Psammomatous Calcifications Research Articles

Calcifying Nested Stromal-Epithelial Tumor of the Liver: A Rare Find

Abstract Introduction/Objective Calcifying Nested Stromal-Epithelial Tumor (CNSET) is a rare tumor of the liver with less than 40 cases described in the literature. It is a low-grade tumor characterized by a distinctive nested architecture surrounded by a cellular myofibroblastic stroma and psammomatous calcifications. CTNNB1 gene deletions have been identified in several cases. CNSET typically arises in the right lobe and there is a female predominance with a predilection for children, adolescents, and young adults. Methods/Case Report We report an interesting case of CNSET in a 13-year-old male with no pertinent medical history who presented with a one-month history of fatigue, paleness, and liver mass on physical examination. MRI abdomen showed a 9.8 cm heterogenous mass with a central scar involving the right lobe of the liver, radiologically favored to be fibrolamellar hepatocellular carcinoma. AFP levels were normal. The patient underwent a partial hepatectomy. On gross examination, the specimen showed a yellow, circumscribed, firm mass. H&E slides showed scattered round to oval nests of bland spindle and epithelioid cells arranged in short fascicles at the periphery of nests. Collagenous stroma surrounding the nests showed spindle cells with tapered nuclei and pinpoint nucleolus. Areas with calcification and osseous metaplasia were also present. Immunohistochemistry performed showed the tumor cells to be positive for pan-cytokeratin (weak), WT-1, and vimentin, and negative for Hepar-1, arginase-1, synaptophysin, chromogranin, S100, NUT-1, myogenin, and desmin. Beta-catenin showed nuclear and cytoplasmic staining pattern. INI-1 was retained within the tumor cells and Ki-67 showed a proliferative index of approximately 10-20%. On MSK-Impact (next- generation sequencing), a mutation in CTNNB1 was detected. Archer FusionPlex was negative for gene fusions within the tumor. Results (if a Case Study enter NA) NA Conclusion It is crucial to become familiar with this rare entity and to avoid mistaking it for hepatoblastoma. CNSET exhibits a biphasic morphology characterized by a nested architecture featuring bland and uniform epithelioid and spindle cells, surrounded by a cellular myofibroblastic stroma. Confirming the diagnosis can be aided by nuclear β- catenin and the expression of WT1.

Liesegang rings in kidney diseases- A Systematic Review.

Liesegang rings (LR) are concentric acellular lamellar structures, usually found in cystic and inflammatory tissues but can also be seen in neoplastic conditions. They have been mistakenly interpreted as various structures like psammomatous calcification, parasites, and algae. This study has aimed to systematically review and summarize the existence of LRs in both non-neoplastic and neoplastic conditions of the kidney. The systematic search in PUBMED, PUBMED CENTRAL, and EMBASE databases along with Google Scholar was performed by using Kidney, Liesegang Rings, or Liesegang structure or pseudo parasitic structure in combination with the Boolean operators ''and'' as searching terms. Data were collected for demographic characteristics and histopathology diagnosis. The search function was limited to human subjects. Two reviewers independently performed the eligibility assessment and data extraction. Eligibility inclusion criteria were all publications in the English literature worldwide related to Liesegang rings in association with kidney's non-neoplastic and neoplastic conditions, regardless of the years of publication. Also included were those cases whose full articles were unavailable, but the abstract was well-described, fulfilling our inclusive criteria. Eligibility exclusion criteria included LRs found elsewhere in the body organs apart from the kidney and availability of full text in a different language, non-human, and duplicate article/case. After the exclusion of the articles as per the exclusion criteria, the total articles that fulfilled the inclusive criteria were reviewed. In addition, all the articles were further cross-referenced for additional articles. All published papers retrieved from this search were considered for this review. A total of 22 records (26 cases) were found with a diagnosis of LRs in the kidney to date. Some articles were published as case series. Accordingly, 26 patients were reported to have Liesegang rings associated with kidney neoplastic and non-neoplastic conditions, 12 were male and 14 were female. For one case the gender was not mentioned. LRs presented a higher frequency in individuals between the 4th and 5th decades of life. No single case was reported in infants and younger children. Regarding predisposing factors for LRs, cystic fluid contents were the most common underlying condition. In our practice, we encountered an unusual case of a 55-year-old female with a complaint of pain in the left upper quadrant of the abdomen. The ultrasound revealed nephrolithiasis and chronic kidney disease for which a nephrectomy was performed. On the histopathological examination, there was an incidental finding of Liesegang rings and a papillary adenoma along with features of chronic pyelonephritis. Our review will provide insight into LRs in different spectrums of kidney diseases. This study represents the first available systematic review of the literature demonstrating LRs in the kidney. Although Liesegang rings have no great clinical significance, nonetheless, their presence in both tissue and cytological specimens should be kept in mind while dealing with different lesions of the kidney as they are good mimickers of many organic and inorganic substances, parasites, and malignancies.

