were overweight or obese. The mean body mass index was 40.1 kg/m, 75% had irregular menses, 36% had diabetes, 46% were nulliparous, and 95% had endometrioid histology. Thirteen patients (15.7%) had tumor MMR deficiency due to a presumed germline mutation (9 MSH6, 3 MSH2, and 1 MLH1). The pattern of MMR protein loss was consistent with the expected binding properties of the MMR heterodimer complexes. No significant difference was found in clinical or pathological variables between patients with and without MMR deficient tumors. CONCLUSIONS: The prevalence of molecular findings consistent with LS was at least as high as other populations of varied geography, race, and ethnicity. We found no reliable factors to include body mass index, family history, synchronous tumors, or pathologic tumor features to serve as triage markers for which ECs should be screened for MMR protein loss. Our findings support a recommendation for universal screening of ECs utilizing 2-antibody testing with MLH1 promoter methylation testing as indicated up to 60 years or older. Our recommendations should be generalizable to other Hispanic populations in the Southern United States.

Rho Kinase Inhibition as a Therapeutic for Progressive Supranuclear Palsy and Corticobasal Degeneration.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative four-repeat tauopathies with no cure. Mitigating pathogenic tau levels is a rational strategy for tauopathy treatment, but therapeutic targets with clinically available drugs are lacking. Here, we report that protein levels of the Rho-associated protein kinases (ROCK1 and ROCK2), p70 S6 kinase (S6K), and mammalian target of rapamycin (mTOR) were increased in PSP and CBD brains. RNAi depletion of ROCK1 or ROCK2 reduced tau mRNA and protein level in human neuroblastoma cells. However, additional phenotypes were observed under ROCK2 knockdown, including decreased S6K and phosphorylated mTOR levels. Pharmacologic inhibition of Rho kinases in neurons diminished detergent-soluble and -insoluble tau through a combination of autophagy enhancement and tau mRNA reduction. Fasudil, a clinically approved ROCK inhibitor, suppressed rough eye phenotype and mitigated pathogenic tau levels by inducing autophagic pathways in a Drosophila model of tauopathy. Collectively, these findings highlight the Rho kinases as rational therapeutic targets to combat tau accumulation in PSP and CBD. SIGNIFICANCE STATEMENT: Studies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) suggest that mitigating pathogenic tau levels is a rational strategy for tauopathy treatment. In this report, the Rho-associated protein kinases (ROCK1 and ROCK2) are identified as novel drug targets for PSP and CBD. We show that elevated insoluble tau levels are associated with increased ROCK1 and ROCK2 in PSP and CBD brains, whereas experiments in cellular and animal models identify pharmacologic inhibition of ROCKs as a mechanism-based approach to reduce tau levels. Our study correlates bona fide changes in PSP and CBD brains with cellular models, identifies drug targets, and tests the therapeutic in vivo.