Mehran Ghaderi

A prognosis based classification of undifferentiated uterine sarcomas: Identification of mitotic index, hormone receptors and YWHAE‐FAM22 translocation status as predictors of survival

Undifferentiated uterine sarcomas (UUS) are rare tumors with a heterologous biology and a poor prognosis. The goal of this study was to examine clinicopathology, biomarkers and YWHAE‐FAM22 translocation status, in the prognosis of these tumors. Twenty‐six cases of UUS were included. All original slides were rereviewed and age at diagnosis, tumor stage, “Kurihara” diagnosis, mitotic index, presence of necrosis and grade of nuclear atypia were recorded. Additionally, a tissue microarray was constructed from 22 of the cases, and the protein biomarkers P53, P16, Ki‐67, Cyclin‐D1, ER, PR and ANLN were evaluated by immunohistochemistry. All tumors were evaluated for the presence of a YWHAE‐FAM translocation; the translocation was demonstrated in the three Cyclin‐D1 positive tumors. Follow‐up data in the form of overall survival were available on all patients. These tumors could be divided into two prognostic groups, a high mitotic index group (10 cases, M = 36.8, SD = 5.4) and a low mitotic index group (16 cases, M = 8.7, SD = 5.8). These two groups showed a statistically significant difference in prognosis. The expression of ER, PR or presence of the YWHAE‐FAM22 translocation correlated with low mitotic index and an additionally improved prognosis, although the number of cases was small. These results indicate that UUS can be divided into two prognostic groups using mitotic index as a primary criteria, followed by expression of either ER, PR or the presence of a YWHAE‐FAM22 translocation as a secondary criteria. This study demonstrates the presence of statistically significant prognostic subgroups within UUS, and provides treatment insights.

BRAFV600E protein expression in primary cutaneous malignant melanomas and paired metastases.

IMPORTANCE BRAFV600E mutations are present in approximately 50% of cutaneous malignant melanomas (CMMs). The use of BRAFV600E mutation-specific monoclonal antibody VE1 immunohistochemical analysis may facilitate rapid detection of BRAFV600E mutations in CMMs and demonstrate heterogeneity among tumors. OBJECTIVES To characterize the pattern of BRAFV600E protein expression in primary CMMs with matched metastases and to analyze the use of VE1 immunohistochemical analysis in clinical practice using formalin-fixed, paraffin-embedded tumor tissue. DESIGN, SETTING, AND PARTICIPANTS In this retrospective cohort study performed at Karolinska University Hospital from September 2012 to September 2013, we examined CMMs (124 primary tumors and 76 metastases) with VE1 immunohistochemical analysis, and results were compared with DNA mutation analyses. MAIN OUTCOMES AND MEASURES Determination of intratumoral and intertumoral heterogeneity as well as the sensitivity and specificity of VE1 immunohistochemical analysis. RESULTS Positive staining results with the VE1 antibody were detected in 94 of 200 tumors (47.0%). In general, VE1 staining was homogeneous. However, VE1 staining intensity varied among the primary tumors and corresponding metastases in 63 of 135 tumors (46.7%), but a change of mutational status based on DNA analysis was found in only 4 matched tumors (3.0%). Discordant findings between DNA mutation analysis and immunohistochemical analysis were observed in 12 tumors. The overall sensitivity and specificity of VE1 immunohistochemical analysis were 96.7% and 94.5%, respectively. A comparable sensitivity was obtained for primary and metastatic CMMs. The specificity was lower among primary CMMs (92.4%) compared with metastases (98.0%). CONCLUSIONS AND RELEVANCE We found VE1 immunohistochemical analysis to be a useful and rapid assay for BRAFV600E mutations that may contribute to the detection of intratumoral and intertumoral heterogenetic subclones. Tumors with positive results, including strong staining, should be expedited for confirmatory BRAF mutation testing. If this test result is negative, a false-negative result of the mutation analysis should be considered. Validation of VE1 immunohistochemical analysis in clinical practice is needed.

