EUS-FNA diagnosis of pancreatic tophaceous gout: Two rare cases.

We report two patients with pancreatic tophaceous gout diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of presumed cystic mass lesions. The first case involved a patient who had a recent episode of acute pancreatitis 6 months prior, with subsequent imaging concerning for a pseudocyst or mass lesion. The second case involved a patient with epigastric pain associated with a pancreatic head cystic mass and an erroneous original diagnosis of a mucinous pancreatic neoplasm on EUS-FNA. Diff-Quik stained direct smears on fresh material obtained from EUS-FNA of the lesions showed chalky debris with needle shaped negatively birefringent crystals consistent with gout. For the first case, the chalky material was not present on the H&E stained paraffin embedded formalin fixed cellblock slides. The importance of inclusion of cytologic specimen preparations to examine monosodium urate crystals is emphasized.

Morphologic and Molecular Heterogeneity of High-grade Serous Carcinoma Precursor Lesions.

Serous tubal intraepithelial carcinoma (STIC) is the fallopian tube precursor lesion for most cases of pelvic high-grade serous carcinoma (HGSC). To date, the morphologic, molecular, and clinical heterogeneity of STIC and a less atypical putative precursor lesion, termed serous tubal intraepithelial lesion, has not been well characterized. Better understanding of precursor heterogeneity could impact the clinical management of women with incidental STICs (without concurrent carcinoma) identified in cases of prophylactic or opportunistic salpingectomy. This study analyzed morphologic and molecular features of 171 STICs and 21 serous tubal intraepithelial lesions. We assessed their histologic features, Ki-67 and p53 staining patterns, and genome-wide DNA copy number alterations. We classified all precursor lesions into 2 morphologic subtypes, one with a flat surface (Flat) and the other characterized by budding, loosely adherent, or detached (BLAD) morphology. On the basis of pathology review by a panel of 8 gynecologic pathologists, we found 87 BLAD, 96 Flat, and 9 indeterminate lesions. As compared with Flat lesions, BLAD lesions were more frequently diagnostic of STIC ( P <0.0001) and were found concurrently with HGSC ( P <0.0001). BLAD morphology was also characterized by higher Ki-67 proliferation index ( P <0.0001), presence of epithelial stratification ( P <0.0001), and increased lymphocyte density ( P <0.0001). BLAD lesions also exhibited more frequent DNA copy number gain/amplification at the CCNE1 or CMYC loci canonical to HGSCs ( P <0.0001). Both BLAD morphology and STIC diagnoses are independent risk factors for an elevated Ki-67 proliferation index. No correlation was observed between BLAD and Flat lesions with respect to patient age, presence of germline BRCA1/2 mutation, or p53 staining pattern. These findings suggest that tubal precursor lesions are morphologically and molecularly heterogeneous, laying the foundation for further studies on the pathogenesis of HGSC initiation and identifying histologic features predictive of poor patient outcomes.

Aneuploidy Landscape in Precursors of Ovarian Cancer.

PURPOSE: Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression. EXPERIMENTAL DESIGN: We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC (cases, n = 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n = 65). On the basis of a discovery set (n = 67), we developed an aneuploidy-based algorithm, REAL-FAST (Repetitive Element AneupLoidy Sequencing Fallopian Tube Aneuploidy in STIC), to correlate the molecular data with pathology diagnoses. We validated the result in an independent validation set (n = 83) to determine its performance. We correlated the molecularly defined precursor subgroups with proliferative activity and histology. RESULTS: We found that nearly all p53 signatures lost the entire Chr17, offering a "two-hit" mechanism involving both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12 (CCNE1), 19q13.2, 8q24 (MYC), or 8q arm, whereas proliferatively dormant STICs show 22q loss. REAL-FAST classified HU-FTE and STICs into 5 clusters and identified a STIC subgroup harboring unique aneuploidy that is associated with increased proliferation and discohesive growth. On the basis of a validation set, REAL-FAST showed 95.8% sensitivity and 97.1% specificity in detecting STIC/HGSC. CONCLUSIONS: Morphologically similar STICs are molecularly distinct. The REAL-FAST assay identifies a potentially "aggressive" STIC subgroup harboring unique DNA aneuploidy that is associated with increased cellular proliferation and discohesive growth. REAL-FAST offers a highly reproducible adjunct technique to assist the diagnosis of STIC lesions.

