Bernasconi, Barbara

Calabrese, G

Capella, Carlo Renato

Proserpio, I

Ricotti, I

Tibiletti, M. G.

Uccella, Silvia

UCCELLA, SILVIA

BERNASCONI, BARBARA

Ricotti I

Proserpio I

Calabrese G

CAPELLA, CARLO RENATO

Tibiletti M.G.

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Cancer Genetics 205 (2012) 186e189BRIEF COMMUNICATIONPartial trisomy of chromosome 13 as a singlecytogenetic abnormality in an Italian case of nasalNK/T lymphomaSilvia Uccella a,*, Barbara Bernasconi a, Isabella Ricotti a, Ilaria Proserpio b,Giuseppe Calabrese c, Carlo Capella a, Maria Grazia Tibiletti aaDepartment of Surgical and Morphological Sciences, Unit of Pathology, University of InsubriaeOspedale di Circolo, Varese,Italy; bDepartment of Oncology, Ospedale di Circolo, Varese, Italy; cDepartment of Oral Sciences, Nano and Biotechnologies,University “G. D’Annunzio,” Chieti, ItalyReceived Decem15, 2012; accepted* CorrespondingE-mail address:2210-7762/$ - seedoi:10.1016/j.canceExtranodal NK/T lymphoma, nasal type, is an uncommon neoplasm that occurs with a higherprevalence among Asian populations and Native American populations of Central and SouthernAmerica. In Western countries, this tumor is extremely rare, accounting for less than 1.5% of allnon-Hodgkin lymphomas. Cytogenetic analyses have been performed only in a limited number ofcases, mainly because of technical problems related to extensive necrosis and the scarcity ofclinical samples, and these have shown complex karyotypes with no specific chromosomal trans-locations. Here, we report the cytogenetic characterization of a clinically aggressive nasal NK/T-cell lymphoma occurring in a 40-year-old Italian male patient, in which the sole chromosomeabnormality was a partial trisomy of chromosome 13.Keywords Extranodal NK/T lymphoma, nasal type, FISH, spectral karyotypingª 2012 Elsevier Inc. All rights reserved.Extranodal NK/T lymphoma, nasal type, is one of the twomature NK-cells-derived neoplasms reported in the mostrecent World Health Organization (WHO) classification oflymphoid tissues. Although this lymphoma is more prevalentin Asia and Central and Southern America, some rare caseshave also been reported in Europe and North America. Thetypical site of origin is the nasal cavity and upper aero-digestive tract, which is the reason why this lymphoma hasbeen designated as “nasal type.” Extranasal sites of origininclude several extranodal organs, whereas solitary nodalinvolvement in the absence of other localizations has beenanecdotally reported (1).Extranodal NK/T lymphoma, nasal type, is an Epstein-Barrvirus (EBV)related neoplasmregardless of the patient’s ethnicorigin. The virus appears to play an important etiological role inlymphomagenesis, and its detection in neoplastic cells isa desirable criterion for a correct diagnosis (2,3).Conventional and molecular cytogenetic analyses of thislymphoma have only been performed in a limited number ofcases, mainly because of technical problems related tober 12, 2011; received in revised form FebruaryFebruary 15, 2012.author.silvia.uccella@uninsubria.itfront matter ª 2012 Elsevier Inc. All rights reserved.rgen.2012.02.005extensive necrosis and the scarcity of clinical samples. Nospecific pattern of chromosomal abnormalities has beenidentified yet, although the most common changes aredeletion of chromosomes 6q, 8p, 11q, 12q, and 13q, andgains of chromosomes 2q, 15q, 17q, and 22q. No specificchromosomal translocation has been reported (4e9).Here, we report the cytogenetic characterization of a clin-ically aggressive nasal NK/T-cell lymphoma in a 40-year-oldItalian male patient.Case report and histopathologicalexaminationA 40-year-old male patient was admitted to the otorhinolar-yngology department of another institution because he hadnasal polyposis and chronic rhinosinusitis, for which heunderwent functional nasal surgery and ablation of inferiorturbinates. One year later, after a trip to the Sahara Desert, hewas referred to the otolaryngology department of our hospital,with fever, persistent rhinorrhoea with crostous lesions ofnasal mucosa, and enlargement of cervical lymph nodes.The microbiological examination of nasal samples waspositive for Streptococcus viridians and Enterococcusfaecalis group D, but serial hemocultures were negative.Partial trisomy of chromosome 13 in a nasal NK/T lymphoma 187Anti-EBV IgM and anti-Cytomegalovirus antibodies werenegative, as were anti-Treponema pallidum and anti-Toxo-plasma gondi antibodies. In addition, Plasmodium falciparumresearch was negative. An antibiotic therapy was started.The ultrasonographic examination of the neck demonstratedmultiplebilateral adenopathies.Thefineneedleaspirationofonelymph node showed atypical lymphoid cells suspect for lym-phoproliferative disease. In this setting, the patient