Incidence and Epidemiology

It is estimated that 9,060 individuals will be diagnosed with HL in the USA each year, accounting for just 0.6% of all cancers and only 11% of all lymphomas.¹ However, in children, it is the sixth most common type of cancer, with approximately 400 children diagnosed annually.^1,12 This constitutes 4% of all childhood cases of cancer and approximately half of all childhood cases of lymphoma.¹ HL has an incidence of 3.2 cases/100,000 teens aged 15–19 years.¹³ A bimodal distribution exists when considering all ages, but in children alone, a gradual trend is seen of increasing incidence with increasing age. HL is exceedingly rare in children younger than age 2 years and peaks in the adolescent years.¹⁴ Beyond age 11 years, it is the most common of the two types of lymphoma and accounts for about 15% of all cancer in young adults ages 15 to 24 years.¹³ A slight male predominance (1.3 : 1)¹¹ is noted, but in the youngest children, the male-to-female ratio is much larger (12–19 : 1).¹⁵

Monozygotic twins of HL patients have been found to be at greater risk of developing HL than are dizygotic twins, strongly implicating genetics as a principal risk factor.¹⁶ In young adults, an increased risk of HL is found with higher socioeconomic status.¹⁷ Young adults with HL come from smaller families, have fewer infectious exposures as young children, and/or have later exposure to infections than do control populations.^17,18 This correlates closely with socioeconomic status and implicates delayed exposure to infections as a principal risk factor.

Most likely, a combination of genetic risk and infectious exposure predisposes a young adult to HL. Immunodeficiency may be the link between these two risk factors, at least in a subgroup of HL patients. HL is more prevalent in human immunodeficiency virus (HIV)-infected patients.19–21 Also, patients with HL have a higher incidence of cellular immunodeficiency at the time of diagnosis.²² Etiologic theories encompass these two risk factors and focus primarily on the Epstein–Barr virus (EBV). Genomic material from EBV has been found in the RS cells in up to 79% of HL cases.^23–25 A higher risk of HL has been noted in individuals with a history of infectious mononucleosis^26–28 and with previously high titers to EBV.²⁹ One hypothesis that incorporates these factors suggests the following sequence: (1) a genetic, iatrogenic, or viral immunosuppression; (2) subsequently or coincidentally, an EBV infection or oncogenetic rearrangement in a lymphoid precursor cell; (3) further genetic alterations; followed by (4) clonal expansion of lymphoid cells with morphologic features of RS cells; finally resulting in (5) the clinical syndrome known as HL, diagnosed by the presence of RS cells.³⁰

Classification and Histologic Subtyping

The diagnosis of classical HL requires the dual finding of the diagnostic Hodgkin and RS cells (HRS cells) plus a reactive cellular background.³¹ The RS cell is a large cell (15–45 mm) with an ‘owl’s eye’ appearance (Fig. 69-2). It has a multilobed nucleus (or is multinucleated), each with a prominent eosinophilic nucleolus surrounded by a clear zone (halo) and an intensely stained nuclear membrane. The ‘owl’s eye’ appearance is the result of a bilobed nucleus. The RS cell often makes up no more than 2% of the involved cells. Hodgkin cells are the mononuclear variant of RS cells. The cellular background is a reactive, pleomorphic mixture of inflammatory cells including reactive lymphocytes, histiocytes, plasma cells, eosinophils, neutrophils, and fibroblasts, with varying degrees of fibrosis and sclerosis. The HRS cell is a clonal, neoplastic cell seen in classical HL and is thought to induce the reactive background through the abundant release of various cytokines.³² HRS cells typically are CD15 and CD30 positive and negative for CD45 and B-lineage antigens.³³ In contrast, the nodular lymphocyte predominant (LP) HL cells (popcorn cells) are usually positive for B-lineage antigens, CD15 and CD30 expressions are lacking, and the immunoglobulin genes are expressed.³³