Abstract PR001: Development and characterization of novel pre-clinical models of SFPQ-TFE3-driven renal cell carcinoma

Abstract Translocation Renal Cell Carcinomas (tRCC) are characterized by gene fusions that drive expression of chimeric TFE3 (Xp11.2) or TFEB (6p21.2). We developed and characterized a mouse model and inducible cell line expressing the SFPQ-TFE3 gene fusion to aid in biomarker and therapy development for this tumor type. We generated a murine knock-in model at the Rosa26 locus expressing the human SFPQ (exons 1-9) -TFE3 (exons 5-10) fusion gene downstream of a lox-stop-lox (LSL) sequence, under control of a chicken beta-actin promoter, on the C57BL/6 background. We crossed these LSL-SFPQ-TFE3 mice with the Cdh16-Cre model to induce SFPQ-TFE3 expression in renal epithelial cells. As an in vitro companion model, we generated HEK293 cells with stable doxycycline-inducible expression of the identical SFPQ-TFE3 fusion using the Flp-In T-RExTM system (SFPQ-TFE3-HEK293).Cdh16-Cre;LSL-SFPQ-TFE3 mice had reduced survival compared to the wild-type mice (p<0.0001) and none survived past P19. At P1, Cdh16-Cre;LSL-SFPQ-TFE3 mice had scattered mild tubular dilation, with strong nuclear TFE3 protein expression in distal tubules and collecting ducts that was absent in controls. By P15, Cdh16-Cre;LSL-SFPQ-TFE3 kidneys were 30% larger than wild-type mice (p<0.0001), with diffuse and strong nuclear expression of TFE3 throughout the majority of renal tubules. At this timepoint, Cdh16-Cre;LSL-SFPQ-TFE3 kidneys had prominent intratubular proliferation of renal epithelial cells, occasionally occluding the lumen, with diffuse psammomatous intraluminal calcification and mild patchy tubular dilatation. Glomerular morphology and size were not significantly different between the two groups at P15. However, the Cdh16-Cre;LSL-SFPQ-TFE3 mice had a lower density of glomeruli compared to the wild-type controls (5 glomeruli/mm² vs 50 glomeruli/mm²; p=0.03), potentially reflecting tubular expansion or aberrant glomerulogenesis. Wild-type and Cdh16-Cre;LSL-SFPQ-TFE3 mice exhibited similar tubular proliferative rate at P1 as assessed by Ki67. By P7, Cdh16-Cre;LSL-SFPQ-TFE3 mice showed significantly higher expression of Ki67 (p=0.03) but by P15, Ki67 index was lower (p=0.004) in the Cdh16-Cre;LSL-SFPQ-TFE3 mice compared to controls. Interestingly, by 48 hours after doxycycline induction, SFPQ-TFE3-HEK293 cells showed significantly decreased proliferation by MTT assay compared to the same cells without doxycycline treatment or to the parental Flp-In line treated with doxycycline (p=0.0002). A novel transgenic model for SFPQ-TFE3-driven tRCC shows early postnatal lethality, likely due to renal failure, precluding aging of these mice for tumor development. Though tubular proliferation is initially increased with SFPQ-TFE3 expression, Ki-67 expression is reduced by P15, paralleling the reduction in growth seen in inducible SFPQ-TFE3-HEK293 cells. These data suggest that SFPQ-TFE3 expression may paradoxically result in oncogene-induced senescence or cell cycle arrest in renal cells and further studies are underway to test this hypothesis. Citation Format: Adrianna Amaral de Aragao Mendes, Hans Liu, Juhyung Woo, Kaushal Asrani, Avi Rosenberg, Pedram Argani, Tamara Lotan. Development and characterization of novel pre-clinical models of SFPQ-TFE3-driven renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR001.

Posterior cervical congenital dermal sinus tract: case report and review of literature

Background and importanceCongenital dermal sinus tract (DST) is a rare spinal dysraphism characterized by a persistent tract lined by epithelial cells, beginning at the epidermis and terminating in deeper tissue layers. With 1% of all congenital DST cases found in the cervical region, only 4% of all cases are diagnosed after the age of 20.Clinical presentationIn this case, a 65-year-old woman with a congenital DST at the cervical level presented with symptoms of neck and some arm pain, suboccipital headaches, and unique external characteristics. Neck Disability Index and visual analog scale were used to assess the patient’s preoperative and postoperative pain, and quality of life. Patient underwent an operative intervention, where the DST was surgically removed followed by interlaminar decompression at C1–C2, excision of the epidural component, and biopsy followed by plastic surgical repair. Pathology analysis indicated a squamous epithelial-lined sinus tract interacting with the dura. Most notably, a meningothelial proliferation with associated psammomatous calcifications was identified, similar to a meningioma.ConclusionA review of literature was conducted to further discuss clinical and radiological presentation as well as to document the novel appearance of this congenital DST. As one of the oldest cases of DST, it demonstrated unusual pathological characteristics with a meningothelial proliferation, compatible with meningioma, reported at the epidural level.

