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.

High grade infiltrative adenocarcinomas of renal cell origin: New insights into classification, morphology, and molecular pathogenesis.

Collecting duct carcinoma was described over 30 years ago as a renal tumor, based in the medullary collecting system, with tubulopapillary morphology, prominent infiltrative growth, and stromal desmoplasia. While diagnostic workup has always emphasized exclusion of upper tract urothelial carcinoma and metastatic adenocarcinoma to the kidney, the molecular era of renal cell carcinoma classification has enabled recognition of and provided tools for diagnosis of new entities in this morphologic differential. In this review, we consider these developments, with emphasis on renal medullary carcinoma, closely related renal cell carcinoma, unclassified with medullary phenotype, and fumarate hydratase-deficient renal cell carcinoma. Integration of ancillary studies with suggestive patterns of morphology is emphasized for practical implementation in contemporary diagnosis, and several emerging tumor types in the morphologic differential are presented.

Superficial malignant peripheral nerve sheath tumor with overlying intradermal melanocytic nevus mimicking spindle cell melanoma.

Malignant peripheral nerve sheath tumors are rare soft tissue sarcomas with histological and immunohistochemical similarities to spindle cell melanoma. Although spindle cell melanoma is significantly more common, both tumors may express S100 and lack staining for HMB-45, Melan-A or MITF. Here we present a case of superficial malignant peripheral nerve sheath tumor with diffuse S100 positivity arising in a subtle neurofibroma in close proximity to an intradermal melanocytic nevus. This configuration had led to prior misdiagnosis as a desmoplastic melanoma arising in the nevus and to sentinel lymph node biopsy. Identification of the background neurofibroma, as well as CD34 positivity raised consideration of a low grade malignant peripheral nerve sheath tumor, which was confirmed via observation of Schwannian differentiation on electron microscopy. The importance of distinguishing these two tumors is stressed owing to the difference in management.

CIC-DUX sarcomas demonstrate frequent MYC amplification and ETS-family transcription factor expression.

Recent molecular advances have identified a novel, clinically aggressive subgroup of undifferentiated round cell sarcomas defined molecularly by oncogenic fusion of the gene, CIC, and either DUX4 or its paralog, DUX4L, herein termed CIC-DUX sarcomas. Morphologically, CIC-DUX sarcomas are round cell sarcomas with high-grade nuclear features, including vesicular chromatin and nucleoli, patchy clear cell foci, myxoid change, and necrosis. Here, we studied a cohort of 10 cases, including 6 newly identified cases, 2 with paired metastases. Given our prior observation of trisomy 8 in these tumors, we assayed for amplification and expression of MYC (c-Myc) and representative downstream targets. Trisomy 8 was detected in 5/7 testable cases, with further amplification of MYC locus in 6/7 testable cases and immunohistochemical expression of MYC in 10/10. The canonical MYC transcriptional target, p21, but not MTDH, was differentially expressed compared with Ewing sarcomas. Given prior observation of induction of ETS-family transcription factors by the fusion oncoprotein, we assayed and identified highly prevalent positivity for ERG (9/10) and FLI1 (8/8). These findings are cautionary regarding use of these immunostains in prospective case workup, whereas the prevalent MYC amplification may represent a therapeutically targetable oncogenic pathway in CIC-DUX sarcomas.

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.

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.

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.

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.

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.

A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment.

BACKGROUND: Neoadjuvant chemotherapy before cystectomy confers a survival benefit in bladder cancer, but it has not been widely adopted since most patients do not benefit and we are at present unable to predict those that do. Since the most important predictor of recurrence after cystectomy is pathologically positive nodes, our aim was to assess techniques that define this stage for the selection of patients for neoadjuvant chemotherapy. METHODS: We developed a gene expression model (GEM) to predict the pathological node status in primary tumour tissue from three independent cohorts of patients who were clinically node negative. From a subset of transcripts detected faithfully by microarrays from both paired frozen and formalin-fixed tissues (32 pairs), we developed both the GEM and cutoffs that identified patient strata with raised risk of nodal involvement by use of two separate training cohorts (90 and 66 patients). We then assessed the GEM and cutoffs to predict node-positive disease in tissues from a phase 3 trial cohort (AUO-AB-05/95; 185 patients). FINDINGS: We developed a 20-gene GEM with an area under the curve of 0·67 (95% CI 0·60-0·75) for prediction of nodal disease at cystectomy in AUO-AB-05/95. The cutoff system identified patients with high relative risk (1·74, 95% CI 1·03-2·93) and low relative risk (0·70, 95% CI 0·51-0·96) of node-positive disease. Multivariate logistic regression showed the GEM predictor was independent of age, sex, pathological stage, and lymphovascular space invasion (coefficient 9·81, 95% CI 1·64-18·00; p=0·019). INTERPRETATION: Selecting patients for neoadjuvant chemotherapy on the basis of risk of node-positive disease has the potential to benefit high-risk patients while sparing other patients toxic effects and delay to cystectomy. FUNDING: US National Cancer Institute (R01CA143971).

Profiling bladder cancer organ site-specific metastasis identifies LAMC2 as a novel biomarker of hematogenous dissemination.