underwentsurgical excision of a cervical lymph node and multiple biopsiesof the nasal cavity, rhinopharynx, and paranasal sinuses.At routine histopathological examination, the mucosalsamples were largely necrotic. In one rhinopharyngealbiopsy, a diffuse proliferation of small and medium-sizedatypical lymphoid cells was observed, focally invading thewall of blood vessels in an angiocentric fashion. In the lymphnode sections, the normal architecture was completelyeffaced by a lymphomatous proliferation with the samefeatures as described in the rhinopharynx, showing focalareas of necrosis. The immunophenotype of lymphoma cellswas CD2þ, CD3 3þ, CD56/þ, Granzyme Bþ, TIA1þ,perforinþ and CD20, CD4, CD8, CD10, CD30,CD57, MUM1. In situ hybridization for eeEBV-RNA(EBER) was positive. A diagnosis of extranodal NK/Tlymphoma, nasal type, was formulated (Figure 1).Staging procedures with a CT scan, MRI, and PET scanrevealed the presence of pathological tissue involving thenasal mucosa and mascellar sinuses bilaterally, the peri-rhinopharyngeal soft tissues and the left orbital cavity.Pathological enlargement of lymph nodes at all cervicalstations was also documented. A bone marrow biopsy waspositive for lymphoma localization.Figure 1 Histopathological features of the reported nasal NK/Ta diffuse proliferation of small and medium-sized atypical lymphoid cfashion (A) (H & E, original magnification 400). At immunohistocheand granzyme B-positive (C) but faintly immunoreactive for CD2 (D)(EBER) was present in the neoplastic nuclei (F).The patient underwent two cycles of chemotherapy withthe CHOP (cyclophosphamide, doxorubicin, vincristin, pred-nisone) scheme, but no response was observed and he died45 days after diagnosis with pulmonary progression of thedisease and septic shock. A post-mortem examination wasnot performed.Cytogenetic analysisA fresh tumor sample of the cervical lymphnodewasminced intosmall pieces, incubated, and processed according to themethoddescribed by Tibiletti et al. (10). Conventional chromosomeanalysis was performed on direct preparations that were incu-bated for 24 hours. Slides were QFQ-banded (Q-bands by fluo-rescence using quinacrine6) and analyzed according therecommendations of the ISCN 2009 (11). The cytogenetic studyrevealed the presence of a marker chromosome in all theanalyzed metaphases, and the neoplastic karyotype was47,XY,þmar. Fluorescence in situ hybridization (FISH) wasperformed, to better define the marker chromosome, withcommercially available probes for T-cell receptor alpha/delta(TCRAD on 14q11), beta (TCRB on 7q34), and gamma (TCRGon7p14) (Dako Italia S.p.A.,Milano, Italy), again according to theprocedure described by Tibiletti et al. (10). The marker chromo-some was negative for all these probes. As expected, based onthe histologic diagnosis, no T-cell receptor rearrangement wasdetected.Spectral karyotypingFISH (SKY-FISH)wasperformedaspreviously describedbyCalabreseet al. (12), and theanalysisdefined themarker chromosome as a derivative of chromosome13 (Figure 2). FISH performed with probes RB1 and DLEU1 forlymphoma. In non-necrotic areas, the tumor was composed ofells, focally invading the wall of blood vessels in an angiocentricmical analysis, lymphoma cells were strongly CD3 3-positive (B)and CD56 (E). In situ hybridization demonstrated that EBV-RNAFigure 2 SKY-FISH. The marker chromosome was identifiedas a derivative of chromosome 13.188 S. Uccella et al.the 13q14 region andwith probeD13S1160 for the 13qter region(all three probes from Abbott Molecular Europe, Wiesbaden,Germany) revealed a partial trisomy of chromosome 13.Specifically, the marker chromosome was negative for the two13q14 probes and was positive for the 13qter probe. The finalkaryotype of the nasal NK/T-cell lymphoma was definedas: 47,XY,þmar.ish der(13)(WCP13þ,TCRG,TCRB,Rb,DLEU1,D13S1160þ,TCRAD).DiscussionWe conducted a detailed cytogenetic analysis of a case ofextranodal NK/T lymphoma that was well characterizedfrom a morphological and clinical point of view. Cytogeneticinvestigation revealed a partial trisomy of chromosome13 as the sole chromosome abnormality in the neoplasticcells. To our knowledge, this is the first report of a partialtrisomy of chromosome 13 as a single cytogenetic aberra-tion in any type of EBV-positive NK-cell leukemia orlymphoma since the establishment of standardized diag-nostic criteria for NK-cell neoplasms by WHO. The mostcommon cytogenetic aberration reported in extranodalnasal NK/T-cell lymphoma is loss of 6q. Conventionalcytogenetic analysis, FISH, and spectral karyotyping haveestablished 6q deletions, particularly deletions of 6q21,6q23, and 6q24-27, as common recurrent aberrations inthis neoplasm (5). Additional recurrent chromosomeabnormalities include loss of 11q and 13q, loss of 17p, gainof