Exploration of clinicopathological features of rearranged renal cell carcinoma and TFE3, TFEB, and ALK staining performance in renal entities

Rearranged renal cell carcinomas (RCC) are rare types of kidney cancer. The clinicopathological features of rearranged RCC require further validation. The pathological diagnosis usually depends on immunohistochemistry and molecular analysis. This study aimed to explore the expression features of anti-TFE3, TFEB, and ALK in different renal entities. In addition, we collected thirty-six TFE3-rearranged RCC, two TFEB-altered RCC, and one ALK-rearranged RCC to explore their clinicopathological features. We observed that TFE3 can sometimes be weakly expressed in non-TFE3-rearranged RCC. TFE3-rearranged RCC usually exhibited strong TFE3 expression. However, clear cell RCC and FH-deficient RCC also displayed strong TFE3 expression. TFEB also can be weakly expressed in clear cell RCC. However, ALK IHC showed a relatively high specificity and was negative for all non-ALK-rearranged RCC. The ALK-rearranged RCC was analyzed using next generation sequencing to explore gene alterations, and we identified a novel gene partner, SLIT1. ALK-rearranged RCC appears to have eosinophilic cytoplasm. Tumor cells with clear cytoplasm may exclude this diagnosis. Psammomatous bodies (22/38) and pattern multiplicity (35/38) were observed in more than half of the patients. In conclusion, weak TFE3 expression did not indicate TFE3 rearrangement. Strong TFE3 expression had a higher value for indicating TFE3-rearranged RCC, although other entities can also exhibit a strong pattern. Young age combined with morphological features (psammomatous calcification and pattern multiplicity) may indicate the diagnosis of rearranged RCC.

Cystic MED15::TFE3 translocation renal cell carcinoma: histologic mimicker of multilocular cystic renal neoplasm of low malignant potential with review of the literature

Presented are four cystic renal masses which harbored a MED15::TFE3 gene fusion detected by RNAseq, mimicking multilocular cystic neoplasm of low malignant potential. Clinicopathologic and outcomes data were collected for all cases. Radiologically, three cases were diagnosed as complex cystic masses and one case as a renal cyst, three years prior to surgery. The tumors ranged in size from 1.8 to 14.5cm. Grossly, all masses were extensively cystic. Microscopically, cells with a clear or minimally granular cytoplasm and nuclei with inconspicuous nucleoli lined the cysts' septa. Focally, small mass-forming aggregates of malignant cells were present between septae and were associated with psammomatous calcifications. In case one, apparent prior cyst wall rupture was associated with reactive changes and cystic spaces filled with fibrin clots. Two of the tumors were staged as T1a, one as T1b, and the other as T2b. By immunohistochemistry, the tumors were positive for TFE3, MelanA, and P504S, with apical CD10 while CAIX and CK7 were negative. RNA sequencing was performed on all cases revealing a MED15::TFE3 gene fusion. The patients were alive and without evidence of disease 11-49 months (mean 29.5) after partial nephrectomy. To date, 12 of the 15 MED15::TFE3 fusion renal cell carcinomas published in the literature are cystic, with three being extensively cystic. Thus, if a multilocular cystic renal neoplasm is encountered in a kidney specimen, translocation renal cell carcinoma should be included in the differential diagnosis as cystic MED15::TFE3 tRCCs carry an uncertain prognosis making recognition for future characterization necessary.

Highly Recurrent IDH1 Mutations in Prostate Cancer With Psammomatous Calcification

Prostate cancer is a heterogeneous disease with several well-recognized morphologic subtypes and histologic variants—subsets of which are enriched for or associated with specific genomic alterations. Herein, we report a cohort of 4 unique prostate cancers characterized by intratumoral psammomatous calcification—which we have termed prostate cancer with psammomatous calcification (PCWPC). Clinicopathologic review demonstrates that PCWPCs are high-grade (grade group ≥3) tumors that involve the anterior prostate, and integrative targeted next-generation sequencing reveals recurrent hotspot IDH1 mutations. This morphology-molecular correlation is independently confirmed in The Cancer Genome Atlas prostatic adenocarcinoma cohort, with 3 of the 5 IDH1-mutant prostate cancers showing psammomatous calcification (rφ = 0.67; Fisher exact test, P < .0001). Overall, these findings suggest that PCWPC represents a novel subtype of prostate cancer enriched for an anterior location and the presence of hotspot IDH1 mutations. Recognition of these unique morphologic features could help identify IDH1-mutant prostate cancer cases retrospectively and prospectively—facilitating future large research studies and enabling clinical trial enrollment and precision medicine approaches for patients with advanced and/or aggressive disease.