For histologic typing, the Rye classification was commonly used for three decades but has been supplanted by the WHO classification. The 2008 WHO classification lists two main types of HL: classical HL and nodular LP. Classical HL is further divided into four subtypes by morphology. These subtypes include nodular sclerosis (NS, the most common), mixed cellularity (MC), lymphocyte-rich (LRHL), and lymphocyte-depleted (LDHL).³⁴ The NS subtype is seen in 40% of younger patients and 70% of adolescents.³⁵ It is characterized by tumor nodules surrounded by broad sclerotic bands arising from a thickened fibrotic capsule.³¹ This subtype has a strong predilection for involving the lower cervical, supraclavicular, and mediastinal lymph nodes. The MC subtype is found in 30% of cases and has an increased incidence in younger children.¹⁵ HRS cells are typically increased in number. The lymph node architecture is often completely effaced by the HRS cells and their surrounding reactive cells. This subtype often is first seen with advanced, widely disseminated disease in extranodal sites. In addition to its relatively common incidence among all HL patients, it is the most common histologic type seen in HIV-infected patients.²¹

From 2001 to 2009, the National Cancer Institute (NCI)-sponsored SEER data revealed the following 5-year survival rates for patients age 0–19 years: LRHL 100%; NS 95.7%; MC 92%; and nodular LP 100% (Table 69-1). In patients of all ages, the 5-year survival rate for LDHL was 58%.¹¹ Reports have shown that LPHL has a better prognosis and needs markedly reduced therapy to achieve cure.^36,37 This differentiation of therapeutic response between LPHL and the other classic HL histologic types appears to validate the distinction observed in the immunophenotyped RS cells.³⁸ The worse outcome of the MC and LDHL types may reflect their typically higher stage at diagnosis.

Clinical Presentation

Classically, children with HL present with painless enlarged lymph nodes, typically in the cervical or supraclavicular nodal groups (see Table 69-1). Nodes are often described as rubbery and fixed. They may be either single or matted with other nodes. Occasionally, because of rapid growth, tenderness may develop. Tumor lysis syndrome, a result of rapid and extensive tumor growth and a common complication in children with NHL, is rarely seen in children with HL.

HL tends to spread in a contiguous manner. Therefore, at presentation, one must examine carefully the nodal groups adjacent to the initially identified nodes. More than 90% of patients have involvement of either the cervical or mediastinal nodal groups (or both).³⁹ Interestingly, HL tends to spread from the cervical nodes of one side of the neck to the mediastinum before it spreads to the contralateral cervical nodes. When laparotomy was included in the staging process (which is no longer routinely performed), the spleen was noted to be involved in 27% of patients.³⁹ When evaluating the histologic subtypes and patterns of initial involvement, the MC and LD subtypes of HL have more widespread involvement than do the NS or LP HL subtypes (see Table 69-1).

Mediastinal disease, in addition to a predilection for certain histologic subtypes, is most common in girls older than 12 years, and in those with constitutional symptoms (also known as B symptoms).⁴⁰ Mediastinal disease may appear with significant respiratory compromise due to compression of the trachea, carina, (or both), including the major bronchi.⁴¹ These patients may have dyspnea on exertion or at rest, persistent cough, or stridor. They may have recently been treated for presumed asthma or bronchiolitis, without radiographic imaging. Patients with this presentation may have a history of orthopnea and are most comfortable in an upright forward-leaning position to relieve the pressure on the airway (from the anterior mediastinal mass). The physician must be vigilant for mediastinal disease because it can be silent until a patient is sedated for a radiologic or surgical procedure. These patients may prove impossible to ventilate, even with intubation, because of distal tracheal or bronchial obstruction. It is imperative that all patients with suspected lymphoma (HL or NHL) have a chest radiograph or chest CT scan before any sedation or procedure. Signs of superior vena caval obstruction, including edema and cyanosis of the face and jugular venous distention, may also be present. Extralymphatic involvement can include the liver (the most common extralymphatic organ involved), lungs, bone, bone marrow, and skin, among other sites. Whereas bone marrow involvement is present in only 4–14% of patients overall, among those patients with stage IV disease it occurs one-third of the time.⁴²

Most patients have no systemic symptoms at the time of initial diagnosis. About one-quarter of patients will have one or more B symptoms, defined as weight loss of more than 10% in the previous 6 months, unexplained recurrent fevers greater than 38°C, or drenching night sweats.³⁹ Pruritus, fatigue, and anorexia are other nonspecific symptoms seen in HL patients. Laboratory findings at diagnosis are nonspecific and typically are indicative of an inflammatory process. The erythrocyte sedimentation rate (ESR), serum copper, and ferritin levels are frequently elevated and may be useful later as monitors for relapse. A high ferritin (>142 ng/mL) level or increased ESR (>50) has been associated with a worse prognosis.^43,44 The lactate dehydrogenase (LDH) may be elevated as well. Although not common, leukopenia may be indicative of bone marrow involvement.⁴²

