Round Nuclei Research Articles

Esophageal Squamous Cell Carcinoma in Cats

Background: Esophageal neoplasms are rarely reported in cats. The frequency rate is less than 0.5% and those neoplasms are usually malignant. Esophageal squamous cell carcinoma (SCC) is an idiopathic epithelial neoplasm, invasive and metastatic that can induce partial or complete obstruction of the esophageal lumen. There is no breed or sex predisposition, and it is more common in cats over 8-years-old. Esophageal SCC is more frequent in the middle third of the esophagus. The prognosis is poor, as the cats are usually diagnosed at an advanced stage. This report aims to describe clinical, endoscopic, radiographic, and pathological features of two cases of esophageal squamous cell carcinoma in cats.Cases: A 11-year-old neutered male cat presenting regurgitation, weight loss, anorexia and dyspnea was referred to veterinary internal medicine care. Simple and contrast-enhanced radiographic images of the cervical and thoracic regions showed an alveolar pattern in the cranial lung lobes and signs of esophageal lumen irregularity and dilatation in the mediastinum topography. The upper digestive endoscopy showed a dilated esophageal lumen, and an irregular mass was observed in the thoracic esophagus involving the entire esophageal circumference. Biopsy fragments were collected, and the histopathological result was compatible with squamous cell carcinoma. The second case was a 10-year-old neutered male cat presenting hyporexia, regurgitation, dyspnea, tachypnea, and abnormal breath sounds. The ultrasound of the chest showed 3 amorphous hypoechogenic and heterogeneous areas in the right and left hemithorax between parietal and visceral pleura. The cytological examination was compatible with a malignant epithelial tumor. The patient died 3 months after the onset of clinical signs. At gross exam, it was observed a friable, irregular, and ulcerated mass of 5.0 x 3.0 cm in the middle third of the esophagus. Metastatic foci in the lungs and liver were also observed. The histopathological diagnosis was esophageal squamous cell carcinoma, with metastases to liver and lungs. Microscopically, in both cases, were seen aproliferation of polyhedral epithelial cells in the mucosa, arranged in nests or trabeculae with central keratinization. These cells presented oval to rounded nuclei, loose chromatin, prominent nucleolus, and abundant eosinophilic cytoplasm, with marked anisocytosis and anisokaryosis, supported by a thin fibrovascular stroma. In the second cat the neoplastic cells infiltrated the esophageal submucosa, including lymphatic vessels and muscle layer. Lung and liver metastases from theSCC had a cellular pattern similar to the primary neoplasm.Discussion: Esophageal squamous cell carcinoma is extremely rare in cats. The SCC begins in the squamous layer of the mucosa and can infiltrate the muscular layer or protrude into the esophageal lumen, leading to clinical signs, as seen in these 2 cats. The differential diagnoses for esophageal SCC include foreign bodies, esophageal strictures, and infiltrative or compressive non-esophageal tumors. Although uncommon, esophageal tumors should be considered when evaluatingelderly cats with regurgitation and weight loss. The diagnosis of esophageal SCC was confirmed by histopathological findings collected endoscopically or during necropsy. As noted in both cases, the prognosis of SCC is generally unfavorable, usually due to the difficulty in treatment and diagnosis in a late stage of the disease.Keywords: feline, esophagus, neoplasms, metastasis, cancer.

Observation of Clinicopathologic Features of Pituitary Adenoma With Neuronal Differentiation.

