Lymphomas

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56 Lymphomas

Dana Sepe, Leslie Kersun

Lymphomas are malignant neoplasms of the lymphoid tissue and include Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). They are the third most common type of pediatric cancer after leukemia and malignant brain tumors. In the United States, approximately 1700 children and adolescents younger than the age of 20 years are diagnosed with lymphomas each year. This is roughly 15% of the malignancies diagnosed in this age group. This chapter focuses on the presentation, diagnosis, evaluation, and management of children and adolescents with HL and NHL.

Hodgkin’s Lymphoma

Etiology and Pathogenesis

HL is a B-cell malignancy that affects the reticuloendothelial and lymphatic systems. In addition, HL can affect other organ systems including the lungs, bone marrow, bone, liver, and rarely the central nervous system (CNS). The World Health Organization classification divides HL into classical HL (nodular sclerosis, lymphocyte rich, mixed cellularity, and lymphocyte depleted), which accounts for 90% of cases, and nodular lymphocyte predominant HL.

Previous epidemiologic studies suggest that the etiology of HL may be multifactorial and that environmental, genetic, and immunologic factors play a role in the development of the disease. Several studies have documented a link between HL and Epstein-Barr virus (EBV). The idea of this association was first proposed in 1966, and through modern molecular study techniques, it has been found that EBV DNA is expressed in the Hodgkin and Reed-Sternberg cells of 50% and 95% of the cases of HL in developed and developing countries, respectively. EBV is mostly associated with the mixed cellularity type of HL, shows a male predominance, and is more frequent in patients younger than 10 years of age.

Clustering of HL in families suggests a genetic predisposition to HL, with an increased incidence especially among same-sex siblings, monozygotic twins, and parent–child pairs. There is a three- to ninefold increased risk of HL among family members of patients affected by the disease, which leads to the hypothesis that at least a small proportion of cases are inherited.

Clinical Presentation

The clinical presentation of HL can be varied but in most cases is asymptomatic. Approximately 70% to 80% of patients present with firm, rubbery, painless cervical lymphadenopathy. Often, patients will have been placed on antibiotics for presumed adenitis without improvement in the lymphadenopathy. Sixty percent of patients have mediastinal disease and may present with cough, chest pain, shortness of breath, orthopnea, or superior vena cava (SVC) syndrome. However, patients can also have mediastinal involvement without any symptoms. It is therefore important to image this area for disease before any diagnostic procedures given the risk of sedation or anesthesia in this setting. Cytokine production by Hodgkin and Reed-Sternberg cells is believed to be responsible for many of the nonspecific systemic symptoms of HL commonly seen at diagnosis, including fatigue, weight loss, pruritus, urticaria, and anorexia.

Approximately 30% of patients present with at least one constitutional, or B, symptom. These include unexplained fevers of greater than 38°C for at least 3 days, unexplained weight loss of at least 10% within the preceding 6 months before diagnosis, and drenching night sweats. These symptoms are indicative of more advanced disease and have prognostic implications for the patient. The presence of B symptoms often places the patient in a higher risk group category for the purpose of determining appropriate treatment.

Physical examination of any patient suspected of having HL should include a thorough evaluation of all lymph node chains; the presence of hepatosplenomegaly; and signs of bone marrow involvement, including bruising, petechiae, and pallor.

The differential diagnosis for HL includes various infections, other malignancies, and other causes of lymphadenopathy (Table 56-1).

Table 56-1 Differential Diagnosis of Hodgkin’s and Non-Hodgkin’s Lymphoma

	Hodgkin’s Lymphoma	Non-Hodgkin’s Lymphoma
Infections	Lymphadenitis Cat scratch disease Mononucleosis, EBV, CMV Brucellosis Tuberculosis Toxoplasmosis Atypical mycobacterial infections

Cat scratch disease

Mononucleosis, EBV, CMV

Atypical mycobacterial infections

Malignancies

Rhabdomyosarcoma

Germ cell tumors

Lymphoproliferative disorders

Rhabdomyosarcoma

Lymphoproliferative disorders

Other

Bronchogenic cyst

Intussusception

ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CMV, cytomegalovirus; EBV, Epstein-Barr virus.