Clear Cell Renal Cell Carcinoma with Focal Psammomatous Calcifications: A Rare Occurrence Mimicking Translocation Carcinoma.

Renal cell carcinoma (RCC) with clear cells and psammoma-like calcifications would often raise suspicion for MITF family translocation RCC. However, we have rarely encountered tumors consistent with clear cell RCC that contain focal psammomatous calcifications. We identified clear cell RCCs with psammomatous calcifications from multiple institutions and performed immunohistochemistry and fluorescence and RNA in situ hybridization (FISH and RNA ISH). Twenty-one tumors were identified: 12 men, 9 women, ages 45 to 83 years. Tumor size was 2.3 to 14.0 cm (median 6.75 cm). Nucleolar grade was 3 (n=14), 2 (n=4), or 4 (n=3). In addition to clear cell pattern, morphology included eosinophilic (n=12), syncytial giant cell (n=4), rhabdoid (n=2), branched glandular (n=1), early spindle cell (n=1), and poorly differentiated components (n=1). Labeling for CA9 was usually 80-100% of the tumor cells (n=17/21) but was sometimes decreased in areas of eosinophilic cells (n=4). All (19/19) were positive for CD10. Most (19/20) were positive for AMACR (variable staining, 20-100%). Staining was negative for keratin 7, although 4 showed rare positive cells (4/20). Results were negative for cathepsin K (0/19), melan A (0/17), HMB45 (0/17), TFE3 (0/5), TRIM63 RNA-ISH (0/13), and TFE3 (0/19) and TFEB rearrangements (0/12). Seven of 19 (37%) showed chromosome 3p deletion. One (1/19) showed trisomy 7 and 17 without papillary features. Psammomatous calcifications in RCC with a clear cell pattern suggests a diagnosis of MITF family translocation RCC; however, psammomatous calcifications can rarely be found in true clear cell RCC.

TFEB Rearranged Renal Cell Carcinoma: Pathological and Molecular Characterization of 10 Cases, with Novel Clinical Implications: A Single Center 10-Year Experience.

To report our experience with the cases of TFEB rearranged RCC, with particular attention to the clinicopathological, immunohistochemical and molecular features of these tumors and to their predictive markers of response to therapy. We have retrieved the archives of 9749 renal cell carcinomas in the Institute of Urology, Peking University and found 96 rearranged RCCs between 2013 and 2022. Among these renal tumors, ten cases meet the morphologic, immunohistochemical and FISH characterization for TFEB rearranged RCC. The 10 patients' mean and median age is 34.9 and 34 years, respectively (range 23-55 years old), and the male to female ratio is 1:1.5. Macroscopically, these tumors generally have a round shape and clear boundary. They present with variegated, grayish yellow and grayish brown cut surface. The average maximum diameter of the tumor is 8.5 cm and the median 7.7 (ranged from 3.4 to 16) cm. Microscopically, the tumor is surrounded by a thick local discontinuous pseudocapsule. All tumors exhibit two types of cells: voluminous, clear and eosinophilic cytoplasm cells arranged in solid sheet, tubular growth pattern with local cystic changes, and papillary, pseudopapillary and compact nested structures are also seen in a few cases. Non-neoplastic renal tubules are entrapped in the tumor. A biphasic "rosette-like" pattern, psammomatous calcifications, cytoplasmic vacuolization, multinucleated giant cells and rhabdomyoid phenotype can be observed in some tumors. A few tumors may be accompanied by significant pigmentation or hemorrhage and necrosis. The nucleoli are equivalent to the WHO/ISUP grades 2-4. All tumors are moderately to strongly positive for Melan-A, TFEB, Vimentin and SDHB, and negative for CK7, CAIX, CD117, EMA, SMA, Desmin and Actin. CK20 and CK8/18 are weakly positive. In addition, AE1/AE3, P504s, HMB45 and CD10 are weakly moderately positive. TFE3 is moderately expressed in half of the cases. PAX8 can be negative, weakly positive or moderately-strongly positive. The therapy predictive marker for PD-L1 (SP263) is moderately to strongly positive membranous staining in all cases. All ten tumors demonstrate a medium frequency of split TFEB fluorescent signals ranging from 30 to 50% (mean 38%). In two tumors, the coincidence of the TFEB gene copy number gains are observed (3-5 fluorescent signals per neoplastic nuclei). Follow-up is available for all patients, ranging from 4 to 108 months (mean 44.8 and median 43.4 months). All patients are alive, without tumor recurrences or metastases. We described a group of TFEB rearranged RCC identified retrospectively in a large comprehensive Grade III hospital in China. The incidence rate was about 10.4% of rearranged RCCs and 0.1% of all the RCCs that were received in our lab during the ten-year period. The gross morphology, histological features, and immunohistochemistry of TFEB rearranged RCC overlapped with other types of RCC such as TFE3 rearranged RCC, eosinophilic cystic solid RCC, or epithelioid angiomyolipoma, making the differential diagnosis challenging. The diagnosis was based on TFEB fluorescence in situ hybridization. At present, most of the cases reported in the literature have an indolent clinical behavior, and only a small number of reported cases are aggressive. For this small subset of aggressive cases, it is not clear how to plan treatment strategies, or which predictive markers could be used to assess upfront responses to therapies. Between the possible options, immunotherapy currently seems a promising strategy, worthy of further exploration. In conclusion, we described a group of TFEB rearranged RCC identified in a large, comprehensive Grade III hospital in China, in the last 10 years.