Mimickers of neuroendocrine tumors on endoscopic ultrasound-guided fine-needle aspirate material: Need for caution.

Cytologic diagnosis of neuroendocrine tumors can be straightforward on cytologic preparations, given the classical neuroendocrine morphology and expression of neuroendocrine markers confirmed by immunohistochemistry. However, overreliance on neuroendocrine markers can lead to misdiagnosis even if individual cell features suggest a neuroendocrine tumor. We present three unusual cases, two of which were initially diagnosed as neuroendocrine tumors and the third one carried preliminary diagnosis of neuroendocrine tumor on endoscopic ultrasound-guided fine-needle aspirates. These cases subsequently turned out to be cholangioblastic cholangiocarcinoma, metastatic melanoma, and gastric glomus tumor, respectively. We suggest approaches that could have pointed us towards the correct diagnosis at the outset and discuss potential pitfalls.

Spatial Transcriptomic Analysis of Ovarian Cancer Precursors Reveals Reactivation of IGFBP2 during Pathogenesis.

Elucidating the earliest pathogenic steps in cancer development is fundamental to improving its early detection and prevention. Ovarian high-grade serous carcinoma (HGSC), a highly aggressive cancer, mostly originates from the fallopian tube epithelium through a precursor stage, serous tubal intraepithelial carcinoma (STIC). In this study, we performed spatial transcriptomic analysis to compare STICs, carcinoma, and their matched normal fallopian tube epithelium. Several differentially expressed genes in STICs and carcinomas were involved in cancer metabolism and detected in a larger independent transcriptomic dataset of ovarian HGSCs. Among these, insulin-like growth factor binding protein-2 (IGFBP2) was found to undergo DNA hypomethylation and to be increased at the protein level in STICs. Pyrosequencing revealed an association of IGFBP2 expression with the methylation state of its proximal enhancer, and 5-azacytidine treatment increased IGFBP2 expression. In postmenopausal fallopian tubes, where most STICs are detected, IGFBP2 immunoreactivity was detected in all 38 proliferatively active STICs but was undetectable in morphologically normal tubal epithelia, including those with TP53 mutations. In premenopausal fallopian tubes, IGFBP2 expression was limited to the secretory epithelium at the proliferative phase, and estradiol treatment increased IGFBP2 expression levels. IGFBP2 knockdown suppressed the growth of IGFBP2-expressing tubal epithelial cells via inactivation of the AKT pathway. Taken together, demethylation of the proximal enhancer of IGFBP2 drives tumor development by maintaining the increased IGFBP2 required for proliferation in an otherwise estrogen-deprived, proliferation-quiescent, and postmenopausal tubal microenvironment. SIGNIFICANCE: Molecular studies of the earliest precursor lesions of ovarian cancer reveal a role of IGFBP2 in propelling tumor initiation, providing new insights into ovarian cancer development.

Pleural fluid metastasis of plasmacytoid urothelial carcinoma in comparison to micropapillary and conventional high-grade urothelial carcinoma: Cytologic and immuonohistochemical findings.