Evaluation and Staging

Evaluation of HL should include a detailed history and physical examination, focusing specifically on the previously mentioned typical presenting signs and symptoms. Urgent signs and symptoms, such as cough, chest pain, orthopnea, bruising, and pallor should be evaluated promptly. Specific laboratory and radiographic tests and diagnostic procedures need to be performed to treat the patient and stage the disease. These include a complete blood count (CBC); erythrocyte sedimentation rate; comprehensive metabolic panel; chest radiograph; computed tomography (CT) scans of the neck, chest, abdomen, and pelvis; and a positron emission tomography (PET) scan to assess for disseminated disease. A bone marrow aspirate and biopsy is performed in certain cases.

Staging of pediatric HL is based on the Ann Arbor Classification and is outlined in Figure 56-1.

Figure 56-1 Malignant lymphomas: staging.

Management

Radiation therapy was the first curative modality for the treatment of HL. However, the high doses of radiation needed to cure HL as monotherapy resulted in side effects such as bone growth retardation, cardiac toxicity, and secondary malignancies in the radiation field. Therefore, response-based, low-dose, involved-field radiation is used as adjuvant treatment after chemotherapy.

Current treatment for pediatric HL is based on risk-adapted therapy and includes chemotherapy, radiation, or both. Two principles were critical for the development of chemotherapy treatment regimens for HL. First, multiple chemotherapeutic agents with different mechanisms of action are used to circumvent potential drug resistance. In addition, the treatment is structured to avoid combinations of medications with overlapping toxicities. Common agents used to treat HL include bleomycin, vinblastine/vincristine, etoposide, procarbazine, prednisone, methotrexate, doxorubicin, and cyclophosphamide. The combination and doses of medications depend on risk stratification. Table 56-2 depicts the current risk stratification system for The Children’s Oncology Group; however, there may be small differences in this scheme for patients treated in other countries or cooperative groups.

Table 56-2 Risk Stratification of Patients with Hodgkin’s Lymphoma

Risk Category	Stages
Low risk	IA, IIA; no bulk disease*
Intermediate risk	IA and IIA with bulk disease* All IB and IIB All IIIA and IVA
High risk	All IIIB and IVB

* Bulk disease is defined as a mediastinal mass greater than 33% of the chest width or any nodal aggregate that is larger than 6 cm.

HL has an excellent prognosis, with a 5-year overall survival (OS) for all patients (early stage or advanced disease) of approximately 90%. There is a subset of patients with disease recurrence who are subsequently cured because there are good salvage regimens for relapsed HL. Cure rates after relapse depend on the time from initial therapy, amount of initial therapy received (chemotherapy alone vs. chemotherapy and radiation therapy), and stage of relapsed disease. In particular, early relapses (<12 months from initial therapy) at more advanced stages with more initial therapy have a worse prognosis than later relapses with less initial therapy. Therapy for relapsed HL includes salvage chemotherapy, and depending on the aforementioned factors, can then be followed by high-dose chemotherapy and autologous stem cell transplant.

The general side effects of chemotherapy include nausea and vomiting, hair loss, mouth sores, and myelosuppression. However, each agent has specific acute and late toxicities that are important to carefully monitor during treatment and then follow for years after the completion of therapy. The late effects of therapy include pulmonary fibrosis (secondary to bleomycin exposure), cardiomyopathy (secondary to anthracycline therapy with doxorubicin, mediastinal radiation, or both) and infertility (secondary to alkylating agents like cyclophosphamide and procarbazine) and depend on the total cumulative dose of these medications. In addition, musculoskeletal and thyroid toxicity (secondary to radiation exposure) are of particular concern, with as many as 50% of survivors of HL experiencing hypothyroidism 10 years after treatment. Furthermore, approximately 30% of survivors of HL will develop a second malignant neoplasm (SMN) within 30 years after their initial treatment, with the most common SMNs being thyroid cancer, breast cancer, nonmelanomatous skin cancer, and NHL.