Psammomatous calcifications in thyroid oncocytic (Hürthle cell) follicular tumors

Concentric calcifications, also known as psammoma bodies, are a relatively frequent finding in certain types of tumors, particularly papillary thyroid carcinoma (PTC). In the thyroid, they have been assigned a significant role in the diagnosis of PTC and in distinguishing between these tumors and other types of thyroid neoplasms. Concentric calcifications have also less commonly been noted in other processes in the thyroid, such as in tumors characterized by cells containing abundant oxyphilic cytoplasm (i.e., Hürthle cells). We have studied 12 patients with oncocytic thyroid follicular tumors that contained scattered psammomatous calcifications that led to difficulties in diagnosis. The patients were 9 women and 3 men, aged 34 to 63 years. 10 cases corresponded to benign, non-invasive oncocytic tumors and 2 cases were minimally invasive follicular carcinomas of oncocytic (so called Hürthle cell) type. The psammomatous calcifications were randomly scattered throughout the lesions and were present as a focal, incidental finding in 8 cases and were diffuse in 4 cases. They were composed of concentrically laminated deposits of dense basophilic material closely resembling psammoma bodies, often associated with more homogeneous deposits of lightly eosinophilic material without concentric lamination that were interpreted as precipitated thyroglobulin. Seven patients with clinical follow-up, including one with minimally invasive carcinoma, were alive and well between 5 and 12 years after diagnosis. Concentric laminated calcifications may be encountered in oncocytic (Hürthle cell) follicular tumors and should not be interpreted as indicative of PTC in the context of oncocytic neoplasms of the thyroid.

An Extremely Rare Case of Renal Collision Tumor Comprised of Hyperpigmented Microcystic Chromophobe Renal Cell Carcinoma and Papillary Renal Cell Carcinoma

Abstract Introduction/Objective Renal collision tumors are rare lesions defined as the coexistence of two adjacent but histologically distinct tumors with sharp borders forming a single lesion. A combination of chromophobe renal cell carcinoma (ChRCC) and papillary renal cell carcinoma (RCC) is extremely rare. Here we report a collision tumor of hyperpigmented microcystic ChRCC, an uncommon variant of ChRCC, and papillary RCC. To our knowledge, it is the first reported case of this particular combination. Methods/Case Report A 70-year-old male with aortic stenosis presented with dyspnea and renal insufficiency. A renal mass was discovered incidentally. MRI characterized the left renal mass as 7.2 cm and bilobed. Radical nephrectomy was performed. Grossly, the tumor was located in the upper pole and consisted of two distinct components separated by fibrous tissue: a 5.4 cm black/orange mottled tumor and an adjacent 5.0 cm yellow lobulated tumor. Histologically, the larger tumor displayed a microcystic and solid pattern comprised of large cells with pale cytoplasm, hyperchromatic wrinkled nuclei, perinuclear halos, prominent cell membranes, and extensive intracellular and extracellular brown-black pigment, consistent with hyperpigmented microcystic ChRCC. The adjacent tumor showed diagnostic features of papillary RCC including papillae with fibrovascular cores lined by columnar cells with low nuclear grade, abundant macrophages, and foci of psammomatous calcifications. The hyperpigmented microcystic ChRCC was positive for CD117 and negative for Melan-A. Papillary RCC was strongly positive for Cytokeratin7 and Vimentin. Results (if a Case Study enter NA) N/A Conclusion Meticulous examination of the histologic features, aided by immunohistochemistry, can generate an accurate diagnosis of collision tumor and direct to the appropriate treatment choice.