Plasmacytoid urothelial carcinoma (PUC) is a rare but clinically aggressive variant of high-grade urothelial carcinoma (HGUC). Cytological features include single plasmacytoid neoplastic cells with N:C ratio around 0.5, eccentric nuclei, nuclear hyperchromasia, irregular nuclear membrane, and vacuolated cytoplasm. Micropapillary urothelial carcinoma (MPUC) is another clinically aggressive variant of HGUC that shares some overlapping features of PUC. The diagnosis of these two aggressive variants in pleural effusions can be challenging due to features mimicking adenocarcinoma, unusual immunochemistry profile, and confusion with differential diagnoses, especially when pertinent clinical information is unavailable. We present report on one case each of pleural fluid metastasis of PUC and MPUC respectively, and compare the findings with that of a metastatic conventional HGUC originally thought to be metastatic adenocarcinoma. The diagnosis of PUC was confirmed with immunohistochemical studies showing expression for cytokeratin, GATA-3, uroplakin II, and CD138, diminished or loss of E-cadherin membranous expression, negative expression for p63, p53, Epicam-BerEP4, Epicam-MOC31, and p120. The diagnosis of MPUC was confirmed with immunostain profile similar to that of PUC except positive stain for E-cadherin, p120, and p53. The diagnosis of HGUC was confirmed with immunohistochemical studies showing expression for cytokeratin, GATA-3, uroplakin II, p63, Epicam-BerEP4 (focal weak), and Epicam-MOC31. Our cases of metastatic urothelial carcinoma showed features mimicking adenocarcinoma and others, especially the MPUC and HGUC were diagnosed without prior tissue diagnosis of urothelial carcinoma. This report emphasizes the cytohistological and immunohistochemical details of urothelial carcinoma involving effusion fluid and discusses potential pitfalls in diagnosis.

Cytological Diagnosis of Pancreatic Solid-Pseudopapillary Neoplasm: A Single-Institution Community Practice Experience.

INTRODUCTION: Pancreatic solid-pseudopapillary neoplasm (SPN) is a rare tumor that typically occurs in young females. Although a cytological diagnosis may be easily made in this age group when there are typical features, atypical clinical presentations and unusual cytological features may make this a challenging diagnosis. We present our single-institution experience in a cohort of these tumors, outlining both typical and atypical features. Awareness of unusual clinical and cytological features can help to avoid pitfalls during diagnosis. METHODS: We performed a review of all cases of pancreatic SPNs diagnosed over a 15-year period (January 2007 to December 2021). Detailed cytological, clinical, and follow-up histological features were presented and analyzed. RESULTS: Twenty-two cases of SPN were diagnosed at our institution during this 15-year period. Patients ranged from 12 to 73 years of age (mean 33 y, median 26 y) and included 19 females and 3 males. Seventeen patients had cytological material, and fourteen were diagnosed by EUS-FNA. Typical cytological features included papillary clusters with central capillaries, myxoid stroma, monomorphism, cercariform cells, and hyaline globules. Atypical or unusual cytological features that were seen in a few cases were multinucleated giant cells, clear cells, and/or foamy macrophages. A few cases showed features that were similar to pancreatic neuroendocrine tumors (PanNETs). Tumor cells were always positive for ß-catenin, CD10, CD56, cyclin-D1, progesterone receptor (PR), and vimentin by immunohistochemistry. They were always negative for chromogranin. Pancytokeratin and synaptophysin stains were positive in 9% and 46% of cases evaluated, respectively. All cases had histological confirmation on resection. The median follow-up duration was 69 months (a range of 2-177 months), with only three cases lost to follow-up. No recurrence or metastasis was identified. CONCLUSIONS: We present our experience with cytological diagnoses of SPN in a well-characterized cohort of 22 patients with histological correlation and follow-up data. These tumors occur over a wide range and show varied cytological features. SPNs can be confidently diagnosed on limited cytological material, with limited panel immunohistochemistry aiding diagnosis in atypical cases. Recognizing the associated degenerative changes is crucial in avoiding a misdiagnosis.

Corpora amylacea in pleural effusion.

Corpora amylacea are predominantly found in the brain, prostate, and lung. Recent characterizations of their components suggest an important role in protection and clearing. We report the presence of corpora amylacea in pleural effusion in a patient with lupus. The differential diagnoses and potential significance are discussed.

Cytohistopathologic correlation of ovarian mesonephric-like carcinoma and female adnexal tumor of probable Wolffian origin.

