Aggressive B-cell lymphomas of sinonasal tract and testis : clinical manifestations and treatment outcome

Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma that without treatment rapidly leads to death. Addition of monoclonal CD20 antibody rituximab (R) to cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine and prednisone (CHOP) chemotherapy has clearly improved survival of patients with DLBCL, and now 74% of the patients receiving immunochemotherapy are reported to remain event free in 6-year follow-up. However, extranodal DLBCL, especially primary testicular (PT) DLBCL, primary central nervous system (CNS) DLBCL, renal/adrenal DLBCL, and according to some earlier reports also sinonasal tract (SNT) DLBCL, have worse prognosis than DLBCL in general. In addition, the impact of the addition of R on the survival of specific subgroups, like PT-DLBCL and SNT DLBCL is not clear. In this study the clinicopathological presentation and impact of the addition of R on the survival of the patients with SNT and PT-DLBCL was analysed. SNT and PT-DLBCL have also been considered to have high risk for CNS spread. To prevent CNS spread, CNS-directed therapy (iv high-dose methotrexate or iv cytarabine) is added for patients with high risk for CNS spread. However, the significance of CNS-directed chemotherapy on SNT and PT-DLBCL patients is unclear and this study aimed to explore it. The clinical data and samples of SNT lymphoma patients treated at the Helsinki University Hospital (Helsinki, Finland) and SNT DLBCL patients also from Tampere University Hospital (Tampere, Finland) were collected and the outcomes in response to different treatment modalities were compared. The present study shows the incidence of SNT lymphoid malignancies is slowly increasing, and that nasopharynx is the most common location in the SNT area. Majority (43%) of the patients had DLBCL, whereas 18% had plasmocytoma. SNT DLBCL patients receiving R and CNS-directed therapy in addition to CHOP-like therapy had longer survival than patients not receiving these as part of their therapy, and the patients receiving both R and CNS- directed therapy as part of their therapy had the longest survival. PT-DLBCL patients were chosen here to present another extranodal patient group. Clinical data and samples of PT-DLBCL patients treated at Helsinki, Tampere and Turku University Hospitals were collected, and in addition, Danish lymphoma registry was searched for PT-DLBCL patients. It was observed that PT-DLBCL patients with high international prognostic index (IPI) clearly benefitted from the addition of R to the treatment and that the treatment of contralateral testis associated with better survival among all PT-DLBCL patients. The present study demonstrates non-GCB phenotype in PT-DLBCL was associated with inferior survival. PT-DLBCL patients treated with iv CNS-directed treatment had significantly better survival than other patients. The present study identified absolute lymphocyte count (ALC) as a potential risk factor in PT-DLBCL. Non-lymphopenic PT-DLBCL patients receiving R as a part of their chemotherapy were found to have better survival in comparison to the patients not receiving R, whereas among lymphopenic patients, the difference in the outcome between the patients receiving R and not receiving R as part of their chemotherapy was not observed. Likewise, non-lymphopenic patients benefitted of iv CNS-directed therapy, whereas among lymphopenic patients no clear survival benefit was observed.Diffuusi suurisoluinen B-solu -lymfooma (DLBCL) on agressiivinen