Intraductal Carcinoma of the Prostate versus Simulants: A Differential Diagnosis Growing in Clinical Impact.

Despite its first recognition even longer ago, in the past nearly 20 years, intraductal carcinoma of the prostate has become a standard histopathologic reporting parameter conveying a strong negative prognostic factor for prostatic adenocarcinoma. When seen at biopsy, intraductal carcinoma of the prostate is associated with risk for aggressive prostatectomy outcomes, including frequently high-grade, high-stage, high-volume disease, with increased risk for recurrence and progression. Multiple organizations, including the uropathology subspecialty societies to the World Health Organization, recognize and recommend reporting the presence of intraductal carcinoma, whether sampled in "pure" form or present with concomitant invasive adenocarcinoma. Moreover, emerging scholarship relates intraductal carcinoma to higher prevalence of homologous recombination repair deficiency mutations in prostatic adenocarcinoma, whether somatic or germline, which serve as indications for approved targeted therapies. Taken together, this is a diagnosis for the histopathologist not to miss. In view of these elevated stakes and the opportunity to further precision medicine, this review details neoplastic and non-neoplastic simulants in the differential diagnosis of intraductal carcinoma of the prostate.

Contemporary Diagnostic Reporting for Prostatic Adenocarcinoma: Morphologic Aspects, Molecular Correlates, and Management Perspectives.

The diagnosis and reporting of prostatic adenocarcinoma have evolved from the classic framework promulgated by Dr Donald Gleason in the 1960s into a complex and nuanced system of grading and reporting that nonetheless retains the essence of his remarkable observations. The criteria for the "Gleason patterns" originally proposed have been continually refined by consensuses in the field, and Gleason scores have been stratified into a patient-friendly set of prognostically validated and widely adopted Grade Groups. One product of this successful grading approach has been the opportunity for pathologists to report diagnoses that signal carefully personalized management, placing the surgical pathologist's interpretation at the center of patient care. At one end of the continuum of disease aggressiveness, personalized diagnostic care means to sub-stratify patients with more indolent disease for active surveillance, while at the other end of the continuum, reporting histologic markers signaling aggression allows sub-stratification of clinically significant disease. Whether contemporary reporting parameters represent deeper nuances of more established ones (eg, new criteria and/or quantitation of Gleason patterns 4 and 5) or represent additional features reported alongside grade (intraductal carcinoma, cribriform patterns of carcinoma), assessment and grading have become more complex and demanding. Herein, we explore these newer reporting parameters, highlighting the state of knowledge regarding morphologic, molecular, and management aspects. Emphasis is made on the increasing value and stakes of histopathologists' interpretations and reporting into current clinical risk stratification and treatment guidelines.

The New WHO Category of "Molecularly Defined Renal Carcinomas": Clinical and Diagnostic Features and Management Implications.

The evolution of classification of renal tumors has been impacted since the turn of the millennium by rapid progress in histopathology, immunohistochemistry, and molecular genetics. Together, these features have enabled firm recognition of specific, classic types of renal cell carcinomas, such as clear cell renal cell carcinoma, that in current practice trigger histologic-type specific management and treatment protocols. Now, the fifth Edition World Health Classification's new category of "Molecularly defined renal carcinomas" changes the paradigm, defining a total of seven entities based specifically on their fundamental molecular underpinnings. These tumors, which include TFE3-rearranged, TFEB-altered, ELOC-mutated, fumarate hydratase-deficient, succinate dehydrogenase-deficient, ALK-rearranged, and SMARCB1-deficient renal medullary carcinoma, encompass a wide clinical and histopathologic phenotypic spectrum of tumors. Already, important management aspects are apparent for several of these entities, while emerging therapeutic angles are coming into view. A brief, clinically-oriented introduction of the entities in this new category, focusing on relevant diagnostic, molecular, and management aspects, is the subject of this review.

A TFEB-Amplified Renal Cell Carcinoma with Long-Term, Complete Immunotherapy Response: Retrospective Support for the Value of Molecular Classification.

