Primary Diffuse Large B-Cell Lymphoma of the TonsilIs a Higher Radiotherapy Dose Required?

Siddhartha Laskar, MD1

Gaurav Bahl, MD1

Mary Ann Muckaden, MD1

Reena Nair, MD2

Sudeep Gupta, DM2

Ashish Bakshi, DM2

Sumeet Gujral, MD3

Tanuja Shet, MD3

Shyam Kishore Shrivastava, MD1

Ketayun Ardeshir Dinshaw, FRCR1

1 Department of Radiation Oncology, Tata Memo-rial Centre, Tata Memorial Hospital, Mumbai, India.

2 Department of Medical Oncology, Tata MemorialCentre, Tata Memorial Hospital, Mumbai, India.

3 Department of Pathology, Tata Memorial Centre,Tata Memorial Hospital, Mumbai, India.

BACKGROUND. The purpose was to evaluate the prognostic factors and treatment

outcome of Indian patients with primary diffuse large B-cell lymphoma (DLBCL)

of the tonsil treated at a single institution.

METHODS. In all, 121 patients with DLBCL of the tonsil, treated at the Tata Me-

morial Hospital, Mumbai, India, from January 1990 to December 2002, were

included. The median age was 45 years and the majority of patients (68%) were

males. Systemic symptoms were present in 12% of patients; 28% presented with

stage I and 67% had stage II disease. Treatment consisted of a combination of

chemotherapy (CTh) and radiotherapy (RT) for the majority of patients (69.4%).

Among those receiving RT, 64% received an RT dose of �45 Gy.

RESULTS. After a median follow-up of 62 months, disease-free survival (DFS) and

overall survival (OS) were 66.4% and 81.6%, respectively. Significant prognostic

factors included: WHO performance score �2 (OS: 72.1% vs 95.6%, P 5 .016),

bulky tumors (OS: 68.5% vs 86.9%, P 5 .001), presence of B-symptoms (OS: 36.7%

vs 79.6%, P < .001), and Ann Arbor stage. On multivariate analysis; WHO per-

formance score �2 (hazard ratio [HR], 4.27; 95% confidence interval [CI], 1.20–

15.12), and B symptoms (HR, 6.27; 95% CI, 2.38–16.48), retained statistical signifi-

cance. CTh 1 RT resulted in a significantly better outcome than those treated

with CTh alone (OS: 85.7% vs 70.7%, P 5 .008). The complete response (P 5 .053),

DFS (P 5 .039), and OS (P 5 .014) rates were significantly better for patients

receiving an RT dose �45 Gy.

CONCLUSIONS. Tumor bulk, WHO performance score, the presence of B symp-

toms, and Ann Arbor stage significantly influence outcome. A combined modality

treatment, consisting of CTh and RT (with an RT dose of �45 Gy), results in a

satisfactory outcome in patients with this uncommon neoplasm. Cancer

2007;110:816–23. � 2007 American Cancer Society.

KEYWORDS: diffuse large B-cell lymphoma, non-Hodgkin, extranodal, tonsil,radiotherapy.

M alignant lymphoma is primarily a disorder of the lymph nodes;

however, 24% to 48% of all non-Hodgkin lymphomas (NHL)

may arise from extranodal sites, and there appears to be an increas-

ing incidence of such lymphomas during the past few decades.1

Approximately 10% of patients with NHL present with extranodal dis-

ease in the head and neck region.2 Furthermore, more than half of

these head and neck lymphomas occur in the Waldeyer ring,2,3 and

40% to 50% of these arise from the tonsil.4,5 These lymphomas occur

predominantly in elderly males and present as a tonsillar swelling,

cervical adenopathy, dysphagia, odynophagia, or with a sore throat.

The majority of tonsil lymphomas are of B-cell origin and the most

common histological type is diffuse large B-cell lymphoma

(DLBCL).6,7 Most patients present with localized disease: stage I in

Address for reprints: Siddhartha Laskar, MD,Department of Radiation Oncology, Tata MemorialHospital, Dr. Ernest Borges Road, Parel, Mumbai,India, 400 012; Fax: (011) 91 22 24146937;E-mail: laskars2000@yahoo.com

Received February 16, 2007; revision receivedMarch 20, 2007; accepted March 26, 2007.