ObjectiveTo investigate the clinicopathologic features of pituitary adenoma with neuronal differentiation.MethodsFour patients with mixed gangliocytoma-pituitary adenomas between January 2011 and January 2021 and 111 new-onset patients with adenomas between January 2019 and June 2021 who attended the First Affiliated Hospital of Fujian Medical University were included in the study. The histological and immunohistochemical findings were analyzed. Neuronal differentiation marker staining was performed on new-onset adenomas, and the related literature was reviewed.ResultsAltogether, more than 100 mixed gangliocytoma-pituitary adenoma cases have been reported in the literature until now, of which pituitary-specific POU-class homeodomain transcription 1 (PIT1) positive adenomas are more frequently observed. In the present study, all 4 patients we described were female, aged 29 to 53 years (mean 39 years). Clinically, 3/4 patients presented with acromegaly, and 1/2 patients presented with headache. Histologically, the tumor was composed of two distinct mixed components. The one was a population of neoplastic ganglionic cells with large nuclei, prominent nucleoli, and abundant basophilic cytoplasm embedded in a fibrillary background. Stains of chromograninA (CgA), synaptophysin (Syn), Calretinin (CR) were positive. Axotomy-like expression was observed in neurofilament (NF) staining. PIT1 was expressed in partial ganglionic cells in all cases. The other component was a population of small uniform cells with round nuclei and acidophilic cytoplasm. Prolactin (PRL) and growth hormone (GH) were positive in all 4 cases. PIT1 was positive in the nuclei of adenomas. Although adenomas and ganglionic regions varied in histology, there was a population of cells with neuronal differentiation expressing PIT1. Additionally, axotomy-like expression of NF staining could be seen in a distant area of adenoma regions. A total of 111 cases of adenomas without ganglionic cells were included in this study, including 7 cases with neuronal differentiation. Among them, 4 cases were prolactinomas, 2 cases were somatotroph adenomas, and 1 case was corticotroph adenoma. 6/7 cases were PIT1-positive adenomas. And the remaining one case is T-PIT-positive adenoma.ConclusionsMixed gangliocytoma-pituitary adenomas are rare tumors with neuronal differentiation. The majority of MGAs are associated with endocrinopathies, mainly acromegaly. Our results suggest that PIT1-positive pituitary adenomas may have neural differentiation potential, which may not be unusual. This indication supports the possibility that the neuronal transdifferentiation of adenomatous cells is a possible mechanism, and the underlying mechanism requires further elucidation.

Dissecting Gonadoblastoma of the Ovary Coexistent with an Atypical Endometriotic Cyst: Incidental Detection in Cystectomy Specimen of a Woman with 46,XX Karyotype.

Dissecting gonadoblastoma (DGB) of the ovary, a recently described terminology, defines a unique distribution of neoplastic germ cells. Here, we report a case of incidental DGB coexistent with an atypical endometriotic cyst occurring in a 23-year-old woman. The ovarian cyst was lined by endometrial-like glands and stroma. Some glands displayed nuclear enlargement and hyperchromasia, and abundant eosinophilic cytoplasm with occasional intracytoplasmic hemosiderin and mucin vacuoles. The neoplastic germ cells resembled those of ovarian dysgerminoma and were diffusely distributed within the ovarian stroma, which was stretched around the wall of the endometriotic cyst. These cells were arranged in nests and cords, possessing clear cytoplasm and centrally located round nuclei with prominent nucleoli and occasional mitoses. Chromosomal analysis revealed a 46,XX karyotype. We describe the clinical, histological, immunophenotypical, and genetic features of ovarian DGB incidentally detected in the ovarian cystectomy specimen of a woman with normal female karyotype.

Glioblastoma, IDH-Wild Type With FGFR3-TACC3 Fusion: When Morphology May Reliably Predict the Molecular Profile of a Tumor. A Case Report and Literature Review.

It has been reported that in-frame FGFR3-TACC3 fusions confer to glioblastomas, IDH-wild type (GBMs, IDHwt) some unusual morphologic features, including monomorphous rounded cells with ovoid nuclei, nuclear palisading, endocrinoid network of “chicken-wire” vessels, microcalcifications and desmoplastic stroma, whose observation may predict the molecular profile of the tumor. We herein present a case of recurrent GBMs, IDHwt, exhibiting some of the above-mentioned morphological features and a molecularly-proven FGFR3-TACC3 fusion. A 56-year-old man presented to our hospital for a recurrent GBM, IDHwt, surgically treated at another center. Histologically, the tumor, in addition to the conventional GBM morphology, exhibited the following peculiar morphologic features: (1) monomorphous neoplastic cells with rounded nuclei and scant pale cytoplasm; (2) thin capillary-like vessels with “chicken-wire” pattern; (3) nuclear palisading; (4) formation of vague perivascular pseudorosettes; (5) spindled tumor cells embedded in a loose, myxoid background. Based on this unusual morphology, molecular analyses were performed and an FGFR3 exon17-TACC3 exon 10 fusion was found. The present case contributes to widening the morphologic spectrum of FGFR3-TACC3-fused GBM, IDHwt and emphasizes that pathologists, in the presence of a GBM, IDHwt with unconventional morphology, should promptly search for this fusion gene.

