Case Report

Sinonasal Diffuse Large B Cell Lymphoma

Weng-Chi Lei1, Ruey-Long Hong2* 1Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan 2Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

Abstract. Non-Hodgkin lymphoma arising from the sinonasal tract is rare. We present hereby a 71

year-old man with the chief complaints of a left nasal mass, nasal obstruction, bleeding and anosmia. Functional endoscopic sinus surgery and biopsy yielded diffuse large B cell lympho-ma. The patient remained disease-free for about 6 years after 4 courses of CHOP (Cyclophos-phamide, doxorubicin, vincristine, prednisolone) and consolidative involved field radiotherapy, and then the lymphoma recurred in the right nasal cavity. Lymphoblasts were present in the pe-ripheral blood, which turned out to have originated from lymphoma with bone marrow in-volvement. A cerebrospinal fluid study was also positive for lymphoblasts. The patient died 3 months after the disease recurrence despite salvage chemotherapy. The clinical characteristic of sinonasal diffuse large B cell lymphoma is distinct, and there is no consensus regarding stand-ard treatment in this rare group of patients.

Keywords : sinonasal lymphoma, diffuse large B cell lymphoma

病例報告

鼻及鼻竇 B 細胞淋巴瘤

李泳姿 1 洪瑞隆 2* 1國立臺灣大學附設醫院 內科部血液腫瘤科 2國立臺灣大學附設醫院 腫瘤醫學部

中文摘要 從鼻腔及鼻竇長出之非何杰氏淋巴瘤是非常罕見的，我們報告一位 71 歲的男性病

患，開始以左側鼻腔腫瘤表現，並有鼻塞、流鼻血及嗅覺喪失等症狀。內視鏡鼻竇手術

及切片病理報告顯示瀰漫性大 B 細胞淋巴瘤。此病人在接受了四次 CHOP 化學治療及鞏

固性的放射治療後，有 6 年的完全緩解狀態。其後淋巴瘤於右側鼻腔復發，同時於周邊

血液可見芽細胞，其後證實為淋巴瘤併骨髓侵犯所導致，腦脊髓液也發現有淋巴細胞侵

犯。雖然給予挽救性的化學治療，此病患於疾病復發後三個月左右死亡。鼻及鼻竇 B 細

胞淋巴瘤的臨床表現具獨特性，但目前為止尚未有一致的治療建議。 關鍵字: 鼻及鼻竇淋巴瘤、瀰漫性大 B 細胞淋巴瘤

INTRODUCTION

Diffuse large B cell lymphoma (DLBCL) occurs in about 40% of newly diagnosed cases of non-Hodgkin lymphoma. It is a heterogeneous disease and its clas-

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台灣癌症醫誌 (J. Cancer Res. Pract.) 28(4),183-188, 2012

sification, according to the 2008 WHO classification of hematologic malignancies, depends mainly on the primary site of involvement. Lymphomas arising from the sinonasal site comprise mostly of natural killer (NK)/T-cell origin [1,2], while reports regarding si-nonasal DLBCL are rare. Here we report a case of si-nonasal DLBCL, initially presented as stage IIE dis-ease. The lymphoma relapsed as stage IV disease after remaining disease-free for about 6 years. Clinical characteristics and prognosis of this rare group of DLBCL will also be discussed. CASE REPORT

A 71 year-old man had a history of hypertension and herniated intervertebral disc. He used to smoke one pack per day for over 40 years. He suffered from left nasal obstruction, bleeding and anosmia in Febru-ary 2005. No headache, blurred vision, diplopia, ear fullness, otalgia, local swelling or numbness was complained of. Besides, there was no fever, weight loss or night sweats. He visited an ENT clinic at a lo-cal hospital, and a functional endoscopic sinus surgery and biopsy was performed, which yielded a left nasal mass. Pathology showed medium to large-sized mon-onuclear cells with a pleomorphic nucleus containing a prominent nucleolus (Figure 1A). These large cells were stained positive to CD20, which was compatible with the diagnosis of diffuse large B cell lymphoma. He later visited our hospital for a second opinion. On admission, necrotic tissue and debris were found in the left nasal cavity. No other lesion was noted at the ENT field and no neck lymph node was palpable. A PET scan (Figure 2) showed abnormal focal areas of increased activity due to hypermetabolism at the left

Figure 1. A) Pathology of left nasal mass in February

2005 (H&E stain, x400); B) Pathology of recurrent tumor in right nasal cavity in September 2011 (Left: H&E stain, x400; right: IHC stain for CD20)

ethmoid and maxillary sinus, which was compatible with malignancy. Besides, lymph node metastasis to

*Corresponding author: Ruey-Long Hong M.D.