ª 2007 American Cancer SocietyDOI 10.1002/cncr.22841Published online 20 June 2007 in Wiley InterScience (www.interscience.wiley.com).

816

12% to 42%, stage II in 36% to 60%, and stage III or

IV disease in 10% to 20% or less.6–9 Treatment

approaches that have been used include radiotherapy

(RT) alone, chemotherapy (CTh) alone, or a combina-

tion of both (CTh 1 RT).5,10 Most series in the litera-

ture have reported results of treating lymphomas

of the Waldeyer ring as a group and the resultant di-

versity of primary site, histology, presentation, thera-

peutic modality, and outcome makes it difficult to

draw meaningful conclusions from these studies. In

an attempt to further define the prognostic factors,

appropriate management, and treatment outcome for

patients with primary DLBCL of the tonsil, we re-

viewed our experience with this particular extranodal

lymphoma.

MATERIALS AND METHODSOne hundred and twenty-one patients with DLBCL

of the tonsil were treated at the Tata Memorial Hos-

pital from January 1990 to December 2002. All

patients were of Indian origin. The age at presenta-

tion ranged from 11 to 74 years with a median age of

45 years. There were 82 males and 39 females (male-

to-female ratio 2.1:1). The majority of patients (57%)

presented with cervical lymphadenopathy. The other

common presenting symptoms were growth or ulcer

on the tonsil (38%), dysphagia or foreign-body sensa-

tion (36%), odynophagia or otalgia (20%), change in

voice (5.8%), and presentation with only ‘B’ symp-

toms (1.6%). Thirty-three (27%) patients had lesions

that were clinically or radiologically determined to

be over 7 cm in size (bulky tumors). Pathologic spe-

cimens of all patients were evaluated by experienced

pathologists at our institute and classified according

to the REAL classification system.11 All patients

included in this study were diagnosed on the basis of

histopathology and immunohistochemistry to have

DLBCL. The patients were clinically staged according

to the Ann Arbor system. Staging investigations

included complete blood cell counts, serum bio-

chemistry, bone marrow aspirate and trephine bi-

opsy, chest x-ray, ultrasonography of the abdomen

and pelvis, or computed tomography (CT) scan of

the thorax, abdomen, and pelvis, and CT scan of the

head and neck region. Thirty-four (28%) patients had

stage I disease, 81 (67%) had stage II disease,

whereas 6 (5%) had stage III/IV disease (stage III, 4;

stage IV, 2). Systemic symptoms (B-symptoms) were

present in only 15 (12%) patients, consisting of fever

(80%), weight loss (60%), and night sweats (15%).

Eighty-four (69.4%) patients were treated with a

combination of CTh and RT, whereas the remaining

37 (30.6%) received CTh alone. The distribution of

treatment choice by stage is shown in Table 1. The

various CTh regimens used were CHOP (cyclophos-

phamide 750 mg/M2, doxorubicin 50 mg/M2, vincris-

tine 1.4 mg/M2, and prednisolone 100 mg) in 65.3%

(n 5 79), COP (cyclophosphamide 750 mg/M2, vin-

cristine 1.4 mg/M2, and prednisolone 40 mg) in

24.8% (n 5 30), MACOP-B (methotrexate 400 mg/M2,

doxorubicin 50 mg/M2, cyclophosphamide 350 mg/

M2, vincristine 1.4 mg/M2, prednisolone 75 mg, and

bleomycin 10 U/M2) in 8.3% (n 5 10), and other

CTh regimens in 1.6% (n 5 2) patients. The financial

status of the patient influenced the choice of chemo-

therapy. External beam radiation therapy (EBRT) was

delivered using 60 cobalt c-rays or 6MV photons

using conventional bilateral parallel opposed portals.