Effect of 1,25(OH)2-vitamin D3 on decidualization of human endometrial stromal cells

Decidualization is the differentiation of endometrial stromal cells (eSC) to rounded, epithelioid‐like cells during menstrual cycle and pregnancy. The impairment of this process leads to infertility and a variety of pregnancy disorders, including recurrent miscarriages and uteroplacental disorders. The aim of this study was to evaluate the effect of 1,25(OH)2-vitamin D3 (VD) on transformation of primary eSC into decidual cells. After isolation of eSC from biopsy samples of healthy fertile women and their characterization, the cells were cultured and propagated, and confluent cultures were decidualized for 12 days with progesterone (P4) and estradiol (E2) in presence or absence of VD. Prolactin (PRL) concentration was measured every 48 h in culture medium of eSCs, and ultrastructural changes were evaluated at the end of treatment. The results showed that PRL concentration in culture medium of eSCs was significantly increased in VD-treated decidual cells compared to control groups in a time-dependent manner. Ultrastructural analysis demonstrated that VD enhances many of the ultrastructural changes of decidualized cells including expansion of rough endoplasmic reticulum (rER), increased lipid droplets and high number of euchromatin round nuclei. These results suggest that VD may play an important role during early pregnancy by promoting cellular transformation associated with decidualization.

Phylogenetic analysis of chelonian hemogregarines reveals shared species among the Amazonian freshwater turtle Podocnemis spp. and provides a description of two new species of Haemogregarina.

This study describes two new species of the genus Haemogregarina living in the Amazonian freshwater turtles Podocnemis expansa and Podocnemis sextuberculata. Haemogregarina species isolated from P. expansa have been characterized by the presence of encapsulated, folded immature gamonts, with the parasitophorous vacuole and fragmented chromatin located in the central region. In Haemogregarina found in P. sextuberculata, curved immature gamonts were observed inside a parasitophorous vacuole, with small, slightly arched meronts with rounded nuclei, and mature gamonts with trapezoid-shaped condensed nuclei. The novel 18S rRNA sequences obtained in this study clustered within a well-supported clade composed of hemogregarines isolated from other neotropical freshwater turtles from the families Podocnemididae and Geoemydidae. The hemogregarines found in this study were compared to Haemogregarina podocnemis from Podocnemis unifilis and Haemogregarina sp. from Podocnemis expansa, based on morphological, morphometric, and molecular data. The analysis supports the new species Haemogregarina karaja sp. nov. isolated from P. expansa and Haemogregarina embaubali sp. nov. found in P. sextuberculata.

A row of nodules on the right side of the face

A row of nodules on the right side of the face

Fine Needle Aspiration Cytology of Secretory Carcinoma of the Parotid Gland in a Young Patient

Secretory carcinoma (SC) is a rare recently described entity that has characteristics similar to those of secretory breast carcinoma. We report a case of a 23 years old male with a swelling on the parotid gland. The ultrasonography guided fine needle aspiration cytology was performed on mass. Cytologically, the background of the aspirate is composed of inflammatory cells admixed with mucinous material. There were isolated cells as much as loosely cohesive clusters making papillary follicle-like glands with eosinophilic material in the lumen. Tumor cells were medium-sized round shape and eccentric nuclei with prominent nucleoli, remarkably vacuolated cytoplasm. The parotidectomy was performed and the pathology report revealed a SC. Histologically, the tumor is composed of microcystic, follicular, and micropapillary areas. The cytoplasm is usually vacuolated with also clear eosinophilic appearance. Immunohistochemically, tumor cells labeled with S100, MUC-4. At 5 years, the patient is disease-free and under regular follow-up.

Сочетание светлоклеточного почечно-клеточного рака и высокодифференцированной нейроэндокринной опухоли почки

We present a rare combination of two tumors (clear cell renal cell carcinoma with well-differentiated renal neuroendocrine tumour) in a 67-year-old man. To the best of our knowledge, English literature presents only one similar clinical case and we are the first to describe this tumor combination in Russian. The renal tumor was discovered accidentally on abdominal ultrasound. The patient had neither complaint, nor clinical signs of carcinoid syndrome, nor tumours in his medical history. CT scan showed a heterogeneous tumor, being 35×35×30 mm in size. It was in the upper segment of the left kidney, deforming the contour of the kidney, without renal pelvis expansion. We performed nephrectomy using the da Vinci Surgical System. The postoperative period was uneventful; no complications were reported. Macroscopically the tumour presented as a round encapsulated node of a variegated structure. Microscopic examination showed that the tumor consisted of large cells with clear cytoplasm and monomorphic small round nuclei (nucleoli were determined at ×400). In some regions of the tumor, we detected small polygonal cells, with ovoid nuclei with granular chromatin, forming solid, ribbon-shaped structures and spindle-cell patterns. The neuroendocrine component revealed strong expression of chromogranin A, synaptophysin, CD56, S-100, pancytokeratin, and СK7. Histological and immunohistochemical studies, we diagnosed a combination of clear cell renal cell carcinoma (Grade I–II by Fuhrman classification) and renal neuroendocrine tumour (Grade I), pT1aN0. The size of the neuroendocrine component was of 7×3 mm; the index of proliferation Ki-67 was less than 1.0%; and the mitotic index was less than 2 ×10 HPF. After nephrectomy this patient needed close monitor because renal neuroendocrine tumours are very rare and have a higher malignant potential than renal cell carcinoma. Keywords: urological pathology, kidney tumor, clear cell renal cell carcinoma, neuroendocrine tumor, immunohistochemistry