the X chromosome, and gain of 20q and 13q (4e6,8,9).All these aberrations are consistently present in complexkaryotypes with multiple numeric and structural abnormali-ties. A review of the literature revealed only one extranodalnasal NK/T-cell lymphoma showing an isochromosome7q10 as a single chromosome abnormality (13) and a caseof nasal NK/T-cell lymphoma with a constitutional 11qterminal deletion and an acquired t(1;14) of the bonemarrow specimen (14). The partial trisomy of chromosome13 is the sole chromosome abnormality in the otherwisediploid karyotype of this case; therefore, it may be specu-lated that it is related to the early pathogenesis of thedisease. FISH analysis demonstrated that the trisomicregion did not encompass the RB1 and DLEU1 regions.This observation may indicate that the partial trisomy ofchromosome 13 could have originated by two hits involvingthe deletion of the RB1 and DLEU1 regions and thesubsequent malsegregation of normal chromosome 13, orvice versa. Gains of chromosome 13q in extranodal nasalNK/T-cell lymphoma have been reported by other authorsas a part of complex karyotypes (5,6,8). Interestingly, thedescribed 13q gains mapped to bands 13q21 and 13q31-33, which is the same region involved in the partial trisomyof our case. These bands contain several unidentifiedproto-oncogenes, including the G-protein-coupled receptor18 (4,15).In conclusion, we have reported the case of a clinicallyaggressive extranodal NK/T lymphoma, nasal type, whichoccurred in an Italian patient, with a unique pattern of cyto-genetic alterations. The correlation between the partialtrisomy of chromosome 13 and the early nodal involvement,as well as the rapidly fatal course of this lymphoma, remainsto be established.Partial trisomy of chromosome 13 in a nasal NK/T lymphoma 189References1. Takahashi E, Asano N, Li C, et al. Nodal T/NK-cell lymphoma ofnasal type: a clinicopathological study of six cases. Histopa-thology 2008;52:585e596.2. Au WY, Weisenburger DD, Intragumtornchai T, et al. Clinicaldifferences between nasal and extranasal natural killer/T-celllymphoma: a study of 136 cases from the International Periph-eral T-Cell Lymphoma Project. Blood 2009;113:3931e3937.3. Jaffe S, Harris N, Vardiman J, et al., editors. Hematopathology.Philadelphia: Saunders Elsevier; 2011.4. Ko YH, Choi KE, Han JH, et al. Comparative genomic hybrid-ization study of nasal-type NK/T-cell lymphoma. Cytometry2001;46:85e91.5. Nakashima Y, Tagawa H, Suzuki R, et al. Genome-wide array-based comparative genomic hybridization of natural killer celllymphoma/leukemia: different genomic alteration patterns ofaggressive NK-cell leukemia and extranodal Nk/T-celllymphoma, nasal type. Genes Chromosomes Cancer 2005;44:247e255.6. Tien HF, Su IJ, Tang JL, et al. Clonal chromosomal abnormali-ties as direct evidence for clonality in nasal T/natural killer celllymphomas. Br J Haematol 1997;97:621e625.7. Wong KF, Zhang YM, Chan JK. Cytogenetic abnormalities innatural killer cell lymphoma/leukaemiadis there a consistentpattern? Leuk Lymphoma 1999;34:241e250.8. Siu LL, ChanV,Chan JK, et al. Consistent patterns of allelic loss innatural killer cell lymphoma. Am J Pathol 2000;157:1803e1809.9. Siu LL, Wong KF, Chan JK, et al. Comparative genomichybridization analysis of natural killer cell lymphoma/leukemia.Recognition of consistent patterns of genetic alterations. AmJ Pathol 1999;155:1419e1425.10. Tibiletti MG, Bernasconi B, Furlan D, et al. Early involvement of6q in surface epithelial ovarian tumors. Cancer Res 1996;56:4493e4498.11. Shaffer LG, Slovak ML, Campbell LJ, editors. ISCN 2009: aninternational system for human cytogenetic nomenclature.Basel: Karger; 2009.12. Calabrese G, Fantasia D, Spadano A, et al. Karyotype refine-ment in five patients with acute myeloid leukemia using spectralkaryotyping. Haematologica 2000;85:1219e1221.13. Wang HY, Wilson KS, McKenna RW, et al. An extranodal nasalnatural killer/T-cell lymphoma with isochromosome 7q10 as thesole cytogenetic aberration was initially diagnosed via bonemarrow biopsy. Arch Pathol Lab Med 2007;131:1709e1714.14. Gaitonde S, Attele A, Abutalib SA, et al. Extranodal naturalkiller/t-cell lymphoma, nasal type, in a patient with a constitutional11q terminal deletion disorder. Acta Haematol 2007;118:42e46.15. Gantz I, Muraoka A, Yang YK, et al. Cloning and chromosomallocalization of a gene (GPR18) encoding a novel seven trans-membrane receptor highly expressed in spleen and testis.Genomics 1997;42:462e466.

Partial trisomy of chromosome 13 as a single cytogenetic abnormality in an Italian case of nasal NK/T lymphoma.Cancer Genet.

Partial trisomy of chromosome 13 as a single cytogenetic abnormality in an Italian case of nasal NK/T lymphoma.Cancer Genet.

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