The portals included the entire Waldeyer ring and

the lymphatic drainage areas (bilateral level Ib to

level V neck nodes). The EBRT dose ranged from 30

to 54 Gy with a median dose of 45 Gy. Despite the

wide dose range, the use of 2 fractionation schedules

predominated; 56% (n 5 47) of the 84 patients trea-

ted with CTh 1 RT received an EBRT dose of 45 Gy

in 25 fractions, whereas 29% (n 5 24) were irradiated

to a dose of 40 Gy in 20 fractions.

Statistical AnalysisFollow-up information was abstracted from patients’

hospital records and from an existing database of

patients attending the Joint Lymphoma Clinic. Con-

secutive patients with involvement of the tonsils

were considered for this retrospective study based on

the following selection criteria: 1) primary symptoms

and majority of the tumor bulky localized in 1 or

both tonsils; 2) histopathologic examination and

immunohistochemistry confirming the diagnosis of

DLBCL type of NHL. Complete response (CR) rates,

disease-free survival (DFS), and overall survival (OS)

were the endpoints reviewed in this study. The defi-

nitions of CR, partial response (PR), stable disease

(SD), and progressive disease (PD) provided by the

WHO criteria for reporting results12 were used. The

chi-square (v2) test was used to compare CR rates.

OS was calculated from date of registration to the

TABLE 1Treatment by Stage

Stage

Treatment type

Chemotherapy alone Chemo 1 radiotherapy

I 9 (26.5%) 25 (73.5%)

II 25 (30.9%) 56 (69.1%)

III and IV 3 (50%) 3 (50%)

Total 37 (30.6%) 84 (69.4%)

DLBCL of the Tonsil/Laskar et al. 817

date of death due to any cause. Univariate analysis

for DFS and OS rates were done using the Kaplan-

Meier method and prognostic factors were compared

using the log-rank test. Multiple-covariate analysis

was performed using the stepwise Cox proportional

hazards regression model. The hazard ratio (HR)

with the 95% confidence interval (CI) was calculated

for the treatment groups.

RESULTSAfter a median follow-up of 62 months (range, 2–176

months) for surviving patients, 86 patients were alive

and without disease, 17 were alive with disease, 14

patients had died due to disease, 2 patients had died

as a result of chemotherapy-related febrile neutrope-

nia, 1 elderly gentleman had succumbed to a second

cancer (squamous carcinoma of the base tongue) 6

years after radiotherapy, and 1 young man had died

in a traffic accident. The complete response rate to

therapy was 81.8%. The 10-year DFS and OS were

66.4% and 81.6%, respectively (Fig. 1).

Prognostic FactorsVarious prognostic factors were analyzed to establish

their influence on response rates and the survival of

patients with DLBCL of the tonsil. On univariate

analysis, patients with lesions that were clinically or

radiologically determined to be over 7 cm in size

(bulky) had a significantly poorer outcome as com-

pared with those with smaller (nonbulky) tumors.

The CR, DFS, and OS rates for these 2 groups were

66.7% vs 87.5% (P 5 .015), 50.6% vs 72.7% (P 5 .003),

and 68.5% vs 86.9% (P 5 .013), respectively. Male

patients had better CR rates as compared with

females (86.6% vs 71.8%, P 5 .045); however, this did

not translate into any difference in DFS or OS (Ta-

ble 2). Other patient-related factors that had a sta-

tistically significant influence on survival were:

WHO performance score �2 (OS: 72.1% vs 95.6%,

P 5 .016), presence of B-symptoms (OS: 36.7% vs

79.6%, P < .001), and the Ann Arbor stage (Table 2;

Fig. 2). The CR (P 5 .002), DFS (P 5 .005), and OS

(P 5 .012) rates were 97.1%, 90.7%, and 100% for

stage I; 77.8%, 59.5%, and 74% for stage II; and 50%,

0%, and 0% for stage III and IV disease, respectively.

When these factors were entered into multivariate

analysis using the stepwise logistic regression model

to determine independent prognostic variables, a

WHO performance score of �2 (HR, 4.27; 95% CI,

1.20–15.12; P 5 .024) and the presence of B symp-

toms (HR, 6.27; 95% CI, 2.38–16.48; P < .001) retained

statistical significance (Table 3).

