4. Clinical Features

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Non-Hodgkin’s Lymphoma

201

References

Kaplan H, Rosenberg S (1966) The treatment of Hodgkin’s disease. Med Clin North Am

Figure 1. Kaplan regions for lymph node regions.

4. Clinical Features

• Clinical features of NHL vary substantially depending on the pathologic subtype of

NHL and/or the site(s) of disease.

• Indolent lymphomas such as follicular lymphoma (FL) or small lymphocytic

lymphomas (SLL) usually present with painless peripheral adenopathy or occasionally with abdominal pain, bloating, or back pain related to bulky mesenteric or retroperitoneal adenopathy.

• Because spontaneous regressions occur in up to 20% of patients with FL, the patient

may describe a history of waxing and waning adenopathy.

• Majority of patients with indolent lymphoma feel well at presentation, and B

symptoms, including fevers, drenching night sweats, and weight loss, are unusual. MALT (mucosa-associated lymphoid tissue) lymphomas and indolent lymphomas occurring in extranodal sites, most commonly stomach and lung, usually have mild symptoms referable to the site of involvement. Indolent lymphomas are uncommon before the age of 50 years.

Gustavo Arruda Viani

202

• Many aggressive lymphomas, the most common being diffuse large B-cell (DLC),

also often occur as painless, peripheral adenopathy without other associated symptoms. Fevers, night sweats, or weight loss occur in approximately 20% of patients with advanced-stage disease.

• Bulky retroperitoneal nodes are common and may be asymptomatic or associated

with mild abdominal pain, bloating, or back pain.

• Mediastinal adenopathy occurs in only a few patients, usually young women with

DLC lymphoma with sclerosis, and can present with cough, dyspnea, chest pain, or rarely, SVC syndrome.

• Primary extranodal large cell lymphomas are common, accounting for 15% to 20%

of all large cell lymphomas.

• Approximately half of the extranodal lymphomas occur in the gastrointestinal tract,

including stomach, bowel, tonsils, nasopharynx, and oropharynx.

• Other sites include bone, testis, thyroid, skin, orbit, salivary glands, sinuses, liver,

kidney, lung, and central nervous system (CNS).

• Lymphomas associated with HIV-associated (usually DLC or Burkitt’s subtypes)

often have advanced disease, B symptoms, and involvement of liver, bone marrow, or CNS.

• A unique presentation of HIV-associated lymphomas is primary effusion, or body

cavity-based lymphomas, which are characterized by the presence of NHL along serous membranes in the absence of identifiable tumor masses and with ascites or pleural effusions.

• Primary effusion lymphomas and CNS lymphomas are extremely rare in patients on

appropriate retroviral therapy.Less common subtypes of NHL often have a unique clinical presentation.

Reference

Shipp MA, Mauch PM, Harris NL. Non-Hodgkin’s lymphomas. In DeVita VT Jr, Hellman S,

Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 5th ed. Philadelphia:

Lippincott- Raven, 1997, pp 2165-2220.

5. Pathology

NHL is a heterogeneous group of diseases which clinically vary from indolent to aggressive and from incurable to curable disease. Thus, NHL is commonly subdivided into categories that are indicative of their clinical behaviors (Table 2).

The most common histologic subtype is diffuse large B-cell lymphoma (DLBCL), and the second most common subtype is follicular lymphoma; these subtypes account for 45% of all NHL.

Non-Hodgkin’s Lymphoma

203

Types

Description

6. Diagnostic and Evaluation

Diagnosis and evaluation of non-Hodgkin’s lymphoma (NHL) usually start with a complete history and physical examination (table – 3).

Gustavo Arruda Viani

204

Factor

Description

History and physical exam

Unexplained weight loss of more than 10% over 6 months prior to diagnosis. Unexplained fever >38C, and/or drenching night sweats shortness of breath, hemoptysis,

pruritus,

Onset of alcohol beverage intolerance, and unusual fatigue. Special attention should be focused on externally palpable nodal sites, the liver, spleen,

skin, oral cavity, and oral pharynx.

Laboratory Tests

Blood count, basic blood chemistry, liver and renal function tests. Alkaline phosphatase, lactate dehydrogenase (LDH), and erythrocyte sedimentation rate

(ESR)

Imaging Studies

CT scans of the chest, abdomen, and pelvis are required to appropriately evaluate and

stage NHL.

FDG-PET scan is recommended for diagnosis and staging of NHL

Pathology

Histological confi rmation is critical to determine the type, histopathology, and

immunophenotyping for diagnosis and treatment determination of non-Hodgkin’s lymphoma.

Typically, fine-needle aspiration of a suspected lymph node, soft tissue nodule/organ

mass, cytological spin of an effusion, or a bone marrow biopsy (bilateral) will yield sufficient cells to analyze.