Clear cell neurofibroma: A rare and confusing variant

Clear cell change has been demonstrated in many cutaneous entities; however, there have been only two reports of clear cell neurofibroma. We present the third case of this unusual subtype. A 25-year-old female presented clinically with a picture of neurofibromatosis Type 1 including multiple cutaneous nodules. Biopsy from one of these nodules revealed a normal epidermal covering and a dermal benign neoplastic growth formed of a mixture of spindle cells and clear cells showing vacuolated cytoplasm. The neoplastic cells showed round nuclei with prominent nucleoli. Immunohistochemical staining showed positivity to S-100 and CD68 with negative expression of calretinin, CK, Melan-A, HMB-45, CD34, and smooth muscle actin. Clear cell neurofibroma should be considered in dealing with clear cell cutaneous lesions, giving attention to characteristic clinical, histopathological, and immunohistochemical features. CD68 could be expressed in neurofibroma, and this should not be misinterpreted as a histiocytic lesion.

Zona Pellucida sperm-binding protein 3 receptor distribution during Gopc-/- globozoospermic spermatogenesis.

Globozoospermia is a type of teratozoospermia characterized by round morphology of the sperm head. Gopc-/- infertile globozoospermic murine model has failures during spermiogenesis, such as the incorrect biogenesis of the acrosome, disorganized acroplaxome and manchette, round nuclei and spiral flagella. In this study, Western blot, RT-PCR, immunohistochemistry and immunogold were done for the localization of the acrosome protein Zona Pellucida sperm-binding protein 3 receptor (ZP3R), also called sp56, in wild type and Gopc-/- mice testis. The ZP3R protein was located in the acrosome and pseudo-acrosome vesicles of wild type and Gopc-/- mice, respectively. Also, it is distributed through the cytoplasm of the haploid spermatids only. The incorrect spermiogenesis of Gopc-/- mice causes a deregulation in the expression of ZP3R in the globozoospermic spermatids. Our results suggest that although the lack of GOPC causes a failure during the transport of the pre-acrosomal vesicles, the acrosome protein ZP3R is localized in the acrosome and is distributed through the cytoplasm only during spermiogenesis. Furthermore, the failure in spermiogenesis does not impair the synthesis of ZP3R and its localization in the pre-acrosomal vesicles.

CS-1 Cerebellar liponeurocytoma; Report of two cases with detailed metabolic, immunohistochemical, and genetic evaluations

Cerebellar liponeurocytoma (cLNC), World Health Organization grade II neoplasm, is a rare brain tumor characterized by advanced neuronal/neurocytic differentiation and focal lipid accumulation in neuroepithelial tumor cells. However, the expression and genetic profiling of cLNC, as well as metabolic imaging characteristics, have been poorly studied. Two patients with lower vermian tumors were operated on with telovelar approach. Moderate methionine uptake in positron emission tomography was observed in both cases. Histologically, the tumor was composed of small, uniform cells with round nuclei in a sheet-like fashion. Vacuolate cells with displacement of nuclei suggested the lipid accumulation, which was further supported by immunohistochemical staining of S-100. Although the extent of lipidization was relatively low compared with the reported cLNC cases, the immunohistochemical findings confirmed the diagnosis of cLNC. Next-generation sequencing of tumoral DNA in one case detected a splice site mutation of the ATRX gene, which is the first observation in the literature. Neither chemotherapy nor radiotherapy were administered postoperatively in both cases. In one case with spinal dissemination, residual tumor demonstrated progression 7 months after the resection. Long term follow-up data of cLNC cases with detailed expression and genetic profiles are essential for precise diagnosis and better understanding of the oncogenic pathway as well as the natural history of cLNC.

