Ugnius Mickys

Unique Composite Hematolymphoid Tumor Consisting of a Pro-T Lymphoblastic Lymphoma and an Indeterminate Dendritic Cell Tumor: Evidence for Divergent Common Progenitor Cell Differentiation

Until recently, hematopoietic neoplasms were considered monoclonal proliferations belonging to one cell lineage. In the last years, evidence for transdifferentiation from one cell lineage to another or divergent common progenitor cell differentiation has accumulated, mainly based on composite hematolymphoid tumors, sharing common genetic abnormalities. We report the case of a 59-year-old woman with a composite pro-T lymphoblastic lymphoma (LBL) and indeterminate dendritic cell tumor infiltrating the lymph nodes, bone marrow and stomach. Genetic analyses revealed that both cell populations bore +21, while a G13D mutation of the NRAS gene and monosomy 18 were detected only in the pro-T LBL. The synchronous appearance of two distinct uncommon hematolymphoid tumors in the same patient, recurrent at three different anatomic locations, with an identifiable common genetic denominator, namely +21, but also with unique genetic anomalies in the pro-T LBL raises the hypothesis of a divergent common progenitor cell differentiation.

Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania

There is limited knowledge about the BRCA1/2 mutational profile in Lithuania. We aimed to define the full BRCA1 and BRCA2 mutational spectrum and the clinically relevant prevalence of these gene mutations in Lithuania. A data set of 753 unrelated probands, recruited through a clinical setting, was used and consisted of 380 female breast cancer cases, 213 epithelial ovarian cancer cases, 20 breast and ovarian cancer cases, and 140 probands with positive family history of breast or ovarian cancer. A comprehensive mutation analysis of the BRCA1/2 genes by high resolution melting analysis coupled with Sanger sequencing and multiplex ligation-dependent probe amplification analysis was performed. Genetic analysis revealed 32 different pathogenic germline BRCA1/2 mutations: 20 in the BRCA1 gene and 12 in the BRCA2 gene, including four different large genomic rearrangements in the BRCA1 gene. In all, 10 novel BRCA1/2 mutations were found. Nine different recurrent BRCA1 mutations and two recurrent BRCA2 mutations were identified, which comprised 90.4% of all BRCA1/2 mutations. BRCA1 exon 1-3 deletion and BRCA2 c.658_659del are reported for the first time as recurrent mutations, pointing to a possible Baltic founder effect. Approximately 7% of breast cancer and 22% of ovarian cancer patients without family history and an estimated 0.5-0.6% of all Lithuanian women were found to be carriers of mutations in the BRCA1 or BRCA2 gene.

Extracavitary primary effusion lymphoma: clinical, morphological, phenotypic and cytogenetic characterization using nuclei enrichment technique

Primary effusion lymphoma (PEL) is a rare form of aggressive B‐cell lymphoma, which typically manifests as malignant effusion in the body cavities. However, extracavitary solid variants are also described. The aim of this study was to investigate copy number aberrations in two cases of solid PEL at their first occurrences and relapse by applying a newly developed methodology of tumour nuclei enrichment.

Rhabdoid Carcinoma of the Rectum

Rhabdoid colonic tumors are very rare lesions with just a few publications describing such neoplasms. Even more unusual for these lesions are their primary rectal locations, with only two brief case reports having been published on that subject to date. We present a case of a composite rhabdoid rectal carcinoma in a 49-year-old male. The tumor behaved very aggressively, with rapid patient demise despite radical surgery and intensive postoperative chemotherapy (FOLFIRI [folinic acid {leucovorin}, fluorouracil {5-fluorouracil}, and irinotecan] and FOLFOX4 [folinic acid {leucovorin}, fluorouraci {5-fluorouracil}, and oxaliplatin]). Pathologic examination was supportive of a rhabdoid carcinoma, with a compatible immunohistochemical profile, demonstrating synchronous expression of vimentin and epithelial markers in the tumor cells. In addition, BRAF V600E gene mutation, together with a wild-type KRAS gene, was identified, and no evidence of microsatellite instability based on MLH1, MSH2, MSH6, and PMS2 immunophenotypes, i.e., no loss of expression for all 4 markers, was observed. Our reported case confirms previously published observations of the clinical aggressiveness and the poor therapeutic response for rhabdoid tumors.

Favorable outcome with chemo-immunotherapy in Burkitt lymphoma and leukemia

1] Cazzola M, Invernizzi R, Bergamaschi G, et al. Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. Blood 2003;101(5):1996–2000. 2] Levi S, Corsi B, Bosisio M, et al. A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem 2001;276(27):24437–40. 3] Bencze KZ, Yoon T, Millan-Pacheco C, et al. Human frataxin: iron and ferrochelatase binding surface. Chem Commun (Camb) 2007;18:1798–800. 4] Napier I, Ponka P, Richardson DR. Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood 2005;105(5):1867–74. 5] O’Neill HA, Gakh O, Park S, et al. Assembly of human frataxin is a mechanism for detoxifying redox-active iron. Biochemistry 2005;44(2):537–45. 6] Campuzano V, Montermini L, Molto MD, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996;271(5254):1423–7. 7] Steensma DP, Hecksel KA, Porcher JC, Lasho TL. Candidate gene mutation analysis in idiopathic acquired sideroblastic anemia (refractory anemia with ringed sideroblasts). Leuk Res 2007;31(5):623–8. 8] Boultwood J, Pellagatti A, Nikpour M, et al. The role of the iron transporter ABCB7 in refractory anemia with ring sideroblasts. PLoS One 2008;3(4):e1970.