Diagnosis of Endometrial Stromal Tumors

OBJECTIVES To assess the difficulties associated with diagnosing endometrial stromal tumors (ESTs) on endometrial biopsy. METHODS We examined 25 endometrial biopsy specimens from 19 consecutive women diagnosed with either endometrial stromal nodule (n = 3) or endometrial stromal sarcoma (n = 16). RESULTS Rereview of the biopsy specimens revealed a stromal fragment suspicious for an EST in 16, of which eight had received a benign diagnosis on initial review. Most ESTs had an aglandular stromal fragment that was 5 mm or larger. Stromal fragments of this size were not encountered in the control material. Problematic areas included highly cellular leiomyoma and a lack of attention to the stromal compartment. CONCLUSIONS Most endometrial stromal tumors present with large aglandular stromal fragments (≥5 mm). These fragments are large enough that difficulties in diagnosis appear to be due to a lack of attention to the stromal compartment.

Evidence for Ca2+-regulated ATP release in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are thought to originate from the electrically active pacemaker cells of the gastrointestinal tract. Despite the presence of synaptic-like vesicles and proteins involved in cell secretion it remains unclear whether GIST cells possess regulated release mechanisms. The GIST tumor cell line GIST882 was used as a model cell system, and stimulus-release coupling was investigated by confocal microscopy of cytoplasmic free Ca(2+) concentration ([Ca(2+)]i), flow cytometry, and luminometric measurements of extracellular ATP. We demonstrate that GIST cells have an intact intracellular Ca(2+)-signaling pathway that regulates ATP release. Cell viability and cell membrane integrity was preserved, excluding ATP leakage due to cell death and suggesting active ATP release. The stimulus-secretion signal transduction is at least partly dependent on Ca(2+) influx since exclusion of extracellular Ca(2+) diminishes the ATP release. We conclude that measurements of ATP release in GISTs may be a useful tool for dissecting the signal transduction pathway, mapping exocytotic components, and possibly for the development and evaluation of drugs. Additionally, release of ATP from GISTs may have importance for tumor tissue homeostasis and immune surveillance escape.

CD274 (PD‐L1)/PDCD1 (PD‐1) expression in de novo and transformed diffuse large B‐cell lymphoma

Blombery, P., Thompson, E., Jones, K., Mir Arnau, G., Lade, S., Markham, J.F., Li, J., Deva, A., Johnstone, R.W., Khot, A., Prince, H.M. & Westerman, D. (2016) Whole exome sequencing reveals activating JAK1 and STAT3 mutations in breast implant-associated anaplastic large cell lymphoma anaplastic large cell. Haematologica, 101, e387–e390. Clemens, M.W., Medeiros, L.J., Butler, C.E., Hunt, K.K., Fanale, M.A., Horwitz, S., Weisenburger, D.D., Liu, J., Morgan, E.A., Kanagal-Shamanna, R., Parkash, V., Ning, J., Sohani, A.R., Ferry, J.A., Mehta-Shah, N., Dogan, A., Liu, H., Thormann, N., Di Napoli, A., Lade, S., Piccolini, J., Reyes, R., Williams, T., McCarthy, C.M., Hanson, S.E., Nastoupil, L.J., Gaur, R., Oki, Y., Young, K.H. & Miranda, R.N. (2016) Complete surgical excision is essential for the management of patients with breast implant-associated anaplastic large-cell lymphoma. Journal of Clinical Oncology, 34, 160–168. Crescenzo, R., Abate, F., Lasorsa, E., Tabbo’, F., Gaudiano, M., Chiesa, N., Di Giacomo, F., Spaccarotella, E., Barbarossa, L., Ercole, E., Todaro, M., Boi, M., Acquaviva, A., Ficarra, E., Novero, D., Rinaldi, A., Tousseyn, T., Rosenwald, A., Kenner, L., Cerroni, L., Tzankov, A., Ponzoni, M., Paulli, M., Weisenburger, D., Chan, W.C., Iqbal, J., Piris, M.A., Zamo’, A., Ciardullo, C., Rossi, D., Gaidano, G., Pileri, S., Tiacci, E., Falini, B., Shultz, L.D., Mevellec, L., Vialard, J.E., Piva, R., Bertoni, F., Rabadan, R. & Inghirami, G. (2015) Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell, 27, 516–532. Lechner, M.G., Megiel, C., Church, C.H., Angell, T.E., Russell, S.M., Sevell, R.B., Jang, J.K., Brody, G.S. & Epstein, A.L. (2012) Survival signals and targets for therapy in breast implant-associated ALK-anaplastic large cell lymphoma. Clinical Cancer Research, 18, 4549–4559. Merkel, O., Hamacher, F., Griessl, R., Grabner, L., Schiefer, A.I., Prutsch, N., Baer, C., Egger, G., Schlederer, M., Krenn, P.W., Hartmann, T.N., Simonitsch-Klupp, I., Plass, C., Staber, P.B., Moriggl, R., Turner, S.D., Greil, R. & Kenner, L. (2015) Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation. Journal of Pathology, 236, 445–456. Mottok, A., Renn e, C., Seifert, M., Oppermann, E., Bechstein, W., Hansmann, M.L., K€ uppers, R. & Br€auninger, A. (2009) Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities. Blood, 114, 4503–4506. Odejide, O., Weigert, O., Lane, A.A., Toscano, D., Lunning, M.A., Kopp, N., Kim, S., van Bodegom, D., Bolla, S., Schatz, J.H., Teruya-Feldstein, J., Hochberg, E., Louissaint, A., Dorfman, D., Stevenson, K., Rodig, S.J., Piccaluga, P.P., Jacobsen, E., Pileri, S.A., Harris, N.L., Ferrero, S., Inghirami, G., Horwitz, S.M. & Weinstock, D.M. (2014) A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood, 123, 1293–1296. Petitjean, A., Mathe, E., Kato, S., Ishioka, C., Tavtigian, S.V., Hainaut, P. & Olivier, M. (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database (database version R18, April 2016). Human Mutation, 28, 622–629. Swerdlow, S.H., Campo, E., Pileri, S.A., Harris, N.L., Stein, H., Siebert, R., Advani, R., Ghielmini, M., Salles, G.A., Zelenetz, A.D. & Jaffe, E.S. (2016) The 2016 revision to the World Health Organization classification of lymphoid neoplasm. Blood, 127, 2375–2390. Yang, L., Rau, R. & Goodell, M.A. (2015) DNMT3A in haematological malignancies. Nature Reviews Cancer, 15, 152–165.