B-solulymfooma, joka ilman hoitoa johtaa kuolemaan. CD20-vasta-aineen rituximabin (R) lisääminen cyclofosfamidi, hydroxydaunorubicine, vincristine ja prednisone (CHOP) -hoitoon on selvästi parantanut DLBCL:n ennustetta. Nykyisellään noin 74% R-CHOP-hoitoa saavista DLBCL potilaista ei ole kokenut taudin uusimista kuuden vuoden kuluessa diagnoosista. Kuitenkin imusolmukealueiden ulkopuolella ilmenevällä eli ekstranodaalisella DLBCL:llä, etenkin kives-, keskushermosto-, lisämunuais/munuais- ja joidenkin tutkimusten mukaan myös sinonasaali-DLBCL:llä, on katsottu olevan huonompi ennuste kuin DLBCL:llä yleensä. Lisäksi R:n hoitoon lisäämisen vaikutus ei ole selvä kaikissa DLBCL:n alaryhmissä, kuten sinonasaali- ja kives-DLBCL:ssä. Yksi meidän tavoitteistamme oli selvittää R:n lisäämisen vaikutusta sinonasaali- ja kives-DLBCL-potilaiden ennusteeseen. Sinonasaali- ja kives-DLBCL:llä on katsottu myös olevan korkea riski levitä keskushermostoon. Potilaille, joilla on korkea riski keskushermostolevinneisyyteen, lisätään keskushermostolevinneisyyden estämiseksi keskushermostoon kohdistettu hoito (laskimonsisäisesti (iv) korkea-annos metotreksaatti tai iv cytarabiini). Keskushermostoon kohdistetun hoidon merkitys sinonasaali- ja kives-DLBCL-potilaiden ennusteelle ei ole kuitenkaan selvä, ja meidän tavoitteenamme oli selvittää tämä. Kokosimme Helsingin ja Tampereen yliopistollisissa keskussairaaloissa hoidettujen sinonasaali-DLBCL-potilaiden kliiniset tiedot sekä syöpäkudosnäytteet ja vertasimme eri hoidon saaneiden potilaiden hoitotuloksia. Totesimme sinonasaalilymfoomien ilmaantuvuuden olevan hitaassa kasvussa. Nenänielu oli kaikkein yleisin paikka taudille sinonasaalialueella. Valtaosalla (43%) potilaista todettiin DLBCL, kun taas 18%:lla todettiin plasmosytooma. Tuloksistamme kävi ilmi sinonasaali-DLBCL-potilaiden pidempi ennuste R-hoitoa ja keskushermostoon kohdistettua hoitoa osana hoitoaan saaneiden potilaiden ryhmässä. Potilailla, jotka olivat saaneet molempia hoitoja osana hoitoaan, oli pisin ennuste. Toiseksi potilaisaineistoksemme valitsimme kives-DLBCL-potilaat. Kliiniset tiedot ja syöpäkudosnäytteet Helsingin, Tampereen ja Turun yliopistollisissa keskussairaaloissa hoidetuista potilaista kerättiin. Lisäksi koko Tanskan kattavasta lymfoomarekisteristä haettiin Tanskan kives-DLBCL-potilaat ja heidän kliiniset tietonsa. Havaitsimme korkeiden kansainvälisten lymfoomariskipisteiden (international prognostic index, IPI) omaavien kives-DLBCL-potilaiden selkeästi hyötyvän R:n lisäämisestä hoitoon ja vastakkaisen kiveksen hoitamisen olevan yhteydessä parempaan ennusteeseen kaikilla kives-DLBCL-potilailla. Havaitsimme myös ei-itukeskusperäisen (non-germinal centre, non-GC) ilmiasun olevan yhteydessä huonompaan ennusteeseen. Meidän aineistossamme iv keskushermostoon kohdistetun hoidon osana hoitoaan saaneilla potilailla oli pidempi ennuste kuin muilla potilailla. Tunnistimme verestä mitatun lymfosyyttimäärän olevan potentiaalinen riskitekijä kives-DLBCL:ssä. Potilailla, joilla ei ollut alentunutta lymfosyyttimäärää, ja jotka olivat saaneet R:a osana hoitoaan, oli pidempi ennuste kuin potilailla, jotka eivät olleet saaneet R:a osana hoitoaan. Potilailla, joilla oli alentunut veren lymfosyyttimäärä, ei havaittu eroa ennusteessa suhteessa R-hoitoon osana hoitoa. Vastaavasti potilaat, joilla ei ollut alentunutta lyfmosyyttimäärää veressä, hyötyivät iv keskushermostoon kohdistetusta hoidosta, kun taas alentuneen veren lymfosyyttimäärän omaavilla potilailla selkeää eroa ennusteessa suhteessa iv keskushermostoon kohdistettuun hoitoon ei havaittu