Treatment OutcomeNinety-nine of the 121 patients had a CR to treat-

ment resulting in an overall CR rate of 81.8%. At the

time of analysis 12 (12.1%) of the patients who had

achieved CR had recurred. Eight of these patients

had failed at the site of initial disease, 3 patients

developed disseminated disease and involvement of

the bone marrow, whereas 1 patient had developed a

recurrence at a new site altogether.

The 84 (69.4%) patients who were treated with a

combination of multiagent chemotherapy and radia-

tion therapy had a significantly better outcome than

the 37 (30.6%) patients managed with chemotherapy

alone (Fig. 3). The CR, DFS, and OS rates for these 2

treatment groups were: 91.7% vs 59.5% (P < .001),

78.4% vs 35.6% (P < .001), and 85.7% vs 70.7%

(P 5 .008), respectively. The type of therapy used

FIGURE 1. (A) Disease-free survival. (B) Overall survival (Kaplan-Meier).

818 CANCER August 15, 2007 / Volume 110 / Number 4

(CTh alone vs CTh 1 RT) retained statistical signifi-

cance when entered in the multivariate analysis

along with other prognostic factors. The HR for death

in the chemotherapy alone group was 2.71 (95% CI,

1.02–7.19). In the subgroup of patients who received

combined modality therapy, 54 patients (64%) had

received an EBRT dose �45 Gy, whereas 30 (36%)

had received a dose <45 Gy. The CR (96.3% vs 83.3%,

P 5 .053), DFS (91% vs 59.7%, P 5 .039), and OS

(88.2% vs 78.9%, P 5 .014) rates were found to be sig-

nificantly superior for those who had received a dose

�45 Gy (Table 2). The hazard ratio for death in the

subgroup that received a radiotherapy dose of <45

Gy was 9.89 (95% CI, 1.88–52.02) (Table 3). On the

other hand, the chemotherapy regimen used did not

seem to significantly influence the outcome. The CR

(P 5 .096), DFS (P 5 .881), and OS (P 5 .577) rates

were 84.8%, 70%, and 85.6% for patients who

received CHOP chemotherapy vs 80%, 60.9%, and

78.6% for those who received COP vs 66.7%, 67.5%,

and 72.9% for patients who received other chemo-

therapy regimens, respectively (Table 2). A total of 83

of the 121 patients attained a CR to the initial CTh.

Sixty-one (73.5%) of these patients received adjuvant

RT after completion of CTh, whereas 26.5% (n 5 22)

received no further treatment. The DFS was signifi-

cantly better for patients treated with adjuvant radio-

therapy (96.2% vs 54.4%, P < .001); however, there

was no difference in the OS (98.2% vs 95%) (Fig. 4).

DISCUSSIONMost of the Waldeyer ring lymphomas reported in

the literature are of B-cell origin.6,8,9,13,14 Further-

more, the vast majority of these lymphomas, ranging

from 67% to 96%, have been reported to be of high

to intermediate grade.6,15 The Sheffield Lymphoma

Group, in their 30-year experience with extranodal

lymphomas of the head and neck region, found the

most common histologic subtype to be DLBCL.16

TABLE 2Prognostic Factors for Clinical Outcome

Prognostic factor No.

