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Multifocal Extranodal Non-Hodgkin Lymphoma: A Clinicopathologic Study of 37 Cases in Greece, a Hellenic Cooperative Oncology Group Study

^a Second Department of Internal Medicine, Athens University, University General Hospital "Attikon," Haidari, Greece; ^b Pathology Department, Evangelismos Hospital, Athens, Greece; ^c AHEPA Hospital, Aristotle University, Thessaloniki, Greece; ^d University Hospital, Alexandroupoli, Greece; ^e Medical Oncology Department, Ioannina University, Ioannina, Greece; ^f Department of Clinical Therapeutics, University of Athens, Athens, Greece

Key Words. Lymphoma • Extranodal • Multifocal

Correspondence: T. Economopoulos, University General Hospital "Attikon," 1 Rimini Str., 124 62 Haidari, Greece. Telephone: 30-210-5831255; Fax: 30-210-5326450; e-mail: sotirispapageorgiou{at}hotmail.com

Received August 2, 2005; accepted for publication August 10, 2005.

	ABSTRACT

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The purpose of this retrospective study was to illustrate the clinicopathological features of patients presenting with multifocal extranodal non-Hodgkin lymphoma (NHL). Among 810 patients with NHL, 37 cases (4.2%) were found to have multiple extranodal involvement (two or more sites). There were 24 men and 13 women, with a median age of 63 years. The majority of these cases (n = 26) had gastric or intestinal (GI) involvement with or without other extranodal sites. Lung along with another extranodal site was relatively common in the present series. Stratification of the 37 cases according to the International Prognostic Index (IPI) showed that 89% of the patients belonged to the high-risk groups. Diffuse large-B-cell lymphoma (DLBCL) accounted for 62%, and mucosa-associated lymphoma tissue (MALT) lymphoma accounted for 27% of all cases. After induction treatment with anthracycline-based regimens, complete remission was achieved in 21 patients (57%), partial remission was achieved in six patients (16%), and seven patients (19%) had no response, while three patients (8%) were nonevaluable. In conclusion, multifocal extranodal NHL is a heterogeneous group of diseases. The majority of them arise at various sites in the GI tract. DLBCL was the most frequent histological subtype followed by MALT lymphoma. Risk group, as defined by the IPI, was predictive of survival.

	INTRODUCTION

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The involvement of extranodal sites is a common feature during the course of non-Hodgkin lymphomas (NHLs). Moreover, some NHLs are considered to originate at sites other than the lymph nodes or spleen and are referred to as primary extranodal lymphoma (PE-NHL) [1, 2]. The origin of most PE-NHLs can be ascribed to one given organ system or site. However, there exists a heterogeneous collection of NHLs that may involve multiple sites throughout the body at presentation. This group of NHL includes Burkitt’s lymphoma, angiotropic (intravascular) large-cell lymphoma, and angio-centric lymphoma [3]. In addition to the above subtypes of NHL, there is a group of lymphomas that includes patients whose disease is diagnosed simultaneously at several extra-nodal sites. Although most of these cases are localized to the gastrointestinal (GI) tract [4, 5, 6], they also involve a variety of extranodal sites outside the GI tract.

To assess the incidence, disease features, and outcome of patients presenting with multifocal extranodal lymphomas, we performed a retrospective analysis of the Hellenic Cooperative Oncology Group (HeCOG) lymphoma registry.

	MATERIALS AND METHODS

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Between May 1994 and December 2002, 810 patients with NHL were diagnosed and treated in different centers of the HeCOG. Among these, 37 patients (4.2%) were found to have multiple extranodal involvement (two or more sites) at presentation. Patients with concomitant involvement of lymph nodes, spleen, or bone marrow were not included. All patients were classified according to the World Health Organization classification [7]. The original histological slides of the 37 patients with multifocal involvement were reviewed by two expert hematopathologists (D.R., V.K.). Patients with Burkitt’s lymphoma were excluded from the study.