Future Directions

Future directions include evaluating the role of PET scan for diagnosis and follow-up of HL. In addition, in an attempt to decrease late effects of therapy while maintaining or improving upon the current excellent OS in HL, research and future studies are focusing on response-based therapy and targeted agents. Currently, targeted agents such as rituximab (anti-CD 20), bortezomib (NF-κB transcription factor inhibitor), SGN-30 (anti-CD 30), and SGN-35 (antibody–drug conjugate of tubulin inhibitor monomethyl auristatin E conjugated anti-CD30) are being studied.

Non-Hodgkin’s Lymphoma

Etiology and Pathogenesis

Pediatric NHLs are a diverse group of lymphoid neoplasms with varied pathology, cells of origin, natural history, and response to treatment. They arise from both mature and immature cells of both B- and T-cell origin. The four most common pathologic subtypes of pediatric NHL are Burkitt’s lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), and lymphoblastic lymphomas (LL). There are rare and cutaneous types of pediatric NHL in addition to lymphoproliferative disorders that are not discussed in this chapter.

In developed countries, most individuals with NHL have no known cause. However, it is known that patients who are immunosuppressed, such as those with HIV or those who have undergone bone marrow transplantation, are at increased risk of developing NHL. In addition, patients who have been treated previously for HL are at higher risk of developing a secondary NHL. This appears to be an effect of the chemotherapy and radiotherapy of the HL treatment, as well as the immunosuppressive effects of the HL itself. In sub-Saharan Africa, there is a strong association between previous infection with malaria and EBV and the development of endemic BL.

Clinical Presentation

Pediatric NHL usually presents acutely to subacutely, in contrast to many adult lymphomas, which are indolent. Constitutional symptoms are rare in NHL, with the exception of ALCL. Localized disease can manifest as lymphadenopathy or as a mass in any location. Patients with mediastinal involvement may complain of cough, chest pain, and dyspnea, and those with abdominal involvement may complain of constipation, abdominal pain, or distension. Focal bony pain or swelling may be present in patients with bone lymphoma and those with CNS involvement may develop altered mental status, meningismus, back pain, headache, or cranial nerve findings.

In general, patients with NHL look mild to moderately ill and can have pallor, dyspnea, cough, pain, and fever. Patients with a mediastinal mass can develop SVC syndrome and can have distended neck veins and plethora on physical examination. In addition, there are typical findings that can vary by subtype of NHL. For instance, BL tends to have a high growth fraction and can present as intussusception secondary to a rapidly growing abdominal mass. Nearly 75% of LL patients present with a mediastinal mass. Patients with ALCL sometimes present with painful skin lesions that may regress spontaneously, bone lesions, peripheral lymphadenopathy (especially inguinal), and hepatosplenomegaly.

The differential diagnosis of NHL can be found in Table 56-1.

Evaluation and Staging

The evaluation for NHL is similar to that of HL and should include a CBC with differential as a preliminary screen for bone marrow involvement, as well as a comprehensive metabolic panel to look at renal and hepatic function. In particular, because BL can grow rapidly and there may be significant tumor burden at the time of initial presentation, tumor lysis can be of great concern. It is important to check an initial potassium, phosphorus, calcium, uric acid, blood urea nitrogen, and creatinine and to follow these levels closely before and during the initial treatment period. It is also standard practice to obtain a lumbar puncture with CSF differential to assess for CNS involvement and bilateral bone marrow aspirates and biopsies to evaluate spread into the marrow and differentiate certain types of NHL from leukemia. In addition, a radiographic evaluation is necessary for staging of the disease. This evaluation should include a neck, chest, abdomen, and pelvis CT scan and a PET CT.

In B-cell lymphomas, the primary presentation is not confined to a specific organ, nor is there a specific pattern of spread. Therefore, staging systems for NHL reflect tumor volume more than the degree of spread from the primary site. Several staging systems have been established for NHL. However, the Murphy staging system is the most widely accepted (Table 56-3).