Diagnosis

The diagnostic evaluation should include a physical examination and laboratory and radiologic studies (Box 69-1). The physical examination should be directed to the obviously involved nodal groups and also to adjacent groups, keeping in mind the natural history of HL and its propensity for contiguous spread. More than four involved nodal groups in stage II patients is associated with a worse prognosis.⁴⁵ Bulky disease (nodes or nodal aggregates >10 cm and/or mediastinal tumor width more than one-third of intrathoracic width on a posteroanterior chest radiograph or CT) is associated with a worse outcome in low-stage patients, and necessitates additional therapy to achieve equivalent outcomes.^46–48 Auscultation of the airway, palpation of the abdomen, and examination of distant nodal groups are all critical as well.

Laboratory examination should include full blood cell counts and chemistries, including hepatic function tests, LDH, and ESR. Serum copper and ferritin levels also should be obtained. However, no clinical findings are pathognomonic for HL. Ultimately, the diagnosis awaits the biopsy of involved sites, most commonly an excised lymph node. The surgeon’s goal is to biopsy the most accessible nodal region to obtain adequate tissue for diagnosis. Open excision of the largest lymph node is preferred because fine-needle aspirations generally do not provide adequate tissue. Excisional biopsy is where the diagnosis is made, based on the pathognomonic finding of HRS cells within a reactive cellular background. For cytogenetic and molecular genetic evaluations, it is imperative that all tissues are placed in a sterile container for fresh samples. Formalin should not be used. For patients critically ill at diagnosis, such as those with severe airway obstruction, diagnosis by alternative methods may need to be considered. These include nodal biopsy with local anesthesia alone, CT-guided percutaneous needle biopsy of the mass, aspiration of a pleural effusion, or a bone marrow biopsy and aspirate.

Staging

Further evaluation of a patient with HL is required to determine the extent of disease at diagnosis and thus the stage of disease (Table 69-2). The common staging system for HL was adopted in 1971.⁴⁹ This system is based on the observation of contiguous nodal spread in HL. Patients are further divided into asymptomatic (A) and symptomatic (B) subcategories. This subclassification for symptomatic patients is based on the findings of a worse prognosis for B patients and the need for a systemic therapy approach (i.e., chemotherapy in addition to radiation). This likely reflects the finding that patients with B symptoms are more likely to have distant, widespread disease when histologically staged.⁵⁰

For HL, the decision for the type and intensity of therapy rests on the staging results. Traditionally, two methods of staging were used in HL patients: clinical and histologic. In the past, all patients underwent both methods. Clinical staging includes physical, laboratory, and radiologic evaluations. Histologic staging requires a staging laparotomy with splenectomy, nodal sampling, and wedge biopsies of both hepatic lobes. Radiologic evaluations continue to evolve. Lymphangiograms, once a critical component of staging in HL, have been supplanted by more modern and less invasive imaging modalities. CT examination is used most frequently.⁵¹ For those who will be treated by irradiation alone, accurate assessment of abdominal disease is critical. Staging laparotomy with splenectomy, nodal sampling, and wedge biopsies of both hepatic lobes has been shown to increase the stage of disease in up to 35% of patients initially evaluated with CT (i.e., the difference between clinical and histologic staging).^52,53 This would seem to indicate that abdominal exploration is important. However, with the use of systemic chemotherapy and the de-emphasis on irradiation, this discrepancy between clinical and histologic staging no longer appears to have a significant impact on treatment or outcome.^54,55

For the majority of children with HL, staging is based on clinical criteria. Laparotomy (or laparoscopy) is not encouraged or recommended. However, abdominal staging should continue to be used in patients destined to be treated with irradiation alone (although this is now rare in children) because abdominal disease would have a significant impact on planned therapy.⁵⁶ Staging laparotomy (or laparoscopy) with splenectomy is not without its risks. There are the typical postoperative complications of abdominal surgery. Moreover, with splenectomy, there is a lifelong risk of overwhelming sepsis with encapsulated organisms and these patients require lifelong antibiotic prophylaxis.⁵⁷ An increased risk of secondary leukemia also exists in those HL patients treated with chemotherapy who have undergone splenectomy (5.9%) compared with those who have not (0.7%) as part of their staging procedure.^58–60