Patients were staged according to the Ann-Arbor classification [8] with its modification by Musshoff [9] for GI tract lymphomas. Staging was performed by physical examination; surgical reports; complete blood count; computed tomography scan of the thorax, abdomen, and pelvis; biochemical profile; and bone marrow biopsy. When indicated, a bone scan, biopsies of suspicious lesions, and examination of the cerebrospinal fluid were also performed. All patients with GI involvement underwent endoscopy.

Most presenting symptoms were caused by the extra-nodal involvement, and extranodal presentation remained the clinically dominant site of disease.

Of 37 patients, 28 received chemotherapy alone, whereas nine underwent surgery, which was followed by chemotherapy in eight of them. Surgery consisted of subtotal gastrectomy in five cases, small intestine resection in two cases, colectomy in one case, and thyroidectomy in one case. As far as chemotherapy is concerned, 30 patients received an anthracycline-based regimen, CHOP/CEOP/CNOP (cyclophosphamide, doxorubicin [Adriamycin^®; Bedford Laboratories, Bedford, OH, http://www.bedford-labs.com]/epirubicin [Ellence^®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com]/mitoxantrone [Novantrone^®; Serono, Inc., Rockland, MA, http://www.seronousa.com], vincristine [Oncovin^®; Eli Lilly and Company, Indianapolis, http://www.lilly.com], prednisone [Deltasone^®; Pfizer Pharmaceuticals]); three patients received a combination of fludarabine (Fludara^®; Berlex Laboratories, Wayne, NJ, http://www.berlex.com) and mitoxantrone; three patients received a combination of CEOP with the monoclonal antibody rituximab (Rituxan^®; Genentech, Inc., South San Francisco, CA, http://www.gene.com); and one patient refused further treatment after surgery.

Response after treatment was assessed according to the report of the international workshop to standardize response criteria for NHL [10]. Complete response (CR) required the complete disappearance of all detectable clinical and radiological evidence of disease, disappearance of all disease-related symptoms, and normalization of those biochemical abnormalities definitely assignable to the lymphoma. Partial response (PR) required at least a 50% decrease in the sum of the products of the greatest diameters of the involved extranodal site. Any lesser response was considered as a nonresponse (NR). Overall survival was estimated from the date of first biopsy to the date of last follow-up or until the patient’s death. Time to disease progression (TTP) was calculated from the date of the first biopsy to the date of the first progression of the disease. However, the deaths of patients who died because of disease-related factors without having previous documentation of disease progression were considered as events in the estimation of TTP. The Kaplan-Meier method [11] was used to calculate TTP, median follow-up, and survival curves, while the log-rank test was used to compare time-to-event distributions.

Exact binomial confidence intervals were used to determine the 95% upper and lower confidence limits of the response rate [12].

	RESULTS

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Clinical and Laboratory Findings
The clinical and laboratory findings of all patients are listed in Table 1. There were 24 men and 13 women, with a median age of 63 years (range, 19–82). Lymphomas originating from more than one extranodal site do not fit into the Ann-Arbor classification or its modification by Musshoff [9] for GI lymphomas, other than stage IVE. Therefore, all our patients were considered as stage IV. The stratification of the 37 cases according to the International Prognostic Index (IPI) [13] showed that the vast majority of the patients (89%) was in the high-risk groups.

The remaining 11 patients presented with two or more extranodal sites other than the GI tract. Bone and lung were affected most commonly.

Seven of the above cases had DLBCL, two had MALT NHL, one had angiocentric T-cell NHL, and one had lymphoplasmacytoid lymphoma (Table 2).

Response to Treatment and Survival
Thirty-four patients were evaluable for response. Three patients could not be evaluated for the following reasons: patient’s refusal of therapy (n = 1) and lost to follow-up (n = 2).

After induction treatment, CRs were achieved in 21 patients (57%), PRs were achieved in 6 patients (16%), and 7 patients (19%) were NR. The median overall survival duration for all patients was 71.8 months (range, 3.8–132.1), and the median TTP was 25.9 months (range, 2.7–132.1) (Fig. 1).