Stage

Description

Involvement of a single lymph node regions (I) or single extralymphatic organ or site in the absence of any lymph node involvement (IE)

Involvement of two or more lymph node regions on the same side of the diaphragm (the mediastinum is considered as a single site, whereas hilar lymph nodes are lateralized). The number of anatomic sites should be indicated by a subscript (e.g., II3)D.

III

Involvement of lymph node regions or structures on both sides of the diaphragm III1 With involvement of splenic hilar, celiac, or portal nodes III2 With involvement of para-aortic, iliac, and mesenteric nodes

IV Involvement of one or more extranodal sites in addition to a site for which the designation “E” has

been used

Table 3. Initial procedures to evaluate NHL

References

Rosenberg SA. Validity of the Ann Arbor staging classification for the non-Hodgkin’s

lymphomas. Cancer Treat Rep 1977;61: 1023-1027 Bangerter M, Griesshammer M, Bergmann L. Progress in medical imaging of lymphoma and

Hodgkin’s disease. Curr Opin Oncol 1999;11:339-342.

7. Staging

The Ann Arbor Staging System had previously been universally used but has been modified to take into account important prognostic factors, particularly mediastinal bulk (table 4)

Table 4. The modified Cotswolds staging system for Hodgkin’s lymphoma

Non-Hodgkin’s Lymphoma

205

Risk factor

No. of risk factor

Freedom from progression at 5 years (%)

Serum albumin <40 g/l

84%

Hemoglobin <10.5 g/l

77%

Male gender

67%

Age ≥45 years

60%

Stage IV disease

51%

White blood cell count ≥15 × 109/l Lymphocytopenia <0.6 × 109/l

≥5

42%

Reference

Rosenberg SA. Validity of the Ann Arbor staging classification for the non-Hodgkin’s

lymphomas. Cancer Treat Rep 1977;61: 1023-1027.

8. Prognostic Factors

• Histology subtype of lymphoma is the most important prognostic factor for survival

in patients with non-Hodgkin’s lymphoma.

• The stage at the diagnostic is an important prognostic factor.

• The presence of “B” symptoms (unexplained weight loss >10% over 6 months prior

to diagnosis, unexplained fever >38 C, and/or drenching night sweats) at diagnose is associated with poor outcome.

• Other significant prognostic factors include patient age (younger or older than 60

years), gender (female gender has a better prognosis in low grade lymphoma), tumor size (less or more than 10 cm in diameter), performance status, level of serum lactate dehydrogenase (LDH), extent of extranodal involvement, beta-2 and microglobulin.

• The International Prognostic Index (IPI) for aggressive NHL includes five of the

above-mentioned significant risk factors to predict overall survival (table-xx): stage (I or II vs. III or IV), serum LDH (normal vs. abnormal), extranodal site involvement (0 or 1 vs. >1), age of the patient (younger than 60 vs. older than 60), and performance status (ECOG 0 or 1 vs. 2–4), as described in table – 5.

Table 5. International Prognostic Score (IPS) for advanced HD

Reference

Hasenclever, D, Diehl, V. A prognostic score for advanced Hodgkin's disease. International

Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 1998;

339:1506.

Gustavo Arruda Viani

206

Study

Description

Petersen et al

Retrospective study of 460 patients with stage I and II follicular lymphoma

treated with Involved-field radiation alone, using a median dose of 35 Gy.

Median follow-up was12.5 years. 10-year OS, 62%, 10-year DFS 51%.

Vaughan Hudson et al

Retrospective study of 208 patients with stage I low-grade NHL treated with

radiation alone with a median dose of 35 Gy, and fields unknown.

98% achieved complete remission (CR) for at least 3 months. 10-year OS was 64%, 10-year DFS was 47%.

Mac Manus et al

Retrospective review of 177 patients with stage I and II follicular lymphoma

treated with Involved-field, extended-field or total lymphoid irradiation to 35–40 Gy.

Median follow-up, was 7.7 years 10-year OS was 64%, 10-year DFS was 44%.

Soubeyearan et al

Retrospective study of 103 patients with stage I and II follicular lymphoma

treated with radiation with or without chemotherapy

Involved-field or regional-field radiation from 35 to 40 Gy 70% of patients received chemotherapy Median follow-up, 8.3 years 10-year OS was 56%; 10-year DFS was 49%.

9. Treatment

9.1. Indolent NHL

• About 10% of patients with indolent non Hodgkin’s lymphomas present with limited

stage disease.

• Although there are limited data about the best treatment option, radiation is used as

primary treatment for these patients.

• Recommended treatment includes involved-field or regional radiation therapy

(involved nodal region plus one additional uninvolved region on each side of the involved nodes) with doses of 30–36 Gy. This approach is associated with a high rate of local control rate (>90%), and a long-term freedom-from-treatment-failure rate (50%), as described in table-6.