VEGF-C – RET -signaalitien vaikutus ihon, enterisen hermoston ja lymfaattisen kudoksen kehitykseen sekä sikiöiden elinkykyyn

Selvitin tutkimuksessani VEGF-C:n ja RET:n vaikutusta hiiren enterisen hermoston ja imusuoniston kehitykseen. Yhden ja kahden VEGF-C-alleelin puutos johti neuronien määrän vähenemiseen jejunumissa ja koolonissa. RET-alleelien puutos vähensi myös neuronien määrää ja kahden puutos esti neuronien kehittymisen. VEGF-C ja etenkin RET-muuntogeenisiä alkioita oli myös hiiripoikueissa vähemmän kuin Mendelistisen jakauman perusteella voisi olettaa. Tämä viittaa lisääntyneeseen kuolleisuuteen in utero. Myös ihon karvatuppia oli RET-homogeenisissä vähemmän kuin villityyppisissä. Lisäksi selvitin mitkä vasta-aineet soveltuvat käytettäväksi suolten erityyppisissä vastaainevärjäyksiss

Kiveslymfooma

Kiveslymfooma on harvinainen, aggressiivinen lymfooma-alatyyppi. Se on kuitenkin tavallisin iäkkäiden miesten kivessyöpä ja histologialtaan yleisimmin diffuusi suurisoluinen B-solulymfooma. Biologisesti kiveksen diffuusi suurisoluinen B-solulymfooma eroaa primaarisesti imusolmukealueilla esiintyvästä tautimuodosta ja muistuttaa keskushermoston diffuusia suurisoluista B-solulymfoomaa. Sillä on taipumus uusiutua muihin imusolmukealueiden ulkopuolisiin elimiin, erityisesti vastakkaiseen kivekseen ja keskushermostoon. Kiveslymfooman hoito koostuu sairaan kiveksen poistosta, sen jälkeisestä solunsalpaajien ja vasta-aineen yhdistelmähoidosta, keskushermostoon kohdennetusta solunsalpaajahoidosta sekä vastakkaisen kiveksen ehkäisevästä poistosta tai sädehoidosta. Taudin ennuste on nykyisin kohtalaisen hyvä. Uusia hoitomuotoja kaivataan erityisesti iäkkäämpien, hauraiden potilaiden hoitoon.publishedVersionPeer reviewe

Kiveslymfooma

VertaisarvioituKiveslymfooma on harvinainen, aggressiivinen lymfooma-alatyyppi. Se on kuitenkin tavallisin iäkkäiden miesten kivessyöpä ja histologialtaan yleisimmin diffuusi suurisoluinen B-solulymfooma. Biologisesti kiveksen diffuusi suurisoluinen B-solulymfooma eroaa primaarisesti imusolmukealueilla esiintyvästä tautimuodosta ja muistuttaa keskushermoston diffuusia suurisoluista B-solulymfoomaa. Sillä on taipumus uusiutua muihin imusolmukealueiden ulkopuolisiin elimiin, erityisesti vastakkaiseen kivekseen ja keskushermostoon. Kiveslymfooman hoito koostuu sairaan kiveksen poistosta, sen jälkeisestä solunsalpaajien ja vasta-aineen yhdistelmähoidosta, keskushermostoon kohdennetusta solunsalpaajahoidosta sekä vastakkaisen kiveksen ehkäisevästä poistosta tai sädehoidosta. Taudin ennuste on nykyisin kohtalaisen hyvä. Uusia hoitomuotoja kaivataan erityisesti iäkkäämpien, hauraiden potilaiden hoitoon.Peer reviewe

Low Absolute Lymphocyte Counts in the Peripheral Blood Predict Inferior Survival and Improve the International Prognostic Index in Testicular Diffuse Large B-Cell Lymphoma

Low absolute lymphocyte counts (ALC) and high absolute monocyte counts (AMC) are associated with poor survival in patients with diffuse large B-cell lymphoma (DLBCL). We studied the prognostic impact of the ALC and AMC in patients with testicular DLBCL (T-DLBCL). T-DLBCL patients were searched using Southern Finland University Hospital databases and the Danish lymphoma registry. The progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods. We identified 178 T-DLBCL patients, of whom 78 (44%) had a low ALC at diagnosis. The ALC did not correlate with survival in the whole cohort. However, among the patients treated with rituximab (R) containing regimen, a pre-therapeutic low ALC was associated with an increased risk of progression (HR 1.976, 95% CI 1.267–3.086, p = 0.003). Conversely, intravenous (iv) CNS directed chemotherapy translated to favorable outcome. In multivariate analyses, the advantage of an iv CNS directed chemotherapy was sustained (PFS, HR 0.364, 95% CI 0.175–0.757, p = 0.007). The benefit of R and intravenous CNS directed chemotherapy was observed only in non-lymphopenic patients. The AMC did not correlate with survival. A low ALC is an adverse prognostic factor in patients with T-DLBCL. Alternative treatment options for lymphopenic patients are needed