Abstract P136: Response to alpelisib in an adolescent with PIK3CA-mutated metastatic gastrointestinal stromal tumour

Abstract Introduction Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms that arise in the gastrointestinal tract. While most GISTs are driven by mutations in cKIT or PDGFR, approximately 10% lack these variants and are referred to as ‘wild-type’. Wild-type GISTs are commonly succinate dehydrogenase (SDH)-deficient and are characterized by indolent, multi-focal disease at presentation. On occasion, patients experience symptomatic disease progression warranting treatment ; imatinib or sunitinib offer minimal benefit. PIK3CA mutations have recently been described in a small proportion of GIST. Case report A previously healthy 16-year-old female presented with a five-month history of vomiting and weight loss, compatible with gastric outlet obstruction. Computerized tomography demonstrated a large gastric mass, and multiple liver and peritoneal metastases. Biopsy showed nests of epithelioid cells with round nuclei, vesicular chromatin, and eosinophilic cytoplasm. The lesional cells were immunoreactive for CD117, DOG1, CD34, and smooth muscle actin, while negative for SDH-B immunohistochemistry, in keeping with SDH-deficient GIST. Germline and somatic panel sequencing were performed through the SickKids Cancer Sequencing Program along with RNA sequencing by Illumina TruSight RNA Pan-Cancer NGS analysis. Somatic analysis revealed a PIK3CA p.Glu545Lys (E545K) mutation at 0.12 variant allele fraction (VAF). The patient was also found to have germline heterozygous pathogenic splice variant in the SDHB gene c.75+1 G>T (p?). In the light of the molecular findings and no alternative curative options, compassionate access to alpelisib was sought. The patient started drug at the recommended adult dose of 300 mg by mouth daily, and after completing two 28-day cycles, showed marked improvement in her abdominal distension and discomfort. Her appetite improved with documented nutritional weight gain. Reimaging at this time showed a 20% reduction in the sum of maximum dimensions of target lesions (per RECIST 1.1). Repeat imaging after five months on treatment confirmed continued improvement with 25% reduction compared to baseline.The patient did not experience hypersensitivity, severe cutaneous adverse reactions, hyperglycemia or pneumonitis. She currently continues on alpelisib monotherapy. Conclusion We describe the first report of a clinically meaningful response to a PIK3CA inhibitor in an adolescent patient with advanced metastatic SDH-deficient GIST harbouring a somatic activating PIK3CA hotspot mutation. There is still much to be learned about the biology of pediatric/wild-type GIST. In these rare cases, we recommend referral to specialized centers and incorporation of comprehensive next generation sequencing into care. Sequencing should be performed both on germline and somatic DNA to evaluate for a cancer predisposition syndrome, along with possible druggable targets in PIK3CA, cKIT or PDGFRA. We believe that the lack of routine comprehensive genomic analysis may underestimate the frequency of such rare variants. Citation Format: Sarah Cohen-Gogo, Nisha Kanwar, Furqan Shaikh, Reto M. Baertschiger, Adam Shlien, David Malkin, Juan Putra, Ailish Coblentz, Anita Villani, Abha A. Gupta, Daniel A. Morgenstern. Response to alpelisib in an adolescent with PIK3CA-mutated metastatic gastrointestinal stromal tumour [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P136.

Features of the microscopic structure of the adrenal gland of geese

The study of the morphology of the adrenal gland of birds is one of the most critical issues of modern biology and veterinary medicine cause its solution contributes to the scientific justification of technologies for rearing, using, and treating birds. The work aims to clarify the features of the microscopic structure of the adrenal gland of geese. As a peripheral organ of the endocrine system, the adrenal gland affects the growth and differentiation of tissues, regulates water, protein, carbohydrate, fat, and mineral metabolism, the body's resistance to infections, intoxication, stress, and other factors. During research were used histological indagation methods. It was found that blood vessels, clusters of nerve cells are registered in the capsule of the adrenal gland of geese. Nodes of the sympathetic nervous system are registered outside it. Connective tissue septa with hemocapillaries extend from the capsule to the adrenal parenchyma, which is represented by intertwined cell strands of interrenal and suprarenal tissues. The narrow spaces between these cell strands are filled with layers of loose fibrous connective tissue with sinusoidal hemocapillaries and venous sinuses. The subcapsular layer, peripheral and central zones are recorded on the incision of the adrenal gland. The adrenal vein is localized in the central zone. The subcapsular zone is mainly represented by cells of suprarenal tissue, the peripheral and central zone – by cells of interrenal tissue. Suprarenal tissue cells have a polygonal shape, basophilic cytoplasm, and a rounded, centrally located nucleus. Cells of interrenal tissue are columnar or cubic, have eosinophilic colored cytoplasm, a round or oval nucleus placed eccentrically. Venous sinuses are localized in the central and peripheral zones of the adrenal gland. Their wall is thin, formed by flat endotheliocytes, bounded by groups of cells of interrenal and suprarenal tissues. As a result, established microscopic structural features of the adrenal gland of geese can be used to formulate the base of its typical morphological characteristics, which give a possibility to assess the Morpho-functional essential state of the bird adrenal gland of this species by the influence of various factors and pathologies, in perspective of following researches – the exploration of morphometric parameters of the structural components of the adrenal gland of geese.