Table 6. Clinical evidence for radiotherapy in indolent NHL with limited stage

References

Petersen PM, Gospodarowicz M, Tsang R et al (2004) Long-term outcome in stage I and II

follicular lymphoma following treatment with involved fi eld radiation therapy alone. In:

Abstract of the 2004 ASCO annual meeting proceedings (post-meeting edition). J Clin

Oncol 22:S6521. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA et al (1994) Clinical stage 1 non-

Hodgkin’s lymphoma: long-term follow-up of patients treated by the British National

Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer

69:1088–1093.

Non-Hodgkin’s Lymphoma

207

Study

Description

Hiddemann et al. (2005)

428 patients with symptomatic stage III–IV FL grades I–II randomized to either

CHOP vs. R-CHOP.

Median follow-up 18 months. R-CHOP significantly improved Time to treatment failure (TTF) and 2-year OS (95 vs. 90%).

Ardeshna et al. (2003)

309 patients with stage III–IV. A low-grade lymphoma was randomized to

immediate chlorambucil or observation.

There was no difference in OS. MS was 5.9 years (chlorambucil) vs. 6.7 years

(observation).

Haas et al. (2003)

Phase II study was of 109 patients (304 total sites) with recurrent indolent B-cell

NHL. 90% of patients had follicular NHL 94% had prior systemic therapy, 28% had prior radiotherapy 27% had 4 Gy in 1 fraction; 73% had 4 Gy in 2 fractions

Overall response rate of 92%: 61% achieved complete response (CR) and 31%

had partial response (PR)

Median time to local progression was 25 months; median time to local or distant

progression was 14 months

• Patients with advanced-stage disease represent up to 90% of indolent NHL cases.

There are three treatment options for these patients, such as; observation, chemotherapy or radiotherapy. Observation can be recommended for select patients with asymptomatic and low-volume disease.

• For symptomatic patients with advanced stage, the decision to treat is based on

international criteria (FLIPI), which consider symptoms, threatened end-organ dysfunction, cytopenias, bulky disease at presentation, steady progression of disease, or patient preference.

• In this setting, treatment options include; rituximab (R) ± chemotherapy (CHOP,

CVP, or – fludarabineR-), or palliative local RT (4 Gy × 1 or 2 Gy × 2), as described in table – 7.

Table 7. Clinical evidence for chemotherapy, observation and low dose radiotherapy

in indolent NHL with advanced stage

References

Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab assed to the

combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)

significantly improves the outcome for patient with advanced-stage follicular lymphoma

compared with therapy with CHOP alone: results of a prospective randomized study of

the German low-grade lymphoma study group. Blood 2005;106:3725-3732. Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus

immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin’s

lymphoma: a randomised controlled trial. Lancet 2003;362:516-522. Haas RL, Poortmans P, de Jong D et al (2003) High response rates and lasting remissions

after low-dose involved fi eld radiotherapy in indolent lymphomas. J Clin Oncol

21:2474–2480

Gustavo Arruda Viani

208

Study

Description

Miller et al (SWOG 8736)

401 patients with stage I and non-bulky stage II disease to

CHOP for 3 cycles, followed by IFRT to 40–55 Gy versus CHOP for 8 cycles, followed by observation.

Five-year results showed improved OS and FFS with CHOP-

IFRT. Seven and 10-year results no longer show any difference in OS or FFS.

Reyes et al (GELA LNH 93-

631 patients 60 years or younger with stage I–II low-risk

aggressive NHL randomized to chemotherapy with ACVBP versus CHOP for 3 cycles, followed by IFRT to 40 Gy.

ACVBP significantly improved 5-year EFS and OS,

regardless of bulky disease or not.

Bonnet et al (GELA 93-4)

518 patients older than 60 years with stage I–II low-risk

aggressive NHL randomized to CHOP for 4 cycles, followed by observation versus CHOP for 4 cycles, followed by IFRT to 40 Gy.

Median follow-up 7 years. Five-year EFS (64 vs. 61%) and

OS (68 vs. 72%) showed no difference between the groups.

Horning et al (ECOG 1484)

352 patients with bulky stage I, IE, or II aggressive NHL

randomized to CHOP for 8 cycles, succeeded by observation.

if achieved a CR versus CHOP for 8 cycles, followed by

IFRT to 30 Gy if they achieved a CR. If PR, received IFRT to 40 Gy

IFRT improved 6-year DFS (73 vs. 56%), but no OS

difference.

9.2. Aggressive NHL

• Decades ago, radiation therapy alone was considered the standard of care for limited-

stage aggressive NHL. This approach resulted in a 5-year recurrence free survival up to 50%.