Low Absolute Lymphocyte Counts in the Peripheral Blood Predict Inferior Survival and Improve the International Prognostic Index in Testicular Diffuse Large B-Cell Lymphoma

Low absolute lymphocyte counts (ALC) and high absolute monocyte counts (AMC) are associated with poor survival in patients with diffuse large B-cell lymphoma (DLBCL). We studied the prognostic impact of the ALC and AMC in patients with testicular DLBCL (T-DLBCL). T-DLBCL patients were searched using Southern Finland University Hospital databases and the Danish lymphoma registry. The progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods. We identified 178 T-DLBCL patients, of whom 78 (44%) had a low ALC at diagnosis. The ALC did not correlate with survival in the whole cohort. However, among the patients treated with rituximab (R) containing regimen, a pre-therapeutic low ALC was associated with an increased risk of progression (HR 1.976, 95% CI 1.267–3.086, p = 0.003). Conversely, intravenous (iv) CNS directed chemotherapy translated to favorable outcome. In multivariate analyses, the advantage of an iv CNS directed chemotherapy was sustained (PFS, HR 0.364, 95% CI 0.175–0.757, p = 0.007). The benefit of R and intravenous CNS directed chemotherapy was observed only in non-lymphopenic patients. The AMC did not correlate with survival. A low ALC is an adverse prognostic factor in patients with T-DLBCL. Alternative treatment options for lymphopenic patients are needed

Low Absolute Lymphocyte Counts in the Peripheral Blood Predict Inferior Survival and Improve the International Prognostic Index in Testicular Diffuse Large B-Cell Lymphoma

Low absolute lymphocyte counts (ALC) and high absolute monocyte counts (AMC) are associated with poor survival in patients with diffuse large B-cell lymphoma (DLBCL). We studied the prognostic impact of the ALC and AMC in patients with testicular DLBCL (T-DLBCL). T-DLBCL patients were searched using Southern Finland University Hospital databases and the Danish lymphoma registry. The progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods. We identified 178 T-DLBCL patients, of whom 78 (44%) had a low ALC at diagnosis. The ALC did not correlate with survival in the whole cohort. However, among the patients treated with rituximab (R) containing regimen, a pre-therapeutic low ALC was associated with an increased risk of progression (HR 1.976, 95% CI 1.267-3.086,p= 0.003). Conversely, intravenous (iv) CNS directed chemotherapy translated to favorable outcome. In multivariate analyses, the advantage of an iv CNS directed chemotherapy was sustained (PFS, HR 0.364, 95% CI 0.175-0.757,p= 0.007). The benefit of R and intravenous CNS directed chemotherapy was observed only in non-lymphopenic patients. The AMC did not correlate with survival. A low ALC is an adverse prognostic factor in patients with T-DLBCL. Alternative treatment options for lymphopenic patients are needed.Peer reviewe

Clinical findings in 25 patients with sinonasal or nasopharyngeal extramedullary plasmacytoma in a four-decade single-centre series

Objectives: Extramedullary plasmacytoma in the sinonasal tract or nasopharynx is rare. The aim of the study was to review data on symptoms, clinical findings, treatment and follow-up of plasmacytomas in the sinonasal and nasopharyngeal regions in order to delineate the main clinical characteristics and the optimal management. Method: Twenty-five patients with sinonasal or nasopharyngeal plasmacytoma, diagnosed and treated at the Helsinki University Hospital during a 39-year period from 1975 to 2013 were retrospectively reviewed. Results: There were 18 males and 7 females with a median age of 66 years (range, 36-80). Sixty-eight percent received only radiotherapy or (chemo)radiotherapy. Forty-seven percent of them had a complete response to primary radiotherapy and one patient had a complete response after receiving additional brachytherapy. Four patients were treated primarily with surgery only. Two of them had a local recurrence, but were then successfully treated with radiotherapy. Altogether, four patients received a combination of surgery and (chemo)radiotherapy. Forty-four percent were alive with no evidence of disease after a median follow-up time of 78 months. Forty percent died of their disease and 16% died of other causes. Conclusions: Our study supports radiotherapy as a treatment of choice, but for small tumours surgery alone or in combination with radiotherapy may also be considered. Chinese abstractPeer reviewe