Clinical and morphological case of lung cancer with generalized metastases to the internal organs

Lung cancer has occupied a leading position in the structure of cancer morbidity and mortality throughout the world for many years. Lifetime diagnosis is often difficult due to the absence of any defining signs of cancer, and it is quite difficult to track the first signs of lung cancer. This is justified by the fact that the lungs are completely devoid of nerve endings and the presence of 26% of healthy lung tissue is sufficient to provide the body with the required amount of oxygen. Prolonged absence of clinical manifestations leads to late seeking medical help, which is often fatal. Description of the case. A 65-year-old patient who died at home was referred for a postmortem examination. The sectional study revealed signs of peripheral cancer of the right lung with multiple metastases in all fields of the lungs, in the liver, spleen, pancreas, with no metastases in the lymph nodes. Histological examination revealed extensive areas of tumor tissue, consisting of solid structures with glandular differentiation of tumor tissue of various sizes and shapes, with round and oval atypical nuclei. There was a pronounced polymorphism of cells, with a large number of pathological mitoses. Thrombi were detected in the lumen of the segmental and small branches of the pulmonary artery. Thus, the presented case is of particular interest for practicing physicians due to the fact that with adenocarcinoma of the lung, there were no characteristic metastases to the lymph nodes. Hematogenous metastasis occurred with the development of generalized metastases to the internal organs.

Choroid plexus papilloma in a free ranging eared dove (Zenaida auriculata)

Choroid plexus tumors (CPT) are rare neoplasms and histologically classified as choroid plexus papilloma (CPP), atypical choroid plexus papilloma (APP), and choroid plexus carcinoma (CPC). These neoplasms have been described in humans, domestic animals (canine, feline, equine, caprine) and some wild animals (cetaceans and Psittacidae birds). To our best knowledge, herein we report the first CCP in a free-ranging eared dove (Columbiformes; Zenaida auriculata, de Murs 1847). Histologically, the ventricle was dilated, with a papillary proliferation (arboriform pattern) in topography of CP. The neoplasm was well-differentiated, composed by a single layer of cuboidal cells, anchored in a delicate fibrovascular stroma. The neoplastic cells exhibited moderate stroma, with well-defined borders and round nuclei, with vesicular chromatin and inconspicuous nucleoli. Mitotic activity was low (<1 mitosis per 10 high-power fields). Immunohistochemistry for cytokeratin markers (AE1/AE3 antibody) were implemented, however, both neoplastic cells and normal epithelial tissues do not show immunoreactivity.

Synchronous bilateral pheochromocytomas and extra-adrenal paragangliomas without specific gene mutations

Abstract Introduction/Objective Diagnosis of hereditary paraganglioma-pheochromocytoma syndrome (H-PGL/PCC-S) should be suspected in individuals with pheochromocytoma or paraganglioma, especially those with multifocal lesions, positive family history, or early-onset disease. Recent studies suggest one-third to half of these patients have germline/syndromic associations. We present a challenging case wherein a 44-year-old female with high-risk factors, multiple paragangliomas, and bilateral pheochromocytomas did not have any identifiable syndromic involvement. Methods/Case Report Patient presented seven years ago with epigastric pain, weight loss of 50lbs, and chronic diarrhea. Endoscopic ultrasound revealed 2cm hypoechoic mass behind pancreas, diagnosed as neuroendocrine tumor on fine-needle aspiration. Subsequent SPECT-CT and MRI revealed multiple intra-abdominal lesions, including bilateral adrenal-lesions (right 2cm; left 1.6cm), 2.2cm aortocaval-lesion, and multifocal retroperitoneal lesions, consistent with paragangliomas, gradually increasing in size on follow-up imaging. She also developed intermittent palpitations, flushing, and blood pressure fluctuations. Additionally, multiple thyroid nodules were identified on subsequent ultrasound imaging, suspicious for malignancy on both cytology and Afirma studies. Exploratory laparotomy with left para-adrenal, right infra-renal, and aortocaval nodule-excisions revealed nested tumor cells with abundant granular purple cytoplasm, round central nuclei, prominent nucleoli, diagnosed as moderate to poorly differentiated extra-adrenal paragangliomas with increased metastatic risk based on PASS and GAPP-scoring systems. Additionally, right adrenalectomy revealed pheochromocytoma with 7/20 PASS-score and 4/10 GAPP-score suggesting increased metastatic risk. Results (if a Case Study enter NA) NA Conclusion Young age, strong family-history, multiple high-grade paragangliomas, pheochromocytomas, and suspicious thyroid nodules raise concerns for syndromic association. Multitude of autosomal-dominant syndromes, including paraganglioma-syndromes (PGL1-to PGL5), VHL, MEN2A, MEN2B, and NF1, have been reported. Genes identified in these syndromes include SDHA, SDHB, SDHC, SDHD, SDHAF2, MAX, TMEM127, VHL, NF1, RET, FH, and KIF1B. However, no mutations were identified, thus creating a dilemma in risk-stratification. This leaves out only two considerations: either sporadic PGL/PCC or a yet unidentified genetic-mutation.