*通訊作者：洪瑞隆醫師

Tel: +886-2-23123456 ext.67510

Fax: +886-2-23711174

E-mail: rlhong@ntu.edu.tw

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Figure 2. PET scan showing left ethmoid, maxillary

sinus mass with bone destruction and left thoracic inlet lymph node

the left thoracic inlet region was also found. Labora-tory data showed leukocytosis (16000/μL) with nor-mal WBC differentiation. Elevated LDH (481U/L), ALT (122U/L) and ALP (283U/L) levels were found. Staging workup concluded the disease stage as IIE, with the international prognostic index (IPI) as 2 points. The patient later received four courses of CHOP (Cyclophosphamide, doxorubicin, vincristine, prednisolone) plus consolidative involved field radio-therapy (50Gy/25 fractions). A follow-up magnetic

resonance imaging (MRI) in October 2005 showed complete remission (CR). In addition, a PET scan in December 2009 and head and neck and brain MRI in March 2011 all showed no evidence of recurrence.

The patient remained event-free until September 2011, when diplopia developed. A mass in the right nasal cavity was found by ENT endoscopy. Recur-rence of lymphoma was suspected. Biopsy of the right nasal mass showed large-sized cells with pleomorphic nuclei, and some of them contained a prominent nu-cleolus. These large cells were diffusely stained posi-tive for CD20 (Figure 1B), which confirmed recurrent disease. Besides, a hemogram showed anemia and left-shifted white blood cells. Lymphoblasts with a high nucleus-cytoplasmic ratio in the peripheral blood were also found (Figure 3A). A bone marrow study showed lymphoma cell infiltrations (Figure 3B). The-se cells were positive for CD20 and negative for CD3 by flow cytometry. Therefore, recurrent diffuse large B cell lymphoma, stage IV with IPI 4 points was di-agnosed. Salvage chemotherapy with CEOP (Cyclo-phosphamide, epirubicin, vincristine, prednisolone) was administered thereafter. However, he suffered from progressive weakness and remained bed-ridden despite salvage chemotherapy. Cytology of CSF yielded presence of lymphoma cells (Figure 4). A di-agnostic impression of lymphoma with central nerv-ous system (CNS) involvement was made, and intra- thecal chemotherapy (methotrexate, Ara-C and steroid) was given then. Whole brain radiotherapy was also carried out. Because of deteriorating clinical condition and progressively poor performance status, palliative oral chemotherapy with cyclophosphamide was given to this patient. He later died of septicemia in January 2012. DISCUSSION

Although extranodal NK/T cell lymphoma, nasal type has already been included as a distinct entity in the 2008 WHO classification of hematologic malig-nancies, the clinical characteristics and prognosis of

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Figure 3. A) Lymphoblasts in peripheral blood (Liu

stain, x1000); B) bone marrow infiltrated with lymphoma cells (Liu stain, x1000)

Figure 4. Lymphoma cells in CSF (Liu stain, x1000) diffuse large B cell lymphoma arising from this ana-tomic site is not well defined. Noses and sinuses ac-count for about 20% of all extranodal sites involved in non-Hodgkin lymphoma and are the third most com-mon site of all [3]. In addition, a recent study [4] from Tainan, Taiwan, showed that among 76 patients with lymphomas arising from the upper aerodigestive tract, 18 (27%) of them were of the sinonasal region. B cell accounted for 16.7% (3 of 18) and NK/T cell ac-counted for 83.3% (15 of 18) of these 18 patients. Stage I/II disease accounted for over 90% of cases for

both B and T cells. The 5-year overall survival for B and T or NK/T cell lymphomas were 66% and 41%, respectively (p=0.042). Patients with an elevated LDH level had a worse outcome, and LDH was the only independent poor prognostic factor for DLBCL pa-tients in the multivariate analysis in this study.

Another study from Korea, using immunopheno-typic analysis with CD20, CD45RO, CD3, CD56 as differentiating markers [1], identified B cell in 25%, T cell in 33%, and NK/T cell in 42% of lymphoma pri-marily arising from the sinonasal region. The majority (63%) of B cell lymphoma involved the paranasal si-nuses while most of the T cell (67%) and NK/T cell (68%) lymphoma involved the nasal cavity. The pat-tern of treatment failure was similar between B cell and NK/T cell lymphomas. As compared to NK/T cell lymphoma, patients with sinonasal B cell lymphoma had a longer overall survival and disease-free survival. The five year survival rates for B cell and NK/T cell lymphomas were 57% and 37%, respectively.