Nuclear medicine scans are another modality used for staging HL patients. ¹⁸flurodeoxyglocose (FDG) imaging has gradually supplanted gallium scans. Fluorodeoxyglucose-labeled positron emission tomography (FDG-PET) has been found to be more sensitive and specific than either gallium or CT.^61–64 Similar to gallium scanning, it leads to a higher staging in a significant percentage of patients. FDG-PET during and after therapy has been highly predictive of patient outcome^65,66 and helps to differentiate residual scar tissue from residual lymphoma,⁶⁷ although false-positive findings with inflammatory conditions have been reported.⁶⁶ In children, it is important also to recognize the phenomena of thymic rebound after therapy. This may result in both an enlarging mediastinal mass on CT and a positive nuclear medicine scan. An experienced radiologist will recognize this phenomenon by its timing (within the first 6 months after therapy has been completed) and by the normal (although enlarged) homogeneous appearance of the thymic tissue. However, false-negative interpretations can occur. Thus, close follow-up of these patients is critical. Finally, the bone marrow examination continues to be important, regardless of planned methods of therapy, because its involvement would upgrade the patient’s disease to stage IV status and necessitate more intensive chemotherapy.

Treatment

Results

Most patients treated with combinations of chemotherapy and radiation enter into CR (>90%).89,90 Many patients, especially those with the NS subtype, may have persistent adenopathy or mediastinal enlargement for months or years after therapy. Although most prove to be cured, close follow-up is necessary. For those who do not enter remission with today’s front-line chemotherapy/irradiation combinations, the prognosis is poor. Therapeutic intensification with subsequent stem cell transplant will likely be needed.^86,91

For low-risk patients, combined-modality (chemotherapy and radiation) therapy typically results in greater than 90% five-year DFS and OS rates. For intermediate risk patients, greater than 80% 5-year EFS rates are found. For high-risk patients, significant advances have been made, with EFS and OS greater that 90% in relatively recent trials.82,92,93

Early Complications

Early complications of therapy are due to either the tumor itself or the therapy. All patients suspected of having a lymphoma should have an immediate chest radiograph or CT scan to determine whether a mediastinal mass is present. Therapy with chemotherapy (preferable in children) or irradiation is effective in the immediate relief of these symptoms. Complications from splenectomy can occur due to overwhelming sepsis from encapsulated organisms. This risk is increased because of the myelosuppression and immunocompromising effects of chemotherapy. Fever in the neutropenic patient necessitates hospitalization and intravenous antibiotic therapy. Bone marrow suppression may require transfusions of either red cells or platelets. Specific chemotherapy agents may have immediate complications. These include nausea and vomiting, restrictive pulmonary disease (bleomycin, irradiation), extravasation burns (nitrogen mustard, vincristine, vinblastine, doxorubicin [Adriamycin]), and chemical phlebitis (nitrogen mustard, vinblastine, DTIC). To alleviate these risks, right atrial catheters are often placed. This also reduces the discomfort of repeated venipuncture required throughout the duration of treatment.

Long-Term Sequelae

The concern over long-term sequelae guides much of modern therapy for HL, both in adults and particularly in children. These sequelae result from both radiation therapy and chemotherapy.94,95 The long-term sequelae of irradiation in growing children are the overriding reason for the efforts to reduce or eliminate it from therapeutic regimens. Bone irradiation may result in shortening of the clavicles in those patients receiving mantle radiation or a shortened height in those receiving radiation to the spine.⁹⁶ Radiation to the neck often results in permanent hypothyroidism⁹⁷ and increases the risk of thyroid cancer.^98,99 If radiation is to be given to the pelvis of a female patient, consideration should be given to positioning the ovaries away from the field of irradiation.¹⁰⁰

Second malignancies are a major concern after therapy for HL.101–103 The most frequent cause of death in long-term survivors of HL is a second malignancy.¹⁰⁴ The relative risk of a second malignancy in HL patients has been estimated to be five- to 11-fold that of the general population.^102,105 This represents a 15- to 25-year actuarial risk of 7% to 23%.^{102,105–107} Second malignancies are more prevalent in those with HL treated before age 21 years than in the older age groups for all tumors except lung cancer.¹⁰² These second cancers include leukemia and solid tumors. The risk of leukemia seems primarily related to the type of chemotherapy used,^105,108 with a cumulative incidence of 3.3%, with a plateau after about ten years. However, one study found a decrease in secondary leukemia among those treated with the newer hybrid regimens.¹⁰⁷ This likely is a result of the reduction in nitrogen mustard and procarbazine (in MOPP) doses, the principal culprits in the development of secondary leukemia.^109,110 Patients treated with ABVD do not have an increased risk of leukemia. The reduction in the incidence of leukemia may be a result of the decreasing use of splenectomy for staging as this operation has been shown to increase the risk of leukemia in HL patients treated with chemotherapy.^109,111