Little is known about which genes mediate metastasis in bladder cancer, which accounts for much of the mortality of this disease. We used human bladder cancer cell lines to develop models of two clinically common metastatic sites, lung and liver, and evaluated their gene expression with respect to human tumor tissues. Parental cells were injected into either the murine spleen to generate liver metastases or tail vein to generate lung metastases with sequential progeny derived by re-injection and comparisons made of their organ-specific nature by crossed-site injections. Both genomic and transcriptomic analyses of organ-selected cell lines found salient differences and shared core metastatic profiles, which were then screened against gene expression data from human tumors. The expression levels of laminin V gamma 2 (LAMC2) contained in the core metastatic signature were increased as a function of human tumor stage, and its genomic location was in an area of gain as measured by comparative genomic hybridization. Using immunohistochemistry in a human bladder cancer tissue microarray, LAMC2 expression levels were associated with tumor grade, but inversely with nodal status. In contrast, in node-negative patients, LAMC2 expression was associated with visceral metastatic recurrence. In summary, LAMC2 is a novel biomarker of bladder cancer metastasis that reflects the propensity of cells to metastasize via either lymphatic or hematogenous routes.

Depot medroxyprogesterone acetate: a risk factor for cervical stenosis after loop electrosurgical excisional procedure management of cervical intraepithelial neoplasia?

OBJECTIVES: In our anecdotal experience and sporadically in the literature, gynecologists have observed a connection between patient's use of depot medroxyprogesterone acetate (DMPA) and increased occurrence of cervical stenosis during follow-up after loop electrosurgical excisional procedure (LEEP). We decided to formally examine this association in our clinic population. MATERIALS AND METHODS: We performed a chart review, enrolling 257 patients and tabulating data on demography, use of hormonal contraceptives, characteristics of the LEEP, and presence or absence of cervical stenosis at 1- and 6-month follow-up evaluations. Univariate tests of association between the independent variables and the dependent variable of cervical stenosis were examined via the chi and Student t tests for discrete and continuous variables, respectively. To characterize the relative importance of independent variables significantly associated with cervical stenosis, logistic regression was performed. RESULTS: Of the 257 charts reviewed, 127 patients (49.4%) completed 1 and 6 months after LEEP follow-up appointments, providing adequate data for analysis. In this population, we observed 25 cases of cervical stenosis, or an overall rate of 19.7%. Of patients using DMPA at the time of LEEP or during the follow-up period, 9 (41.0%) of 22 developed stenosis, whereas of those who did not use DMPA, 16 (15.2%) of 105 developed stenosis, indicating a significant difference (odds ratio = 3.85, 95% CI = 1.41-10.50). CONCLUSIONS: In our clinic population, use of DMPA was associated with higher rates of development of cervical stenosis, calling for larger studies of the association of DMPA in this LEEP complication.

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.

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.

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.

The Ral GTPase pathway in metastatic bladder cancer: key mediator and therapeutic target.

Bladder cancer is a relatively common and strikingly costly malignancy. Here, we will focus on recent advances in our understanding of the molecular pathogenesis of metastatic bladder cancer, a stage of this disease curable in only a minority of patients. Our group has recently investigated the role of a class of small G-proteins known as the Ras-like or Ral GTPases and their role in this disease. These signaling proteins, regulated by the Ras pathway and other mechanisms, have been shown to be necessary for key cellular phenotypes associated with transformation or cancer progression in diverse cancer systems. In bladder cancer we have observed that these GTPases are overexpressed, are necessary for key phenotypes in models of bladder cancer progression, and finally, are essential for the regulation of expression of key molecules, including the prognostic marker and cell surface GPI-linked glycoprotein, CD24. These findings are reviewed here and suggest that Ral GTPases and their downstream pathways constitute key mediators of bladder cancer progression and may include targets for future therapeutic strategies.

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.

Expression of ral GTPases, their effectors, and activators in human bladder cancer.

PURPOSE: The Ral family of small G proteins has been implicated in tumorigenesis, invasion, and metastasis in in vitro and animal model systems; however, a systematic evaluation of the state of activation, mutation, or expression of these GTPases has not been reported in any tumor type. EXPERIMENTAL DESIGN: We determined the activation state of the RalA and RalB paralogs in 10 bladder cancer cell lines with varying Ras mutation status. We sequenced RalA and RalB cDNAs from 20 bladder cancer cell lines and functionally evaluated the mutations found. We determined the expression of Ral, Ral activators, and Ral effectors on the level of mRNA or protein in human bladder cancer cell lines and tissues. RESULTS: We uncovered one E97Q substitution mutation of RalA in 1 of 20 cell lines tested and higher Ral activation in cells harboring mutant HRAS. We found overexpression of mRNAs for RalA and Aurora-A, a mitotic kinase that activates RalA, in bladder cancer (both P < 0.001), and in association with tumors of higher stage and grade. RalBP1, a canonical Ral effector, mRNA and protein was overexpressed in bladder cancer (P < 0.001), whereas Filamin A was underexpressed (P = 0.004). We determined that RalA mRNA levels correlated significantly with protein levels (P < 0.001) and found protein overexpression of both GTPases in homogenized invasive cancers. Available data sets suggest that RalA mRNA is also overexpressed in seminoma, glioblastoma, and carcinomas of the liver, pancreas, and prostate. CONCLUSION: These findings of activation and differential expression of RalA and RalB anchor prior work in model systems to human disease and suggest therapeutic strategies targeting both GTPases in this pathway may be beneficial.