Recent years have seen the recognition and establishment of numerous subtypes of renal cell carcinoma (RCC), including adoption of an entire category of "molecularly defined renal carcinomas" in the fifth Edition of World Health Organization Classification. To add value, new diagnostic entities should be clinicopathologically distinct, or better, imply specific management and treatment angles, especially if adjunctive testing is needed for diagnosis. One such promising future treatment angle for a molecularly defined subtype, TFEB-amplified RCC, is immunotherapy, for which recent scholarship has demonstrated frequent expression of PD-L1. Herein, we report a case of metastatic TFEB-amplified RCC, where the patient experienced a long-term, complete response to PDL1-directed therapy, which had been serendipitously used years ago under a renal tumor subtype-agnostic indication. This promising experience suggests formal exploration of immunotherapy for these tumors.

Unexpected Clinical Outcome for Myxoinflammatory Fibroblastic Sarcoma, When Should They Be Considered High Grade?

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare tumor of soft tissue. It typically presents as a low-grade sarcoma with myxoid stroma, has a predilection for distal extremities, and displays a high propensity for local recurrence, but low metastatic potential. The risk factors associated with high-risk lesions metastasizing are poorly defined. In cases where the tumor metastasizes, therapeutic options are few, and death is rare. Our case discusses an aggressive MIFS that progressed from a painless lesion on a patient's calf, to her death from a malignant pleural effusion within 21 months. The 58-year-old woman presented with a mass on her left calf. It was excised and was originally thought to be a benign process. It re-grew quickly after the initial resection, and she underwent re-excision of the mass. The pathologic examination was consistent with an MIFS. Despite negative margins on her second resection and an attempt at local control with radiotherapy, it metastasized to her lungs within less than 2 years. This resulted in a malignant pleural effusion that caused her death. An MIFS is typically benign but can metastasize in atypical cases. Even if the disease is metastatic, it is unlikely to be the cause of death. Treatment of metastatic MIFS is poorly defined, but there are suggested therapies beyond surgical resection and radiotherapy. Successful treatment of an MIFS should include a high index of suspicion in extremity lesions, screening for metastasis, and possible targeted therapies based on tumor genomics.

Epinephrine autoinjector prescribing following anaphylaxis presentation to the emergency department.

Background: Guidelines recommend patients with anaphylaxis are prescribed epinephrine autoinjectors (EAI), carry the EAI with them, and are referred to an allergist. There also are barriers to EAI administration, such as acquiring the medication, having it available, recognizing when to use it, and administering it appropriately. Objective: The objective was to describe how often patients with anaphylaxis discharged from the emergency department (ED) receive an EAI prescription and allergist referral; also, to assess the frequency of EAI pick-up by the patient from the outpatient pharmacy, out-of-pocket cost, change in EAI device during dispensing, and if patient training on EAI use and allergist follow-up occurred. Patient-specific factors associated with the occurrence of these variables were investigated. Methods: This was a retrospective, observational study of adult and pediatric ED patients who presented with anaphylaxis between July and December 2020. Data were collected from medical records and telephone calls to outpatient pharmacies and included patient demographics; ED treatment; EAI prescribing, EAI pick-up from the outpatient pharmacy, and cost; device changes; EAI training; and allergist referral and follow-up. Data are presented descriptively, and bivariate analyses were used for comparisons between patient-specific factors and incidence of EAI prescribing, patient pick-up, and allergist referral. Results: A total of 102 patients were included; mean age ± standard deviation 34 ± 7 years, 52% were < 18 years of age; and 54% had a history of allergy and/or anaphylaxis. EAI prescribing occurred in 79% of the patients. Of these, 71% picked up the EAI from the outpatient pharmacy, the median cost to the patient was $5 (range, $0-$379), 18% had an EAI device change at dispensing, and 23% received EAI training. Allergist referral occurred in 22%, and 28% followed up with an allergist within 60 days. Presenting symptoms of mucosal edema and respiratory stridor were associated with the occurrence of EAI prescribing. Presenting symptoms of respiratory wheezing, hoarseness, throat itching, skin flushing and allergist referral from the ED were associated with the occurrence of EAI pick-up from the outpatient pharmacy. Conclusion: Overall, 79% of ED patients with anaphylaxis had an EAI prescribed and 22% had an allergist referral; 71% picked up the EAI from the outpatient pharmacy, EAI dispensing changes occurred, and training was infrequent. Collaboration between emergency medicine clinicians, allergists, and pharmacists is needed to streamline treatment and follow-up.