PD-L1(+) tumor-associated macrophages and PD-1(+) tumor-infiltrating lymphocytes predict survival in primary testicular lymphoma

Primary testicular lymphoma is a rare and aggressive lymphoid malignancy, most often representing diffuse large B-cell lymphoma histologically. Tumor-associated macrophages and tumor-infiltrating lymphocytes have been associated with survival in diffuse large B-cell lymphoma, but their prognostic impact in primary testicular lymphoma is unknown. Here, we aimed to identify macrophages, their immunophenotypes and association with lymphocytes, and translate the findings into survival of patients with primary testicular lymphoma. We collected clinical data and tumor tissue from 74 primary testicular lymphoma patients, and used multiplex immunohistochemistry and digital image analysis to examine macrophage markers (CD68, CD163, and c-Maf), T-cell markers (CD3, CD4, and CD8), B-cell marker (CD20), and three checkpoint molecules (PD-L1, PD-L2, and PD-1). We demonstrate that a large proportion of macrophages (median 41%, range 0.08-99%) and lymphoma cells (median 34%, range 0.1-100%) express PD-L1. The quantity of PD-L1+CD68+ macrophages correlates positively with the amount of PD-1+ lymphocytes, and a high proportion of either PD-L1+CD68+ macrophages or PD-1+CD4+ and PD-1+CD8+ T-cells translates into favorable survival. In contrast, the number of PD-L1+ lymphoma cells or PD-L1- macrophages do not associate with outcome. In multivariate analyses with IPI, PD-L1+CD68+ macrophage and PD-1+ lymphocyte contents remain as independent prognostic factors for survival. In conclusion, high PD-L1+CD68+ macrophage and PD-1+ lymphocyte contents predict favorable survival in patients with primary testicular lymphoma. The findings implicate that the tumor microenvironment and PD-1. PD-L1 pathway have a significant role in regulating treatment outcome. They also bring new insights to the targeted therapy of primary testicular lymphoma.Peer reviewe

Clinical features and outcome of the patients with sinonasal tract diffuse large B-cell lymphoma in the pre-rituximab and rituximab eras

Purpose Sinonasal tract diffuse large B-cell lymphoma (SNT-DLBCL), a rare extranodal lymphoma, is not well characterized. We performed a population-based study to determine cell-of-origin, clinical presentation and impact of rituximab (R) and central nervous system (CNS) directed chemotherapy on survival. Patients and methods Patients with SNT-DLBCL were identified from pathology databases. Clinical information was collected and outcomes between different treatment modalities evaluated. Results Thirty-two percent of the patients had germinal centre B-cell phenotype. Forty-six patients were treated with curative intent using CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like chemotherapy, 21 (46%) before and 25 (54%) in the R-era. Additionally, 24 (52%) received CNS-directed chemotherapy. Addition of R to chemotherapy reduced the risk of progression (RR = 0.368, 95% CI 0.138-0.976, P = 0.045) and death (RR = 0.245, 95% CI 0.068-0.883, P = 0.032), and translated into better survival (5-year PFS, 67% vs 38%, P = 0.037; 5-year OS, 81% vs 48%, P = 0.020). CNS-directed chemotherapy reduced the risk of progression (RR = 0.404, 95% CI 0.159-1.029, P = 0.057) and death (RR = 0.298, 95% CI 0.093-0.950, P = 0.041), and translated into favorable survival (5-year PFS, 67% vs 32%, P = 0.050; 5-year OS 82% vs 43%, P = 0.030). Conclusion Patients with SNT-DLBCL benefit from rituximab and CNS-directed chemotherapy.Peer reviewe