Contemporary primary treatment of women with stage II-IV low-grade serous ovarian/peritoneal cancer (LGSOC): Determinants of relapse and disease-free survival

ObjectiveThe purpose of the present study is to describe a cohort who received contemporary primary treatment for stage II-IV low-grade serous ovarian/peritoneal cancer (LGSOC), including patient characteristics and determinants of relapse and disease-free survival. MethodsThe study included 99 patients: 1) with pathologically confirmed stage II-IV LGSOC of the ovary or peritoneum, 2) who underwent primary treatment consisting of cytoreductive surgery and either a) platinum/taxane chemotherapy followed by aromatase inhibitor maintenance therapy or b) aromatase inhibitor monotherapy, and 3) for whom there was availability of clinical data. Descriptive statistics were used to characterize clinicodemographic features. Subgroups were compared for PFS and OS. Multivariable Cox regression analyses were performed. ResultsMedian PFS for the entire cohort was 56.8 months (95% CI, 41.3-NE), and median OS was 130.7 months (95% CI, 115.0–146.4). Forty-nine of 99 (49.5%) patients have relapsed to date. For these 49 patients, median time from diagnosis to relapse was 29.6 months (95% CI, 24.6–33.1) (range, 5.4–69.1 months). Only 1/49 (2%) patients who relapsed did so >5 years from diagnosis. Fifty (50.0%) patients have not experienced disease progression or relapse. Median follow-up time for these 50 patients is 86.2 months (range, 25.3–169.0). Thirty-three of the 50 (66.0%) have been followed for >5 years from diagnosis. On regression analyses, factors associated with improved patient outcomes—either PFS, OS, or both–included no gross residual disease, normal serum CA 125 at diagnosis, primary peritoneal site, and presence of extensive psammomatous calcifications. ConclusionsThis is the first report to describe the clinicopathologic features and outcomes of women with stage II-IV LGSOC who received contemporary primary therapy.

Histologic characterization of paediatric mesenchymal neoplasms treated with kinase-targeted therapy.

Recurrent alterations involving receptor tyrosine or cytoplasmic kinase genes have been described in soft-tissue neoplasms such as infantile fibrosarcoma (IFS) and inflammatory myofibroblastic tumour (IMT). Recent trials and regulatory approvals for targeted inhibitors against the kinase domains of these oncoproteins have allowed for increased use of targeted therapies. We aimed to characterize the histologic features of paediatric mesenchymal neoplasms with kinase alterations treated with targeted inhibitors. Eight patients with tyrosine kinase-altered mesenchymal neoplasms with pre- and posttreatment samples were identified. Tumours occurred in five females and three males with a median age at presentation of 6.5 years. Tumour sites were bone/somatic soft-tissue (n = 5) and viscera (n = 3). Pretreatment diagnoses were: IMT (n = 3), epithelioid inflammatory myofibroblastic sarcoma (n = 1), and descriptive diagnoses (n = 4) such as "kinase-driven spindle cell tumor." Fusions identified were ETV6::NTRK3 (n = 2), TPM3::NTRK1, SEPT7::BRAF, TFG::ROS1, KLC1::ALK, RANBP2::ALK, and MAP4::RAF1. Patients were treated with larotrectinib (n = 3), ALK or ALK/ROS1 inhibitors (n = 3), and MEK inhibitors (n = 2). Posttreatment tumours exhibited a striking decrease in cellularity (7/8) and the presence of collagenous stroma (7/8) with extensive glassy hyalinization (5/8). In two cases, abundant coarse or psammomatous calcifications were seen and in one case prominent perivascular hyalinization was noted. Residual viable tumour was seen in 3/8 cases (<5% in one case, and >75% in 2/8 cases). Mesenchymal neoplasms with tyrosine kinase alterations treated with targeted inhibitors show a pathologic response, which includes decreased cellularity and stromal hyalinization. The presence of these features may be helpful in assessing tumour response after targeted therapy.

NF2-mutated Renal Carcinomas Have Common Morphologic Features Which Overlap With Biphasic Hyalinizing Psammomatous Renal Cell Carcinoma: A Comprehensive Study of 14 Cases.

Genetic alterations involving NF2 occur at low frequencies in renal cell carcinoma across all of the major histologic subtypes and have been associated with adverse outcomes. To better characterize tumors harboring these alterations, we identified 14 cases with NF2 mutations that had been previously diagnosed as papillary renal cell carcinoma; renal cell carcinoma, unclassified; or translocation associated renal cell carcinoma. These tumors were characterized by a tubulopapillary architecture, sclerotic stroma, microscopic coagulative necrosis, and psammomatous calcifications. All the cases displayed eosinophilic cytology as well as a high nuclear grade (World Health Organization/International Society of Urological Pathology [WHO/ISUP] grade 3 to 4) in all but 1 case. A subset of cases shared features with the recently described biphasic hyalinizing psammomatous renal cell carcinoma. Next-generation sequencing demonstrated mutations involving NF2 gene in all cases. In 10 cases, this was paired with the loss of chromosome 22. Additional mutations involving PBRM1 were found in 5 cases that were associated with a more solid growth pattern. Eight patients presented with metastatic disease including all 5 with PBRM1 mutations. Despite the aggressive disease course seen in many of the patients in our series, 2 patients exhibited a dramatic response to immunotherapy. Our results support the existence of a distinct group of cases of renal cell carcinoma characterized by distinct although admittedly nonspecific morphology, an aggressive disease course, and NF2 mutations, often paired with the loss of chromosome 22.