Antagonism between Prdm16 and Smad4 specifies the trajectory and progression of pancreatic cancer.

The transcription factor Prdm16 functions as a potent suppressor of transforming growth factor-beta (TGF-ß) signaling, whose inactivation is deemed essential to the progression of pancreatic ductal adenocarcinoma (PDAC). Using the KrasG12D-based mouse model of human PDAC, we surprisingly found that ablating Prdm16 did not block but instead accelerated PDAC formation and progression, suggesting that Prdm16 might function as a tumor suppressor in this malignancy. Subsequent genetic experiments showed that ablating Prdm16 along with Smad4 resulted in a shift from a well-differentiated and confined neoplasm to a highly aggressive and metastatic disease, which was associated with a striking deviation in the trajectory of the premalignant lesions. Mechanistically, we found that Smad4 interacted with and recruited Prdm16 to repress its own expression, therefore pinpointing a model in which Prdm16 functions downstream of Smad4 to constrain the PDAC malignant phenotype. Collectively, these findings unveil an unprecedented antagonistic interaction between the tumor suppressors Smad4 and Prdm16 that functions to restrict PDAC progression and metastasis.

Understanding API Static Drying with Hot Gas Flow: Design and Test of a Drying Rig Prototype and Drying Modeling Development.

Developing a continuous isolation process to produce a pure, dry, free-flowing active pharmaceutical ingredient (API) is the final barrier to the implementation of continuous end-to-end pharmaceutical manufacturing. Recent work has led to the development of continuous filtration and washing prototypes for pharmaceutical process development and small-scale manufacture. Here, we address the challenge of static drying of a solvent-wet crystalline API in a fixed bed to facilitate the design of a continuous filter dryer for pharmaceutical development, without excessive particle breakage or the formation of interparticle bridges leading to lump formation. We demonstrate the feasibility of drying small batches on a time scale suitable for continuous manufacturing, complemented by the development of a drying model that provides a design tool for process development. We also evaluate the impact of alternative washing and drying approaches on particle agglomeration. We conclude that our approach yields effective technology, with a performance that is amenable to predictive modeling.

Universal Mismatch Repair Protein Screening in Upper Tract Urothelial Carcinoma.

OBJECTIVES: Universal screening of upper tract urothelial carcinoma (UTUC) for Lynch syndrome by mismatch repair (MMR) protein immunohistochemistry (IHC) has been recommended by some investigators. Herein, we assess this recommendation retrospectively by simulating its performance on a retrospective, unselected cohort of UTUCs, with comparison to the established setting of colorectal and endometrial adenocarcinoma. METHODS: We assessed for complete loss of MMR protein (MLH1, MSH2, MSH6, and PMS2) IHC in 74 consecutive cases of UTUC and then tabulated clinical and pathologic factors. MMR findings from same-institution colorectal and endometrial adenocarcinomas were tabulated for comparison. RESULTS: We observed loss of at least one MMR protein in 12% in our UTUC cohort (three MSH2/MSH6, three MSH6 only, one MLH1/PMS2, and two PMS2 only). Of these nine cases (seven males, two females, median age 67 years, five associated with colorectal adenocarcinoma), at least three (4% of the overall cohort) proved to be Lynch syndrome. Overall, MMR loss in UTUC was comparable to colorectal (11%; 50 of 471 cases) and endometrial (12%; 12 of 101 cases) adenocarcinomas. CONCLUSIONS: The rate of MMR loss observed in UTUC was comparable to that in the established setting of colorectal and endometrial adenocarcinomas, supporting universal UTUC screening at our institution and others.