Dysregulation of shelterin factors coupled with telomere shortening in Philadelphia chromosome negative myeloproliferative neoplasms.

Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are a group of clonal neoplastic diseases originating from the myeloid lineage. MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF).[1][1] Most MPNs are sporadic but familial

TERT promoter mutations are rare in parathyroid tumors

Research Letter for Endocrine-Related Cancer 1 2 TERT promoter mutations are rare in parathyroid tumors 3 4 Felix Haglund* 1 , Carl Christofer Juhlin* 1,2,3 , Taylor Brown 2,3 , Mehran Ghaderi 1 , Tiantian 5 Liu 4 , Adam Stenman 1 , Andrii Dinets 1 , Manju Prasad 5 , Reju Korah 2,3 , Dawei Xu 6 , 6 Tobias Carling 2,3 and Catharina Larsson 1 7 *These authors contributed equally to this study. 8 9 Author affiliations: 10

Validation of a Mitotic Index Cutoff as a Prognostic Marker in Undifferentiated Uterine Sarcomas

Undifferentiated uterine sarcomas (UUS) are a heterogenous group of high-grade mesenchymal tumors. Although these tumors are highly aggressive, a subset of patients may experience long-term survival. These tumors have previously been divided morphologically into uniform and pleomorphic types. A previous study demonstrated that a mitotic index cutoff of 25 mitoses/10 high-power fields (corresponding to 11.16 mitotic figures/mm2) could successfully divide tumors into 2 prognostic groups with significantly different overall survival. The goals of the current study were to (1) validate this mitotic index cutoff in an independent, multicenter cohort and (2) explore the prognostic value of the mitotic index groups in relation to other clinicopathologic variables. Cases were included from 3 independent institutions: The Norwegian Radium Hospital, The Mayo Clinic, and Skåne University Hospital. A total of 40 tumors were included after central review. All cases were negative for the YWHAE-FAM22A/B and JAZF1-JJAZ1 translocations. Survival data were available on all patients. In this study, one-third of patients with UUS survived beyond 5 years. The crude (unadjusted) Cox Proportional Hazards model revealed a number of parameters that significantly impacted overall survival, including mitotic index group, patient age, stage, and the presence of tumor necrosis. Classification into the uniform and pleomorphic types was not prognostic. Combining these parameters into an adjusted model revealed that only the mitotic index group and stage were prognostic. On the basis of these findings, it is proposed that UUS be subdivided into “mitogenic” and “not otherwise specified” types.