Dzyaloshinskii-Moriya interaction probed by magnetization reversal in bilayer Pt/Co/Ir/Co/Pt synthetic ferrimagnets

Here, we study the effect of the Dzyaloshinskii-Moriya interaction (DMI) on magnetic nuclei expansion in Pt/Co/Ir/Co/Pt perpendicular synthetic ferrimagnets. Magnetization reversal is explored as a response to the DMI, affecting the expansion of the magnetic nuclei. We report a nontrivial inverted dependence of the velocity of the double domain wall on the in-plane (IP) magnetic field. This effect is due to competition of the DMI contributions, resulting in effective fields of different signs in the two Co layers. We report a macroscopic manifestation of the DMI as magnetization reversal accelerated by the applied IP magnetic field. Accelerated magnetic relaxation is provided by the DMI-induced ellipticity of the magnetic nuclei, the spreading of which is accompanied by an enhanced number of nuclei contacts in comparison with round nuclei in the absence of an IP field. The obtained results clarify how the DMI contributes to macroscopic magnetic relaxation in the presence of the interlayer Heisenberg exchange interaction in synthetic ferrimagnets with perpendicular anisotropy.

Intracranial myxoid mesenchymal tumour with EWSR1-ATF1 fusion mimicking high grade glioma

Abstract Aims Molecular profiling is increasingly used in the diagnosis of CNS and non-CNS neoplasms. More than a quarter of all soft tissue tumours are characterized by specific recurrent chromosomal translocations which can be used as molecular signatures. With increasing frequency, EWSR1 rearrangements are found on both mesenchymal tumours and primary glial/neuronal tumours. Here we present a case of intracranial myxoid mesenchymal tumour (IMMT), a rare tumour which is becoming more recognised in recent years, affecting mainly children and young adults, and rarely older adults. It can be found in intraaxial and extraaxial location, with frequent dural connection. The tumour is defined by the genetic hallmark of EWSR1-CREB family gene fusion. Including our case, 16 intracranial tumours with this gene fusion have been reported to date. Our goal is to contribute further to the characterisation of the morphological spectrum, fusion partners and biological behaviour of rare EWSR1-CREB (non-ETS)-rearranged tumours of the CNS. Method Case: The patient is a 27 year old woman with a frontal lobe lesion, radiologically described as a tumour with dural attachment. She underwent surgical debulking, and tumour tissue was histologically examined with conventional immunohistochemistry. Additional genetic testing included targeted mutation screening, FISH, EPIC (Illumina BeadChip) methylation array and next generation sequencing. Histology showed a mitotically active neoplasm with relatively uniform cells, round nuclei and oligodendroglioma-like clear cell change, but no myxoid change. Glomeruloid microvascular proliferation and large areas of tumour necrosis were present. Immunohistochemistry was focally positive for GFAP, and negative or normal for synaptophysin, IDH1 R132H mutation, ATRX and p53. The ki-67 index reached ~20%. Sequencing of IDH1 and IDH2 did not reveal rare IDH mutations, and FISH did not show 1p19q codeletion. Testing for BRAF V600 mutation was negative. Results Although the histology initially suggested a diagnosis of oligodendroglioma, the integrated diagnosis was compatible with glioblastoma, IDH wildtype. Methylation array analysis by EPIC array did not result in classification of currently known entities, neither confirming glioblastoma, nor providing a new diagnosis, when analysed on both brain tumour and sarcoma classifier. This suggested a novel tumour entity not yet represented in the classifier algorithm. Additional testing including next generation sequencing revealed EWSR1 gene rearrangement with fusion partner ATF1 (EWSR1-ATF1 fusion). Based on this, the diagnosis was revised to the emerging new entity of ‘intracranial myxoid mesenchymal tumor’ (IMMT) characterised by EWSR1 fusion with members of the cAMP response element binding protein (CREB) family (ATF1, CREB1 and CREM). Subsequent immunohistochemistry demonstrated positive staining for CD99 and EMA but not desmin. The patient underwent various oncological treatments and is recurrence-free 3 years after initial diagnosis. Conclusion Histologically, IMMT demonstrates a spectrum of features that overlaps with other tumours, but often displays circumscribed growth, uniform cellularity, cytoplasmic clearing and variable myxoid change. The clinical behaviour of these tumours is not fully understood, however provisionally considered intermediate grade. EWSR1-CREB family fusion is not specific but shared with a diverse group of extracranial tumours including soft tissue, salivary gland, odontogenic and myoepithelial tumours. Therefore, clinico-radiologico-pathological correlation is essential to achieve the final diagnosis, and ensure the absence of a primary tumour elsewhere. Familiarisation with IMMT, its characteristic genetic profile and its as yet underreported natural course is crucial, as it can clinically mimic other intracranial tumours such as malignant meningioma or glioma but appears to behave less aggressively than high grade glioma. It is also important to further our understanding of its optimal treatment through review of larger case series and global comparison of patient management.