Peyronie disease: a clinicopathologic study of 71 cases with emphasis on histopathologic patterns and prevalent metaplastic ossification.

Peyronie disease (PD) is a benign, superficial fibromatosis involving the fascial structures of the penis, causing deformity, pain, and loss of function, for which there are few contemporary studies of the histopathology. We performed a multi-institutional review of 74 routine and consultation specimens submitted with clinical concern for PD. Of these, three non-PD lesions were identified and excluded (a myointimoma, a mammary-type myofibroblastoma, and fibrocalcific atherosclerosis). Of the 71 confirmed to be PD, the majority of patients were white (83%), with a median age of 55 years (range: 26-88). The dorsal aspect of the penis was the most common site involved (78%), followed by lateral (12%) and ventral (10%) aspects. The median degree of curvature was 70° (range: 20-360°). On review, three overall histologic patterns characterized the lesions resected: dense fibrotic plaque (61%), dense fibrotic plaque with focal or patchy metaplastic ossification (35%), and plaque composed predominantly of metaplastic ossification (4%). The fibrotic component was predominantly nodular (18%), hyalinized/lamellar (46%), or mixed (32%), excepting two cases consisting entirely of metaplastic bone. Chronic inflammation, when present, was most often focal and perivascular in distribution. In one case, an excision after collagenase treatment showed myxoid change and increased stromal cellularity. Overall, these findings define the range of PD histology, particularly emphasizing that the calcification noted clinically nearly always represents bona fide metaplastic ossification. Such context will be of value in evaluating specimens prospectively, in light of changing practices and the use of new technologies for treatment.

A Reappraisal of Superficial Pleomorphic Liposarcoma.

OBJECTIVES: Superficial pleomorphic liposarcoma (PL) has a favorable prognosis compared to deeply seated PL. Given developments in the classification of lipomatous neoplasms, we reappraised a series of cases. METHODS: Retrospective clinicopathologic evaluation and genome-wide single-nucleotide polymorphism (SNP) microarray studies were performed for cases previously designated superficial PL. RESULTS: Four cases were identified (age, 48-70 years). Two were dermally confined, whereas two were superficial subcutaneous; no recurrences or metastases were reported. Tumors demonstrated pleomorphic spindled morphology with variable cellularity. Multivacuolated atypical lipoblasts were focal in 3 and abundant in 1. Dermal tumors demonstrated atypical cells within sclerotic collagen. Genome-wide SNP microarray studies revealed consistent gains and losses, including losses at the 13q14.2 locus encompassing RB1 and DLEU2 and deletion/disruption of the TP53 locus. Although subcutaneous examples showed genomic changes similar to deep PL, the dermal examples showed fewer genetic alterations, including changes reported in the spectrum of atypical spindle cell/pleomorphic lipomatous tumors (ASPLT). All lacked MDM2 amplification. CONCLUSIONS: Careful integration of histologic and genetic features may improve classification of lipomatous neoplasms with atypia, allowing reclassification of some superficial PL as ASPLT.

Developing a Batch Isolation Procedure and Running It in an Automated Semicontinuous Unit: AWL CFD25 Case Study.