Recently we encountered two cases with mesonephric features, mesonephric-like carcinoma (MLC) of the ovary, and female adnexal tumor of probable Wolffian origin (FATWO). They are thought to be related to mesonephric remnants (or Wolffian duct remnants). Herein we describe the cytohistolgical features, differential diagnoses, and potential pitfalls in diagnosis of these neoplasms. On cytological examination, the case of MLC showed tight 3-dimensional clusters of overlapping round cells, corresponding to solid growth pattern seen on histological examination. Tubular architecture and papillary formations composed of neoplastic cells of medium size with scant cytoplasm were readily identified. Intraluminal eosinophilic secretions were better seen on histological examination. Additionally, areas resembling features of papillary thyroid carcinoma were noted. Mitoses and apoptotic bodies were not identified on cytology but seen on histological sections. The neoplastic cells were positive for CK7, CD10, PAX-8, TTF-1, and GATA-3, and negative for ER, PR, and WT-1 immunostains. In contrast to MLC, cytological examination of FATWO showed smaller oval to spindle monotonous cells without mitotic figures. Some cells contained paranuclear vacuoles and were arranged individually or in loose cohesive clusters. Other cells were closely associated with pericellular hyalinized basement membrane-like material and they were arranged in cohesive clusters as well. On histological examination, similar to MLC, the FATWO had areas with thyroid-like features, such as, intraluminal eosinophilic secretions, paranuclear vacuoles, in the background of collagenous stroma. The neoplastic cells were positive for CK AE1/AE3, calretinin, WT-1, inhibin, and CD10, and negative for CK7, PAX-8, GATA-3, ER, PR, and C-kit immunostains.

Ultrasound-guided fine-needle aspiration of a rectal submucosal nodule.

Although endoscopic biopsy of a rectal submucosal nodule may be nondiagnostic, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) can be an important tool to make diagnosis. We report a case of a female patient who had an EUS-FNA of a submucosal nodule after a nondiagnostic rectal biopsy. The original diagnosis was erroneously rendered as concerning for necrotic neoplasm. The correct diagnosis of Solesta-induced foreign body reaction was made on reviewing the slides once the history of remote Solesta injection was made available. This case illustrates the pathognomonic features of Solesta-induced rectal nodule and underscores the importance of detailed history as well as inclusion of iatrogenic diseases in the differential to prevent erroneous diagnosis and management. Potential pitfalls in cytopathological diagnosis are discussed.

Unusual trifecta of infections, aspiration, and metastatic prostatic adenocarcinoma in a bronchoalveolar lavage specimen.

Bronchoalveolar lavage (BAL) is a useful procedure to evaluate lung infiltrates in order to identify infection, foreign body aspiration, and neoplasms. However, it is indeed unusual to find all three in the same sample. We report such a case in a 68-year-old male with a history of metastatic prostate adenocarcinoma and longstanding chronic obstructive pulmonary disease who presented with features of pneumonia. BAL revealed Aspergillus and parainfluenza infections, food particle aspiration pneumonia, as well as metastatic prostatic adenocarcinoma. The food particles were initially confused for yeast infection, but we finally identified them as nut products. This may be the first documented case of nut product aspiration diagnosed on BAL. The potential pitfalls that may complicate the evaluation are also discussed.

Genomic landscape and evolutionary trajectories of ovarian cancer precursor lesions.

The clonal relationship between ovarian high-grade serous carcinoma (HGSC) and its presumed precursor lesion, serous tubal intraepithelial carcinoma (STIC), has been reported. However, when analyzing patients with concurrent ovarian carcinoma and tubal lesion, the extensive carcinoma tissues present at diagnosis may have effaced the natural habitat of precursor clone(s), obscuring tumor clonal evolutionary history, or may have disseminated to anatomically adjacent fimbriae ends, masquerading as precursor lesions. To circumvent these limitations, we analyzed the genomic landscape of incidental tubal precursor lesions including p53 signature, dormant STIC or serous tubal intraepithelial lesion (STIL) and proliferative STIC in women without ovarian carcinoma or any cancer diagnosis using whole-exome sequencing and amplicon sequencing. In three of the four cancer-free women with multiple discrete tubal lesions we observed non-identical TP53 mutations between precursor lesions from the same individual. In one of the four women with co-existing ovarian HGSC and tubal precursor lesion we found non-identical TP53 mutations and a lack of common mutations shared between her precursor lesion and carcinoma. Analyzing the evolutionary history of multiple tubal lesions in the same four patients with concurrent ovarian carcinoma indicated distinct evolution trajectories. Collectively, the results support diverse clonal origins of tubal precursor lesions at the very early stages of tumorigenesis. Mathematical modeling based on lesion-specific proliferation rates indicated that p53 signature and dormant STIC may take a prolonged time (two decades or more) to develop into STIC, whereas STIC may progress to carcinoma in a much shorter time (6 years). The above findings may have implications for future research aimed at prevention and early detection of ovarian cancer. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Follicular dendritic cell sarcoma of the porta hepatis.