Complete response

rate (CR) P

10-year disease-free

survival (DFS) P

10-year overall

survival (OS) P

All 121 81.8% — 66.4% — 81.6% —

Sex

Male 82 86.6% .045 67.3% .384 84.2% .189

Female 39 71.8% 66.0% 76.6%

Age

�30 y 28 85.7% .38 85.0% .109 85.0% .857

[30 y 93 80.6% 61.1% 80.2%

WHO performance score

0–1 51 92.2% .016 66.9% .180 95.6% .016

2–4 70 74.3% 64.8% 72.1%

B symptoms

Yes 15 53.3% .006 32.1% .003 36.7% \.001

No 106 85.8% 70.1% 87.5%

Tumor size

Bulky,[7 cm 33 66.7% .015 50.6% .003 68.5% .001

Nonbulky 88 87.5% 72.7% 86.9%

Ann Arbor stage

I 34 97.1% .002 90.7% .005 100% .012

II 81 77.8% 59.5% 74.0%

III and IV 6 50% 0% 0%

Treatment

Chemotherapy alone 37 59.5% \.001 35.6% \.001 70.7% .008

Chemotherapy 1 radiotherapy 84 91.7% 78.4% 85.7%

Chemotherapy

COP 30 80.0% .096 60.9% .881 78.6% .577

CHOP 79 84.8% 70.0% 85.6%

Other 12 66.7% 67.5% 72.9%

Radiotherapy dose

\45 Gy 30 60% .01 59.7% .039 78.9% .014

�45 Gy 54 82% 91.0% 88.2%

COP indicates cyclophosphamide, vincristine, and prednisolone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone.

DLBCL of the Tonsil/Laskar et al. 819

Although T-cell and NK/T-cell lymphomas may make

up a sizeable fraction of nasopharyngeal NHL, the

most common histologic subtype to involve the ton-

sils is, by far, DLBCL.14–18 Ezzat et al.14 reported 84%

of their patients to have DLBCL, whereas Qin et al.18

found 64% of the tonsil lymphomas in their series to

be of the DLBCL subtype. Furthermore, a majority of

these patients (60%–70%) present with early stage

(stages I and II) disease.6,7 Gao et al.19 reported

69.6% of their patients to have localized (stage I or

FIGURE 2. Overall survival for prognostic factors (n 5 121). (A) Stage. (B) Performance score (WHO). (C) Presence of B symptoms. (D) Size of tumor ([7 cm 5 bulky).

TABLE 3Multiple-Covariate Cox Regression Analysis for Prognostic Factors

Variable

Disease-free survival Overall survival

P HR 95% CI P HR 95% CI

WHO performance score �2 .111 1.81 0.87–3.79 .024 4.27 1.20–15.12

Presence of B symptoms .040 2.42 1.04–5.62 \.001 6.27 2.38–16.48

Presence of bulky lesions, �7 cm .012 2.48 1.22–5.01 .130 2.36 0.85–6.53

Treatment with chemotherapy alone. no radiotherapy \.001 7.07 3.31–15.09 .045 2.71 1.02–7.19

Radiotherapy dose\45 Gy .005 9.65 1.98–46.98 .007 9.89 1.88–52.02

CI indicates confidence interval; HR, hazard ratio.

820 CANCER August 15, 2007 / Volume 110 / Number 4

II) disease, whereas in the series by Mohammadian-

panah et al.17 18% of patients had stage I and 67%

had stage II disease.

From January 1990 to December 2002, 148

patients with NHL involving the tonsil were treated

at the Tata Memorial Hospital, Mumbai. The vast

majority of these patients (81.7%) had the DLBCL

histologic subtype. To avoid the confounding influ-

ences of the other histologies, we only included the

121 patients with primary DLBCL of the tonsil in this

analysis.

In our current study we found a relatively

younger cohort of patients as compared with the

reported literature. The median age at presentation

was 45 years and 23% of our patients were under

30 years of age. The majority of our patients pre-

sented with early stage disease, 28% had stage I, and

67% had stage II disease.

Treatment policies for Waldeyer ring lymphomas

have included RT with or without CTh for limited

stage disease and aggressive CTh with or without RT

for advanced stage disease. Authors have reported

5-year survival rates of 60% to 80% for patients with

early stage disease.8,9 Qin et al.18 reported a 5-year

OS of 84% for stage I-II tonsil NHL, whereas Gao

et al.20 reported an OS of 65% for these patients. In a

study by Gao et al.19 larger size of the tumor, poor

performance status, presence of systemic symptoms,

and a higher Ann Arbor stage were indicative of a

poor prognosis. Other studies have also found size

and stage of disease to be poor prognostic fac-

tors.6,7,21 In our current series, WHO performance

score �2, the presence of B-symptoms, tumor bulk

[7 cm, and higher Ann Arbor stage were associated

with inferior outcome (Table 2). On multivariate

analysis, a performance score �2 and the presence

of ‘B’ symptoms retained their poor prognostic sig-

nificance (Table 3). The 10-year DFS for patients

with stage I or stage II disease was 90.7% and 59.5%,

respectively.