Histopathological correlation of punctate echogenic foci on ultrasonography in papillary thyroid carcinoma

To investigate the pathological entities of punctate echogenic foci (PEF) by correlating PEF with histopathological features of papillary thyroid carcinoma (PTC). This study included 121 consecutive patients who had undergone thyroidectomy for PTC. The inclusion criterion was entire tumor resection with a 3-mm thickness for histopathological examination. We assessed the presence and number (<5 or ≥5) of PEF defined as punctate hyperechoic foci within the solid component of nodules. All surgical tumor specimens were retrospectively reviewed for the presence of microcalcifications, including the psammomatous calcification, coarse microcalcification, and micro-ossification, and inspissated colloid. PEF were detected in 71 (58.7%) PTCs. Psammomatous calcifications, coarse microcalcifications, and inspissated colloids were more frequently found in PTCs with PEF than in those without (74.6%, 42.3%, and 46.5%, respectively, p ≤ 0.024). Any type of microcalcification was found in 90.1% of PTCs with PEF. Psammomatous calcifications, coarse microcalcifications, and inspissated colloids were independently associated with PEF (p ≤ 0.012). Psammomatous calcifications were found in all PTCs with a high number (≥5) of PEF. Microcalcifications were found in most PTCs with PEF and psammomatous calcification was the main pathological entity of PEF in PTC. Our study validates reliability of PEF as a predictor of microcalcifications in PTC.

MA14.02 RET Fusion Testing in Advanced Non-Small Cell Lung Carcinoma Patients: the RETING Study

The approval of selective RET inhibitors for patients with advanced RET fusion positive non-small cell lung carcinoma (NSCLC) means that the importance of accurately identifying those patients has never been greater. Due to the co-existance of single-gene testing and next-generation sequencing (NGS), we hypothesized that a comparison of RET fusions testing assays is urgently needed. Along those lines, the performance of RET immunohistochemistry (IHC) and RET fluorescence in situ hybridization (FISH) has recently been challenged. Physicians across 17 hospitals contributed to identify patients with RET fusion positive NSCLC as part of routine clinical care. In addition, RET fusion negative samples from NSCLCs diagnosed at the referral institution were also included. All tumors underwent targeted RNA-based NGS (Oncomine Comprehensive Assay v3), break-apart RET FISH (Vysis) with an automated scanning system (BioView), and RET IHC (clone EPR2871, Abcam). The material available for all tumors had been formalin-fixed and paraffin-embedded. Only cases with enough tissue available (i.e. a minimum of 50 tumor cells, as per FISH test requirements) and sufficient sequencing coverage after NGS were included. FISH and IHC results were interpreted by using previously described criteria. The NGS result was used as the gold-standard. Analyses by the three assays was succesful in all 80 tumors. Thirty-seven RET-positive samples and 43 RET-negative NSCLCs were identified. Signet ring cells and psammomatous calcifications were frequently observed in RET-positive samples (in 30% and 27% of tumors, respectively). The most common partners were KIF5B (29/37, 78%), followed by CCDC6 (6/37, 16%). Other partners included NCOA4 (1/37, 3%) and AKAP13 (1/37, 3%). Thirty-five out of the 37 (95%) NGS-positive samples were FISH-positive (86% with a split pattern and the remaining 14% with a single 3’ signal pattern). Six of those FISH-positive cases (6/35, 17%) displayed very challenging split signals (≤2 signal diameter). The two FISH-negative samples were KIF5B-RET variants that showed a narrow split (≤1 signal diameter) in 36% and 38% of tumor cells, respectively. All 43 NGS-negative tumors were also FISH-negative. Regarding RET IHC, all NGS-positive cases showed cytoplasmic staining with a mean H-score of 210 (median 210, range 5-300). Within the NGS-negative cohort, cytoplasmic staining was observed in 8 cases (19%), with a mean H-score of 9 (median 0, range 0-150). Interestingly, the two RET FISH-negative but NGS-positive samples showed relevant IHC positivity (H-score of 165 and 255, respectively). The most frequent partner in this large multicenter series of RET fusion positive NSCLCs was KIF5B. The concordance between RNA-based NGS and FISH was high, with 0% failure rate. However, the interpretation of RET FISH is very challenging due to the frequent occurrence of narrow split signals (22% in this series). RET IHC should be investigated further as an alternative method to resolve an equivocal FISH or NGS result. Funding This study was mainly funded by Lilly. We also thank Instituto de Salud Carlos III (ISCIII) (Fondos FEDER and Plan Estatal I+D+I 2008–2011 [PI11/02866] and 2013–2016 [PI14-01176 y PI17-01001]) and the iLUNG Program (B2017/BMD-3884) from the Comunidad de Madrid.