• Recently, the addition of chemotherapy improved recurrence free and overall

survival, and the standard of care is now monoclonal antibody rituximab combined with cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisone/ prednisolone (R-CHOP) with or without radiation (table – 8).

• R-CHOP is the current standard systemic therapy for B-cell marker CD-20–positive

aggressive NHL.

• Although current treatment regimens vary widely among institutions, they commonly

include 3-8 of R-CHOP, followed by IFRT. Radiation is usually given to 30–36 Gy for initial sites of disease, especially if a complete response (CR) to chemotherapy is achieved. For patients with partial response (PR) to chemotherapy with residual fluorodeoxyglucose (FDG) avidity, doses of at least 40 Gy should be considered.

Table 8. Some of the randomized trials assessing the role of radiation therapy

for patients with early-stage aggressive NHL

Non-Hodgkin’s Lymphoma

209

Study

Description

Pfreundschuh et al. (2008)

1,222 patients 61–80 years with stage I–IV DLBCL (50% stage

III/IV) randomized to six vs. eight cycles of CHOP-14 (given at 2 week intervals) ± rituximab.

Patients with initial bulky disease (diameter >7.5 cm) or

extranodal involvement received 36 Gy RT. Six-cycle R-CHOP improved

3-year EFS (47 vs 66%) and OS (68 vs 78%) vs. CHOP alone,

and there was no benefit of increasing to eight cycles of R-CHOP even for patients with only a PR after four cycles of chemo.

Coiffier et al. (2007)

399 patients >60 years with stage II–IV disease randomized to

CHOP × 8 or CHOP × 8 plus rituximab.

Median follow-up 7 years. R-CHOP improved CR (76 vs. 63%),

7-year EFS (42 vs. 25%) and OS (53 vs. 35%).

Pfreundschuh et al. (2006)

824 patients < 60 years with IPI 0–1, stage II–IV or bulky stage I

DLBCL randomized to CHOP-like × 6 or CHOPlike + rituximab × 6. CHOP-like + R improved 3-year EFS (79 vs. 59%) and 3year OS (93 vs. 84%).

References

Miller TP, Dahlberg S, Cassady JR et al (1998) Chemotherapy alone compared with

chemotherapy plus radiotherapy for localized intermediate- and high-grade non-

Hodgkin’s lymphoma. N Engl J Med 339:21–26. Updated results shown at the 2001

American Society of Hematology annual meeting. Reyes F, Lepage E, Ganem G et al (2005) ACVBP versus CHOP plus radiotherapy for

localized aggressive lymphoma. N Engl J Med 352:1197–1205 Bonnet C, Fillet G, Mounier N et al (2007) CHOP alone compared with CHOP plus

radiotherapy for localized aggressive lymphoma in elderly patients: a study by the

GELA. J Clin Oncol 25:787–792 Horning SJ, Weller E, Kim K et al (2004) Chemotherapy with or without radiotherapy in

limited-stage diffuse aggressive non-Hodgkin’s lymphoma: Eastern Cooperative

Oncology Group study 1484. J Clin Oncol 22:3032–3038

• Chemotherapy is considered the standard treatment for patients with disseminated

aggressive NHL. CHOP or CHOP-like chemotherapy regimens have resulted in 4year DFS rates of 35–45%.

• The addition of rituximab has increased the rates of survival in about 15%, and a

schedule 6-8 cycles of R-CHOP is now considered the standard of care. The use of radiation for these patients remains controversial. However, some trials have shown a benefit to radiation to bulky sites of disease and to sites with residual FDG avidity after completion of chemotherapy (table 9).

Table 9. Clinical evidence for chemotherapy with or without radiotherapy

in aggressive NHL

Gustavo Arruda Viani

210

References

Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14

with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas:

a randomised controlled trial (RICOVER-60). Lancet Oncol 2008;9(2):105-116. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-

CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma

show good survival in poor-risk patients. J Clin Oncol 2007;25(suppl 18S):443s. Abstract

8009. mper L, Österborg A, et al. CHOP-like chemotherapy plus rituximab

versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7:379-391.

10. Radiotherapy Technique

To reduce toxicity to normal adjacent organs, and optimise dose distribution for the target volume, CT planning should be used. Thus, CT scans of 3 mm slice thickness are taken using intravenous contrast to aid delineation of lymph nodes adjacent to vascular structures. PETCT and CT scans taken in the treatment position before chemotherapy are co-registered with the post-chemotherapy CT planning scans for target volume delineation. (figure-2).

Figure 2. CT simulator for radiotherapy planning.

Patients are scanned lying supine with appropriate immobilisation devices for the anatomical site to be treated, with a system of skin tattoos. For axillary radiotherapy, the arm is abducted and supported using an arm pole or other restraint. For cervical nodal irradiation, a thermoplastic or vacuum shell is used with reference points on the shell for alignment with lasers (figure-3).

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