Follicular dendritic cell (FDC) sarcoma is a very rare neoplasm which commonly involves the lymph nodes and less commonly involves extranodal organs such as the liver. Most cases of FDC sarcoma are idiopathic, however some cases are associated with other disease states. Management of FDC sarcoma is primarily focused on surgical resection of the mass, and secondarily focused on radiotherapy, chemotherapy and/or biologic pharmacotherapy. We report the case of a patient who was found to have FDC sarcoma presenting as an obstructing mass of the porta hepatis, a manifestation which does not appear to be reported in the literature.

Does on-site adequacy evaluation reduce the nondiagnostic rate in endoscopic ultrasound-guided fine-needle aspiration of pancreatic lesions?

BACKGROUND: This retrospective study compared the nondiagnostic rate for endoscopic ultrasound-guided (EUS) fine-needle aspiration (FNA) of pancreatic lesions in 2 settings: 1 with and 1 without on-site evaluation. METHODS: The authors reviewed 381 consecutive cases and divided them into groups with and without on-site adequacy evaluation. For the group with on-site evaluation, cytopathology personnel prepared and evaluated Diff-Quik-stained direct smears and rinsed the remaining material in CytoLyt solution (Cytyc Corporation, Marlborough, Mass). The group without on-site evaluation was divided into 2 subgroups: the clinical team either prepared an air-dried smear for each FNA pass and then rinsed the remaining material in CytoLyt, or the entire sample was rinsed in CytoLyt. The cytologic diagnoses were reviewed and the nondiagnostic rates for each group were calculated. RESULTS: On-site evaluation was provided for 167 cases with a nondiagnostic rate of 25.8% (43 of 167 cases). On-site evaluation was not provided for 214 cases with a nondiagnostic rate of 24.3% (52 of 214 cases). The nondiagnostic rate for the subgroup with air-dried smears prepared by the clinical team was 25.6% (43 of 168 cases) and that for the subgroup with the entire sample rinsed in CytoLyt was 19.6% (9 of 46 cases). There were no significant statistical differences in nondiagnostic rates noted among the different groups or subgroups. CONCLUSIONS: The results of the current study indicate that when experienced operators perform EUS FNA of pancreatic lesions, on-site adequacy evaluation offers no benefit in reducing the nondiagnostic rate. Optimizing visualization of the sampled material by omitting the preparation of direct smears and rinsing the entire sample in liquid-based media demonstrated a trend toward improving the diagnostic rate.

Upstaging pathologic stage I ovarian carcinoma based on dense adhesions is not warranted: a clinicopathologic study of 84 patients originally classified as FIGO stage II.

BACKGROUND: FIGO stage II ovarian cancer comprises 8% of ovarian cancers. It is a common but not universal practice to upstage densely adherent pathologic stage I tumors to stage II. FIGO guidelines are not clear, and data supporting this practice are sparse. METHODS: We retrospectively reviewed patients with stage II ovarian cancer and grouped them based upon histologic evidence of extraovarian extension. Tumors densely adherent to extraovarian structures but without histologic tumor outside the ovary were considered pathologic stage I. All others were considered surgical-pathologic stage II. Three histologic patterns of extraovarian tumor involvement were identified. RESULTS: Eighty-four patients were studied. Twenty-four patients had pathologic stage I disease and 60 had histologic evidence of extraovarian pelvic spread and were surgical-pathologic stage II. The 5-year survival for stage I was 100%, and the median survival was not reached. The 5-year survival for those with surgical-pathologic stage II disease was 56.8% and the median survival was 73 months. There were no differences observed based upon pattern of extraovarian spread. The survival difference between pathologic stage I and surgical-pathologic stage II was significant (p<0.001). There were no differences seen in 5-year survival among surgical-pathologic stage II patients with serous, endometrioid or clear cell histologies (64.5%, 64.8% and 64.3% respectively). CONCLUSION: These retrospective data suggest that the practice of upstaging densely adherent pathologic stage I tumors to stage II may not be warranted. Cell type is not a prognostic factor in stage II.