Pseudoendocrine Sarcoma: Clinicopathologic Analysis of 23 Cases of a Distinctive Soft Tissue Neoplasm With Metastatic Potential, Recurrent CTNNB1 Mutations, and a Predilection for Truncal Locations.

The number of recognized epithelioid soft tissue neoplasms continues to increase and includes epithelioid schwannoma, sclerosing epithelioid fibrosarcoma, and emerging entities such as sarcomas with GLI1 alterations. Here, we describe 23 cases of a previously unrecognized entity, provisionally termed "pseudoendocrine sarcoma." Pseudoendocrine sarcoma is a rare, distinctive tumor of uncertain lineage with a predilection for paravertebral soft tissue in older adults. Fifteen patients (65%) were male and 8 were female. Age at presentation ranged from 29 to 78 years (median: 62 y). Nineteen tumors (83%) occurred in truncal locations, including 15 tumors (65%) in paravertebral soft tissue; other locations included the posterior head (2 tumors), thigh (1), and orbit (1). Tumor size ranged from 2 to 19 cm (median: 6.35 cm). Pseudoendocrine sarcoma is composed of sheets, trabeculae, and nests of epithelioid or ovoid cells with indistinct borders, palely eosinophilic cytoplasm, and highly monomorphic, round nuclei with speckled chromatin. Pseudoglandular architecture was at least focally present in 16 tumors (70%), large extracellular hyaline globules were identified in 12 tumors (52%), and psammomatous calcifications were present in 8 (35%). Metaplastic ossification was identified in 2 tumors, and myxoid stroma was present in 1. Lymphovascular invasion was present in 5 of 18 tumors (28%). Immunohistochemistry demonstrated that most tumors showed nuclear positivity for β-catenin (20/21 tumors; 95%), and some showed at least focal positivity for S-100 (9/22; 41%), desmin (3/8; 38%), or CD34 (2/8; 25%). All tumors were negative for neuroendocrine and epithelial markers, including synaptophysin (21 tumors), chromogranin (19), INSM1 (4), pan-K (16), CAM5.2 (13), AE1/AE3 (6), epithelial membrane antigen (20), and E-cadherin (13). DNA sequencing detected CTNNB1 point mutations in all 6 sequenced tumors: D32H, S33C, S33F, S37A, S37C, and S37F. RNA sequencing was negative for gene fusions in all 6 sequenced tumors. Clinical follow-up was available for 17 patients (74%; range: 4 mo to 20 y; median: 3.5 y), including 14 patients with >1 year of follow-up. Six of 14 patients with long-term follow-up experienced local recurrence (43%, at intervals of 3 to 6 y). One tumor showed a local lymph node metastasis within the primary excision specimen, and 3 patients developed distant lung metastases (21%). No patient died of the disease as yet. Despite its bland morphology and resemblance to the well-differentiated neuroendocrine tumor, pseudoendocrine sarcoma is best considered an intermediate-grade sarcoma, given its pathologic characteristics and clinical behavior.

Mucinous Carcinoma of the breast with micropapillary pattern and psammomatous calcification: A case study.

Mucinous carcinoma with a micropapillary pattern is an unusual form of Invasive breast cancer exhibiting dual mucinous and micropapillary differentiation. The present case is of a 47-year-old nulliparous female who presented with an incidental finding of a hard lump in her left breast. Mammography revealed a BIRADS 4 lesion. Modified radical mastectomy was done and the specimen was grossed, revealing a tumor of 3x2.6x2.6 cm in the outer quadrant. Microscopy revealed the tumor having extracellular mucin pools with floating psammoma bodies and focal micropapillary pattern. Four of the twenty-six lymph nodes sampled were found to have tumor deposits. The micropapillary pattern was maintained in the metastatic deposits. Immunohistochemistry revealed ER and PR positivity and Her2Neu negativity. EMA corroborated the findings. It is important to recognize the micropapillary pattern in mucinous carcinomas of the breast as these tumors tend to be more aggressive than pure mucinous breast lesions.

Unusual Cytological Finding in Body fluid in an Elderly Female. Psammomatous Calcification.

Unusual Cytological Finding in Body fluid in an Elderly Female. Psammomatous Calcification.

Kalcificirani fibrozni tumor rektuma: prikaz slučaja

A calcifying fibrous tumor (CFT) is a benign tumor of unknown etiology. A calcifying fibrous tumor is rare in the intestinal tract. A calcifying fibrous tumor is characterized by hyalinized collagenous fibrous tissue, psammomatous or dystrophic calcification, and focal lymphoplasmacytic infiltrates on histology. Magnetic resonance imaging is the standard method for evaluating the lesions of the rectum, and CFTs should be considered in differentiating the rectal wall tumors. Herein, we report a case of a 68-year-old man with a rectal wall CFT.