Another study from China focused on 25 patients with primary nasal DLBCL [5]. The median age was 48 years with male predominance (72%). Most of the patients had stage I disease (72%) with paranasal ex-tension (84%). B symptoms (weight loss, night sweats, and fever) (4%) and an elevated LDH level (20%) were infrequent and over three-fourths of them were of low risk (IPI 0-1 point). Median overall survival was 35 months, and 3-yr overall survival rate was 51%. Patients with an ECOG performance score of 0-1 had a better outcome than patients with a score of 2-3 (3-yr OS: 51% vs 20%, p=0.025). Patients with low risk also had longer survival than those with higher risks (3-yr OS: 54% vs 17%, p=0.033). In addi-tion, patients achieving CR after therapy also fared better than non-CR patients (3-yr OS: 67% vs 13%, p=0.008). In this study, 7 of 8 patients with sufficient data evaluable for the pattern of failure had extranodal failures. One had local recurrence. Among the 7 ex-tranodal sites involved, only one (14%) was CNS in-volved in recurrence.

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Four of 14 patients (29%) suffered from CNS re-lapse in another case series of primary paranasal sinus DLBCL [6]. Two of the 4 patients were in CR and 2 were in PR after CHOP or CHOP-like regimen. None of these 4 patients achieved second CR after salvage intrathecal and systemic chemotherapy and all of them died of their disease 2 to 11 months after CNS relapse. CNS prophylaxis was suggested in addition to sys-temic chemotherapy by the authors because of the high rate of CNS relapse.

Rituximab plus anthracycline-based chemotherapy became the standard treatment of DLBCL in the past decade[7,8]. In the prospectively randomized study by Feugier et al. [9] adding rituximab to CHOP did not influence the risk of CNS occurrence in elderly DLBCL patients compared to CHOP alone. Low rituximab diffusion across the blood–brain barrier was proposed as the mechanism of the lack of influence of rituximab. Age-adjusted IPI was the only identified risk factor that influenced relapse of CNS disease. Although a few reports discussed the role of rituximab in treating sinonasal DLBCL, concerning its high rate of CNS relapse, CNS prophylaxis has nevertheless been proposed by some authors [6]. Guirguis et al. [10] retrospectively reviewed the impact of CNS prophy-laxis and outcome of DLBCL patients treated with R-CHOP. Patients receiving CNS prophylaxis tended to be more advanced in the disease, and had more se-vere extranodal disease and a higher IPI score. Pa-tients who did not receive CNS prophylaxis had lower events (2.7%) than those who did (11.1%). Testicular involvement was the only significant prognostic factor for CNS relapse (HR: 33.5, p<0.001). They concluded that R-CHOP may negate the need of CNS prophylax-is except for patients with testicular lymphoma.

There seems to be some differences regarding the clinical manifestations and outcome of patients with lymphomas from the sinonasal region between the West and the East. Fifty-eight patients presenting with lymphoma from the nasal cavity or paranasal sinuses were reported from Massachusetts General Hospital

[11]. In this report, DLBCL was more frequent than NK/T cell lymphoma (57% vs. 29%). Besides, there were more female patients with NK/T cell lymphoma while there were more male patients with DLBCL. At last follow-up, 73% of NK/T cell lymphoma patients had no evidence of disease, in contrast to 67% of DLBCL patients remaining disease-free. Furthermore, more continuous complete remission was noted in NK/T cell lymphoma patients (73% vs. 58% of DLBCL).

CONCLUSIONS

In conclusion, DLBCL is a rare presentation of malignancy in the sinonasal region. In most of cases DLBCL presents as stage I or II disease. There are some discrepancies regarding clinical characteristics and treatment outcome between Eastern and Western sinonasal lymphomas, with NK/T cell more prevalent in the East and DLBCL more prevalent in the West. Besides, NK/T cell lymphoma confers a worse out-come in the East, while it is similar to DLBCL in the West. Until now, there is no consensus regarding standard treatment in this rare group of patients. CNS prophylaxis may be needed on account of the high rate of CNS relapse. More studies are needed to better un-derstand the biologic nature of DLBCL and define its proper treatment. REFERENCES 1. Kim GE, Koom WS, Yang WI, et al. Clinical rel-

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3. Yang QP, Zhang WY, Yu JB, et al. Subtype dis-tribution of lymphomas in Southwest China: analysis of 6,382 cases using WHO classification

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