View larger version (12K): [in this window] [in a new window]   Figure 1. Overall survival (solid line) and time to progression (dashed line) for all patients.

Two patients developed a second malignancy. One patient with initial involvement of the testis, nasopharynx, and skin, with diffuse large-cell histology, developed esophageal cancer. Another patient with thyroid involvement and an abdominal mass, with MALT histology, developed colon cancer.

	DISCUSSION

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NHL constitutes a group of disorders originating from the malignant transformation of lymphocytes and involving either the lymph nodes or extranodal sites. Extranodal lymphomas may comprise 24%–48% of NHL cases, and there appears to be an increasing incidence of these lymphomas during the past decades [1]. Extranodal lymphomas may occur in any organ. They present most frequently in the GI tract, followed by Waldeyer’s ring, when tonsils are regarded as an extranodal site. Other common sites are skin and bone. Less common primary localizations of PE-NHL have also been reported [1, 2, 14].

Although there are reports on PE-NHL of various sites, especially GI-NHL, there remain many questions concerning the clinicopathological features and treatment outcome of these patients. These factors are well known for Burkitt’s, angiotropic, and angiocentric lymphomas [3], but the subject of the multifocal extranodal appearance of the various histological subtypes is not well studied. The incidence of such cases is poorly defined, apart from GI multifocal lymphomas, which comprise 4%–7% [4, 6, 15].

Our study included 37 patients with primary lymphoma involving multiple extranodal sites at presentation. Among 810 patients diagnosed and treated in our centers, the incidence of multifocal extranodal disease was 4.2%. The majority of these cases (n = 26) had gastric or intestinal involvement with or without other extranodal sites. Lung along with another extranodal site was relatively common in the present series. The remaining multifocal cases were patients with head and neck lymphoma, bone lymphoma, and testicular lymphoma.

In our series of multifocal extranodal lymphoma, DLBCL was the most frequent histological subtype, comprising 62% of cases. Next in frequency were low-grade MALT lymphomas (27%). These findings are in agreement with those reported in a large series of GI lymphomas with multiple sites of involvement [6]. However, in another series [4], low-grade MALT lymphoma was the most frequent histological subtype among cases with multiple GI involvement.

The reason for multifocal extranodal lymphomas or the preferential involvement of specific extranodal sites at recurrence is not clear, but it is likely that this is closely linked to the homing process regulated by homing receptors or lymphoid cells and ligands on high endothelial venules [16]. This tropism for specific sites has been particularly noticeable for the tonsils and stomach [17, 18], testis and nasopharynx, and skin and bone [16, 19].

The vast majority of the lymphomas in our study were of B-cell origin, in particular DLBCL from cells at the germinal-center or postgerminal-center stage of development. One explanation for the high frequency of B-cell lymphomas might be the fact that the B cells undergo clonal expansion during proliferation in the microenvironment of the germinal centers. It appears that B-cell lymphomas often need stimulation that involves the antigen receptor or other receptors on the surface of the lymphoma cells. It could be that the stimulus is the same in the different sites of origin of B-cell lymphomas. The genetic events that take place in germinal cells and give rise to B-cell lymphoma do not exist during the development of T-cell lymphocytes. This could be the reason for the fact that the T cells give rise to lymphomas one tenth to one twentieth as often as B cells [20].

Since our study is retrospective, conclusions about treatment efficacy should be made with caution. It is noteworthy, however, that all patients were treated with anthracycline-based regimens, and that low-risk patients had excellent treatment responses. For patients in the high-risk group, the prognosis was less favorable.

In summary, our results indicate that lymphomas that are multifocal at presentation are a heterogeneous group of diseases. The majority of them arise at various sites in the GI tract, while a considerable number of cases include lung involvement along with other extranodal sites. Histologically aggressive NHL accounted for the majority of cases, and risk group, as defined by the IPI, was predictive of survival.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicate no potential conflicts of interest.

	REFERENCES

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