Table 56-3 Murphy Staging System of Non-Hodgkin’s Lymphoma

Stage	Definition
I	A single tumor (extranodal) or single anatomic area (nodal), excluding mediastinum or abdomen
II	A single tumor (extranodal) with regional node involvement; or a primary GI tract tumor with or without associated mesenteric node involvement, grossly completely resected; or, on the same side of the diaphragm, two or more nodal areas or two single (extranodal) tumors with or without regional node involvement
III	All primary intrathoracic tumors (mediastinal, pleural, thymic); or all extensive primary intraabdominal disease that is unresectable; or all primary paraspinal or epidural tumors regardless of other sites; or on both sides of the diaphragm, two single tumors (extranodal) or two or more nodal areas
IV	Any of the above with initial CNS or bone marrow involvement (<25%)

CNS, central nervous system; GI, gastrointestinal.

Management

Patients with NHL are at risk for developing tumor lysis syndrome (TLS) both before and during the initial phases of chemotherapy because this can be a highly proliferative and bulky group of malignancies. TLS develops from the rapid turnover of malignant cells and the release of their contents, leading to hyperkalemia, hyperphosphatemia, and hyperuricemia. To prevent TLS, patients with NHL should be aggressively hydrated with alkalinized fluids containing sodium bicarbonate. These fluids should not contain potassium. If patients have evidence of renal insufficiency or oliguria at diagnosis, this balance of aggressive fluid management and potential need for dialysis should be discussed early with the nephrology team. In addition, patients should be placed on allopurinol to lower or prevent an increase in uric acid. Some patients in high-risk situations, including extreme elevations of uric acid or impaired renal function at time of presentation, may require the administration of rasburicase (a recombinant urate oxidase) to decrease their uric acid levels.

Current treatment for NHL includes combination chemotherapy, including medications directed at prevention of CNS recurrence. The backbone of therapy for pediatric NHL includes cyclophosphamide, methotrexate, and vincristine with the addition of various other agents depending on the subtype and staging of the disease. In addition, intrathecal chemotherapy is a crucial component of therapy and is given to patients with LL and those with a risk for CNS recurrence or CNS involvement at diagnosis.

The overall prognosis for NHL varies by stage at diagnosis and subtype. In patients with stage I and II mature B-cell NHL (BL and DLBCL) disease, there is a more than 90% disease-free survival (DFS) rate with chemotherapy alone. In patients with advanced disease (stage III or IV, bone marrow or CNS involvement), the OS is 80% to 90% with chemotherapy alone. With LL, neither the stage nor phenotype (T cell vs. B cell) seems to be a prognostic factor. DFS in LL is approximately 85%. However, in less favorable subgroups, such as BL with combined bone marrow and CNS involvement, primary mediastinal DLBCL, and in a certain subset of patients with systemic ALCL, the DFS ranges from 45% to 70%.

Future Directions

Great advancements have been made in the area of NHL research with current treatment leading to an overall DFS of greater than 80%. However, these therapies do not come without significant toxicity and late effects. Therefore, future directions in the field of NHL research include trying to better risk stratify patients such that low-risk patients can have a reduced-intensity treatment protocol. In addition, this would allow for high-risk patients to perhaps receive novel therapeutics earlier in their treatment course because salvage for relapsed or refractory NHL is difficult. Novel therapeutics would include biologically targeted agents, such as monoclonal antibodies and immunotherapy, which are currently under investigation. Finally, improved therapy targeting the CNS is undergoing investigation because patients with initial involvement of the CNS have a low OS compared with other groups.

Suggested Readings

Gross TG, Termuhlen AM. Pediatric non-Hodgkin’s lymphoma. Curr Oncol Rep. 2007;9(6):459-465.

Olson MR, Donaldson SS. Treatment of pediatric Hodgkin lymphoma. Curr Treat Options Oncol. 2008;9:81-94.

Smith MA, Ries LA, Gurney JG, et al. Leukemia. In: Ries LAG, Smith MA, Gurney JG, et al, editors. Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995, NIH Pub. No. 99-4649. Bethesda, MD: National Cancer Institute, SEER Program, 1999.

Thomas RK, Re D, Zander T, Wolf J, Diehl V. Epidemiology and etiology of Hodgkin’s lymphoma. Ann Oncol. 2002;13(suppl 4):147-152.

Weinstein HJ, Hudson MM, Link MP. Pediatric Lymphomas. Heidelberg, Germany: Springer; 2007.

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