Metachronous oligodendroglial tumours with different IDH mutational profile in a young patient

Abstract Aims Oligodendroglioma is molecularly defined by mutation of isocitrate dehydrogenase (IDH) and 1p19q codeletion. IDH mutation is an early driver of tumorigenesis, via its oncometabolite 2-hydroxyglutarate, regardless of the exact mutational subtype in homologues IDH1 or IDH2. IDH mutant cells then acquire 1p19q codeletion, with haploinsufficiency likely to contribute to oncogenesis by reduced expression of genes on 1p and 19q, as well as mutations in TERT, FUBP1 (on 1p31.1) in ~30% and CIC (on 19q13.2) in ~>60% of 1p19q-codeleted gliomas. We present a case of a young patient with metachronous oligodendroglial tumours, initially thought to represent contralateral recurrence of the same disease. However, IDH mutation analysis in each tumour revealed distinct types of mutations, involving both IDH1 and IDH2, indicating different cellular lineages of tumorigenesis. We aim to present this unusual combination by illustrating the histology and molecular profile, and review the literature with regards to multifocal but molecularly distinct glioma. Method Case: The patient is a 33 year old man initially presenting with seizures, who was found to have a frontal lobe lesion (hence called tumour 1) with focal radiological enhancement, followed by a contralateral lesion in the parietal lobe 6 months later (hence designated as tumour 2). He underwent separate surgical debulking, and each time, tumour tissue was histologically and genetically examined. Testing included targeted mutation screening by immunohistochemistry and PCR based methods, pyrosequencing for MGMT methylation analysis, FISH for chromosomal LOH analysis of 1p and 19q, immunohistochemistry for mismatch repair enzymes and next generation sequencing. Results Histology of tumour 1 revealed a neoplasm with uniform cells, round nuclei and oligodendroglioma-like clear cell change, without mitoses, microvascular proliferation or necrosis. Immunohistochemistry showed absence of IDH1 R132H mutation, retained expression of ATRX and no altered p53 staining. The ki-67 index reached 6%. Sequencing of IDH1/2 mutations revealed a rare IDH2 mutation (non-/R172K). FISH confirmed codeletion of 1p19q, and the integrated diagnosis was oligodendroglioma, IDH mutant and 1p19q codeleted, WHO grade II. Histology of tumour 2 demonstrated oligodendroglioma morphology in areas, but more cellular and nuclear pleomorphism and focally brisk mitotic activity (7 mitoses in 10 hpf; ki67 index 20%), while both microvascular proliferation and necrosis were absent. Immunohistochemistry showed IDH1 R132H mutation and retained ATRX, while p53 was not expressed. FISH studies confirmed codeletion of 1p19q, and the integrated diagnosis was anaplastic oligodendroglioma, IDH mutant and 1p19q codeleted, WHO-2016 grade III. NGS data and MMR results are compared. Conclusion We present a patient with two histologically similar, but molecularly distinct oligodendroglial tumours affecting both cerebral hemispheres. Apart from the grade, the important difference is the presence of different IDH mutations, 1) a rare IDH2 mutation (non-R172K) and 2) the common IDH1 (R132H) mutation. While both types of IDH mutations identified are known to occur in oligodendroglioma, the difference clearly indicates two distinct lineages of tumorigenesis, especially as IDH mutation is considered an early event in gliomagenesis. IDH2 mutations are often associated with oligodendrogliomas, while IDH1 R132H is recognised to be frequent in both diffuse oligodendroglial and astroglial neoplasms. Multifocal divergent gliomas have been described previously but oligodendrogliomas with differing IDH mutations in the same patient have not knowingly been reported yet. Importantly, though therapeutically irrelevant here, multicentric gliomas do not automatically imply relatedness. However, a common origin or predisposition (here, even predating IDH mutation) may not be ruled out.