A key challenge during the transition from laboratory/small batch to continuous manufacturing is the development of a process strategy that can easily be adopted for a larger batch/continuous process. Industrial practice is to develop the isolation strategy for a new drug/process in batch using the design of experiment (DoE) approach to determine the best isolation conditions and then transfer the isolation parameters selected to a large batch equipment/continuous isolation process. This stage requires a series of extra investigations to evaluate the effect of different equipment geometry or even the adaptation of the parameters selected to a different isolation mechanism (e.g., from dead end to cross flow filtration) with a consequent increase of R&D cost and time along with an increase in material consumption. The CFD25 is an isolation device used in the first instance to develop an isolation strategy in batch (optimization mode) using a screening DoE approach and to then verify the transferability of the strategy to a semicontinuous process (production mode). A d-optimal screening DoE was used to determine the effect of varying the input slurry. Properties such as solid loading, particle size distribution, and crystallization solvent were investigated to determine their impact on the filtration and washing performance and the characteristics of the dry isolated product. A series of crystallization (ethanol, isopropanol, and 3-methylbutan-1-ol) and wash solvents (n-heptane, isopropyl acetate and n-dodcane) were used for the process. To mimic a real isolation process, paracetamol-related impurities, acetanilide and metacetamol, were dissolved in the mother liquor. The selected batch isolation strategy was used for the semicontinuous isolation run. Throughput and filtration parameters, such as cake resistance and flow rate, cake residual liquid content and composition, cake purity, particle-particle aggregation, and extent and strength of agglomerates, were measured to evaluate the consistency of the isolated product produced during a continuous experiment and compared with the isolated product properties obtained during the batch process development. Overall, the CFD25 is a versatile tool which allows both new chemical entity process development in batch and the production of the active pharmaceutical ingredient in semicontinuous mode using the same process parameters without changing equipment. The isolated product properties gained during the semicontinuous run are overall comparable between samples. The residual solvent content and composition differs between some samples due to filter plate blockage. In general, the mean properties obtained during semicontinuous running are comparable with the product properties simulated using the DoE.

New entities, new technologies, new findings: A review of the cytologic features of recently established subtypes of renal cell carcinoma.

Several new renal tumor types with distinctive pathologic, epidemiologic, and genetic signatures have recently been adopted in the fourth edition of the World Health Organization classification. In succeeding years, the cytologic features of most of these new types have been described, adding to the trend of increasing diagnostic accuracy for most common renal cell carcinoma subtypes and the important diagnostic role of cytologic sampling in the management and personalization of therapy. The current article reviews the cytologic findings from these recently established renal cell carcinoma subtypes. Emphasis is placed on cytologic diagnostic clues, confirmatory ancillary testing, salient differential diagnoses, and challenges that can be encountered in an attempt to render accurate interpretations in small samples.

Development of a Novel Continuous Filtration Unit for Pharmaceutical Process Development and Manufacturing.

The lack of a commercial laboratory, pilot and small manufacturing scale dead end continuous filtration and drying unit it is a significant gap in the development of continuous pharmaceutical manufacturing processes for new active pharmaceutical ingredients (APIs). To move small-scale pharmaceutical isolation forward from traditional batch Nutsche filtration to continuous processing a continuous filter dryer prototype unit (CFD20) was developed in collaboration with Alconbury Weston Ltd. The performance of the prototype was evaluated by comparison with manual best practice exemplified using a modified Biotage VacMaster unit to gather data and process understanding for API filtration and washing. The ultimate objective was to link the chemical and physical attributes of an API slurry with equipment and processing parameters to improve API isolation processes. Filtration performance was characterized by assessing filtrate flow rate by application of Darcy's law, the impact on product crystal size distribution and product purity were investigated using classical analytical methods. The overall performance of the 2 units was similar, showing that the prototype CFD20 can match best manual lab practice for filtration and washing while allowing continuous processing and real-time data logging. This result is encouraging and the data gathered provides further insight to inform the development of CFD20.

Mesenchymal Neoplasms of the Genitourinary System: A Selected Review with Recent Advances in Clinical, Diagnostic, and Molecular Findings.

Mesenchymal neoplasms of the genitourinary (GU) tract often pose considerable diagnostic challenges due to their wide morphologic spectrum, relative rarity, and unexpected incidence at GU sites. Soft tissue tumors arise throughout the GU tract, whether from adventitia surrounding or connective tissues within the kidneys, urinary bladder, and male and female genital organs. This selected article focuses on a subset of these lesions, ranging from benign to malignant and encompassing a range of patterns of mesenchymal differentiation, where recent scholarship has lent greater insight into their clinical, molecular, or diagnostic features.