Evaluation of normal-sized ovaries associated with primary peritoneal serous carcinoma for possible precursors of ovarian serous carcinoma.

OBJECTIVE: Three groups of "high-risk" ovaries have previously been studied for possible precursors of ovarian carcinoma: ovaries removed prophylactically from women at high risk, normal ovaries contralateral to a unilateral ovarian carcinoma, and normal ovarian tissue found adjacent to primary ovarian carcinomas. No data are available for a fourth high-risk group: normal-sized ovaries from women with primary peritoneal serous carcinoma. METHODS: Grossly normal-sized ovaries from 26 patients with primary peritoneal serous carcinoma were compared to normal-sized ovaries from 75 controls. Controls were divided at the median age for age matching. Cortical inclusions, surface epithelial invaginations (clefts), surface papillary proliferation, and calcifications were examined. RESULTS: Case versus control comparisons showed, respectively, inclusions in 92% and 68% of patients, clefts in 54% and 59%, and papillomatosis in 35% and 16%. For each profile of ovary on one section, cases versus controls, respectively, had a mean number of inclusions of 5.55 and 3.97, size of the largest inclusion of 1.28 and 1.27 mm, and depth of the deepest cleft of 1.04 and 0.9 mm. After controlling for age, correcting for multiple comparisons and using two-sided chi square, there were no significant differences between cases and controls in all the parameters measured. In comparing the two control groups, the only significant finding was that the young group displayed deeper clefts than the older group (2.06 versus 0.9 mm, respectively). CONCLUSION: Grossly normal-sized ovaries from women with primary peritoneal serous carcinoma display no significant differences in inclusions, clefts, papillomatosis, and calcifications in comparison to age-matched controls.

Elementary steps of the cross-bridge cycle in fast-twitch fiber types from rabbit skeletal muscles.

To understand the molecular mechanism underlying the diversity of mammalian skeletal muscle fibers, the elementary steps of the cross-bridge cycle were investigated in three fast-twitch fiber types from rabbit limb muscles. Skinned fibers were maximally Ca(2+)-activated at 20 degrees C and the effects of MgATP, phosphate (P, P(i)), and MgADP were studied on three exponential processes by sinusoidal analysis. The fiber types (IIA, IID, and IIB) were determined by analyzing the myosin heavy-chain isoforms after mechanical experiments using high-resolution SDS-PAGE. The results were consistent with the following cross-bridge scheme: where A is actin, M is myosin, D is MgADP, and S is MgATP. All states except for those in brackets are strongly bound states. All rate constants of elementary steps (k(2), 198-526 s(-1); k(-2), 51-328 s(-1); k(4), 13.6-143 s(-1); k(-4), 13.6-81 s(-1)) were progressively larger in the order of type IIA, type IID, and type IIB fibers. The rate constants of a transition from a weakly bound state to a strongly bound state (k(-2), k(4)) varied more among fiber types than their reversals (k(2), k(-4)). The equilibrium constants K(1) (MgATP affinity) and K(2) (=k(2)/k(-2), ATP isomerization) were progressively less in the order IIA, IID, and IIB. K(4) (=k(4)/k(-4), force generation) and K(5) (P(i) affinity) were larger in IIB than IIA and IID fibers. K(1) showed the largest variation indicating that the myosin head binds MgATP more tightly in the order IIA (8.7 mM(-1)), IID (4.9 mM(-1)), and IIB (0.84 mM(-1)). Similarly, the MgADP affinity (K(0)) was larger in type IID fibers than in type IIB fibers.