Apparently "BRCA-related" breast and ovarian cancer patient with germline TP53 mutation.

Abstract:  Germline TP53 gene mutations are associated with complex cancer predisposition syndrome, the Li–Fraumeni syndrome, and are not as rare as were previously thought. Currently, the identification of Li–Fraumeni syndrome is mostly based on a conformance to descriptive criteria, which recently were amended to include wider spectrum of malignancies. The presence of very young age‐onset breast cancers in TP53 mutations families is a feature that overlaps with hereditary breast/ovarian cancer families with BRCA1/2 genes mutations. Peri‐diagnostic germline TP53 testing results in breast cancer patients can significantly affect surgical and adjuvant radiotherapy choices. The aim of this case report is to emphasize the importance of peri‐diagnostic germline TP53 molecular testing in patients with early‐onset breast cancer and its effect on the management and outcome of the disease. We present the apparent BRCA1‐related, although mutation negative, breast and ovarian cancer patient who subsequently was confirmed to be TP53 c.817C>T (p.R273C) mutation carrier and discuss the importance of peri‐diagnostic oncogenetic TP53 testing in early breast cancer cases. Histopathology and genetic modifiers (MDM2 SNP309G; TP53 R72P, PIN3) data are also addressed.

Centrosome Linker–induced Tetraploid Segregation Errors Link Rhabdoid Phenotypes and Lethal Colorectal Cancers

Centrosome anomalies contribute to tumorigenesis, but it remains unclear how they are generated in lethal cancer phenotypes. Here, it is demonstrated that human microsatellite instable (MSI) and BRAFV600E-mutant colorectal cancers with a lethal rhabdoid phenotype are characterized by inactivation of centrosomal functions. A splice site mutation that causes an unbalanced dosage of rootletin (CROCC), a centrosome linker component required for centrosome cohesion and separation at the chromosome 1p36.13 locus, resulted in abnormally shaped centrosomes in rhabdoid cells from human colon tissues. Notably, deleterious deletions at 1p36.13 were recurrent in a subgroup of BRAFV600E-mutant and microsatellite stable (MSS) rhabdoid colorectal cancers, but not in classical colorectal cancer or pediatric rhabdoid tumors. Interfering with CROCC expression in near-diploid BRAFV600E-mutant/MSI colon cancer cells disrupts bipolar mitotic spindle architecture, promotes tetraploid segregation errors, resulting in a highly aggressive rhabdoid-like phenotype in vitro. Restoring near-wild-type levels of CROCC in a metastatic model harboring 1p36.13 deletion results in correction of centrosome segregation errors and cell death, revealing a mechanism of tolerance to mitotic errors and tetraploidization promoted by deleterious 1p36.13 loss. Accordingly, cancer cells lacking 1p36.13 display far greater sensitivity to centrosome spindle pole stabilizing agents in vitro. These data shed light on a previously unknown link between centrosome cohesion defects and lethal cancer phenotypes providing new insight into pathways underlying genome instability. Implications: Mis-segregation of chromosomes is a prominent feature of chromosome instability and intratumoral heterogeneity recurrent in metastatic tumors for which the molecular basis is unknown. This study provides insight into the mechanism by which defects in rootletin, a centrosome linker component causes tetraploid segregation errors and phenotypic transition to a clinically devastating form of malignant rhabdoid tumor. Mol Cancer Res; 16(9); 1385–95. ©2018 AACR.

Surgical or endoscopic management of malignant colon polyps: Malignant colon polyps treatment

To evaluate indications for colectomy in T1 polyps and possible risk factors for lymph node metastasis.

Hibridinė transanalinė ir laparoskopinė TME po TEM dėl netikėto T2 tiesiosios žarnos vėžio

A 57-year-old woman underwent transanal endoscopic microsurgery (TEM) for T1 rectal cancer. Final histology demonstrated T2 invasion (Figure 1). A total mesorectal excision (TME) was recommended. Operation started in a prone-jacknife position performing partial TME from below (Figure 2, 3). The mobilized rectum (Figure 4) and rectal stump (Figure 5) were closed with purse-string sutures. A completion laparoscopic TME was performed with colonic J pouch anal stapled anastomosis. An intact rectal specimen was achieved (Figure 6).

Successful treatment of advanced stage yolk sac tumour of extragonadal origin: a case report and review of literature

Background. Yolk sac tumour diagnosis should be considered for young age patients admitted to the hospital with non-specific complaints of widespread disease. Correct diagnosis and carefully planned treatment is the key to a successful outcome. Methods and materials. We present a rare case of a widespread yolk sack tumour of a uterine broad ligament. Our team directed a special attention towards the patient’s young age, advanced disease, and fertility sparing strategy of treatment. Results and conclusions. Stage IV yolk sac tumours of extragonadal origin are rarely reported in the literature. Hence, diagnosis and treatment often pose a challenge for emergency care unit doctors, gynaecologists, and oncologists. However, it can be a potentially curable disease. Moreover, patients’ fertility can also be preserved. We believe that further analysis of similar cases is necessary to study outcomes and evaluate patients’ responses to a sequence of medical decisions taken for this specific case.