The majority of our patients (69.4%) were treated

with a combination of CTh and RT, resulting in a

DFS and OS of 78.4% and 85.6%, respectively, which

was superior to the group receiving CTh alone (DFS:

35.6%, P < .001; OS: 70.7%, P 5 .008). Furthermore,

even patients who attained CR after chemotherapy

benefited significantly from the addition of adjuvant

RT (96.2% vs 54.4%, P < .001). Similarly, Gao et al.20

FIGURE 3. Overall survival by treatment type (Kaplan-Meier). (A) Chemotherapy alone (n 5 37) vs chemotherapy plus radiotherapy (n 5 84). (B) Radiotherapy

dose �45 Gy (n 5 54) vs\45 Gy (n 5 30).

FIGURE 4. Disease-free survival for patients attaining complete responseto chemotherapy: adjuvant radiotherapy (n 5 61) vs no radiotherapy

(n 5 22).

DLBCL of the Tonsil/Laskar et al. 821

also reported a significantly improved DFS (P 5 .046)

with a combined modality treatment in their series

of patients. Furthermore, Ezzat et al.14 demonstrated

a significantly better event-free survival for the com-

bination of CTh 1 RT. In a previously reported large

randomized trial of 316 patients with stage I disease

of Waldeyer ring, patients were randomized to

receive RT alone, CTh alone, or a combination of

both. Failure-free survival (FFS) and OS at 5 years of

follow-up were significantly superior in the group

receiving combined modality therapy compared with

RT or CTh alone (FFS, 83% vs 48% vs 45%; OS, 90%

vs 56% vs 58%).5 Similar improvements in FFS and

OS have been reported by the Eastern Cooperative

Oncology Group (ECOG) with the addition of RT after

full-course CTh in limited-stage aggressive NHL.10

The subset analysis of our patients treated with a

combination of CTh and RT revealed that patients

receiving an RT dose of �45 Gy had a statistically

significant improvement in CR (P 5 .01), DFS

(P 5 .039), and OS (P 5 .014) rates over those treated

with a lower dose. Although there has been no report

to date on the most appropriate RT dose for primary

NHL of the tonsil, there are a few studies that have

suggested a benefit with the use of higher RT doses

in patients with nasal and nasopharyngeal NHL.22–24

Isobe et al.23 reported a local failure rate of 67% for

patients with nasal-type NK/T-cell lymphoma treated

with an RT dose of less than 50 Gy as compared with

27% (P 5 .038) for 50 Gy or more. In another study,

Koom et al.22 used a median dose of 45 Gy and

reported a local failure rate of 64% for an RT dose

less than 45 Gy vs 38% (P 5 .02) for 45 Gy or higher.

Furthermore, in a previously reported series on NHL

of the nasopharynx from our institute, we found a

significant improvement in the CR (72% vs 21%,

P 5 .00001), DFS (68% vs 23.3%, P 5 .00001), and OS

(68.3% vs 31%, P 5 .00001) rates using an RT dose of

�45 Gy.24 Similarly, in this study we observed that

the escalation of RT doses to 45 Gy and above may

result in an improved locoregional control and OS

for patients with DLBCL of the tonsil.

In conclusion, we note from this relatively large

single-institution study that primary DLBCL of the

tonsil is best managed with a combination of CTh

and RT. The CTh should consist of a CHOP or

CHOP-like regimen, followed by involved field radio-

therapy (IFRT) to a dose of �45 Gy with conven-

tional fractionation. We also report that DLBCL of

the tonsil involves a larger proportion of young

patients (median age of 45 years) in the Indian sub-

continent as compared with the rest of the world,

where it usually presents in the sixth decade of life.

Considering the young age and good prognosis of

these patients, the possibility of using 3D-conformal

radiotherapy or intensity-modulated radiotherapy to

limit the late toxicities of treatment must be kept in

mind if radiotherapy doses are to be escalated.

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