Solid tumors, including those of lung, stomach, melanoma, bone, and soft tissue, have accounted for most of the second malignancies, with a cumulative incidence of 13–22% at 15 to 25 years. No plateau has been appreciated.102,105,106 This risk in HL survivors has not decreased when cohorts treated in the 1960s are compared with those in the 1980s.¹⁰² This increased risk of solid tumors is related primarily to irradiation,^112,113 with some added risk when subsequent chemotherapy is used in relapse patients.¹¹⁴ It has been recognized that radiation exposure to the breast tissue in adult women has resulted in a fourfold increase in rates of subsequent breast cancer,^115–118 whereas the risk of subsequent breast cancer is increased by 39-fold if the breasts are irradiated during adolescence.¹¹⁹ For an adolescent, this increases the probability of developing breast cancer between the ages of 20 and 30 years from 0.04% to 1.6%¹²⁰ and may be as high as 35% by age 40 years. Other long-term sequelae include cardiac complications secondary to mantle irradiation and/or the use of doxorubicin (Adriamycin in ABVD regimens) that affect up to 13% of patients.^121,122

Incidence and Epidemiology

NHL accounts for 4% of all cancers in adult and pediatric patients. It is estimated that 70,130 men and women will be diagnosed with NHL in the USA in 2012.¹¹ In children (ages 0 to 14 years), NHL patients accounted for 4% of childhood cancers¹ and approximately 50% of all lymphomas.¹ The annual incidence is 1.3 cases/100,000 children ages 10–14 and 1.8 cases/100,000 children ages 15–19 years.¹¹ Before age 11 years, it is the most common of the two types of lymphoma. A high male-to-female ratio of 3.0 is found,¹¹ making it the most disproportionately occurring tumor between the two genders during childhood. This large difference is found in all ages of childhood. The age distribution demonstrates two small peaks in incidence from 6 to 7 years and between 12 and 14 years (see Fig. 69-1). The 6- and 7-year-olds overwhelmingly have BL, and the teenagers typically have T-LL.

NHL of B-cell origin, either BL or DLBCL, occurs more often in patients with prior EBV exposure, in individuals with a history of immune suppression, and in equatorial Africa.125–127 It is known that in patients with an iatrogenic (e.g., post-transplant, immunosuppressive therapy) or acquired immunodeficiency, congenital-EBV infection has an etiologic role in either the development or the predisposition to B-cell NHL.^128,129 Correlations have been made between the viral load and the risk of post-transplant lymphoproliferative disorders (PTLDs).^130–132 Patients at greatest risk for PTLDs are those in whom their primary infection with EBV occurs within the first 3 to 4 months after transplantation. For T-LL or ALCL, no such etiologic correlations have been found.

Classification

Over the years, several classification schemes have been used.¹³³ The Revised European American Lymphoma Classification is the basis for the WHO classification that was updated in 2008.³⁴ Childhood NHL primarily consists of four major subtypes in the WHO system: (1) BL/leukemia and Burkitt-like (mature B-cell neoplasms accounting for 39% of NHL patients³); (2) lymphoblastic lymphoma (28%³); (3) DLBCL; and (4) ALCL. DLBCL and ALCL were previously lumped together as large cell lymphomas and comprised about one-third of the NHL of childhood. With the separation of these two entities, the cases previously identified as large cell lymphoma are now divided almost equally between DLBCL and ALCL.¹³⁴ The first two classifications are part of the ‘small, round, blue cell tumors,’ which presents the pathologist with the challenge of proper identification. To differentiate these from the other three classic small round blue cell tumors (neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma) requires the presence of the immunocytochemical marker leukocyte common antigen CD45 (LCA), which is absent in the other tumor cell types.

BL has classically been divided into Burkitt and non-Burkitt (Burkitt-like in the REAL classification) subtypes. These are of a mature B-cell origin, with flow cytometric immunophenotyping revealing the presence of surface immunoglobulin IgM, CD10, CD19, CD20, CD22, CD79a, and human leukocyte antigen (HLA)-DR antigens. The histologic appearance of these two types differs in the degree of pleomorphism, with Burkitt being more uniform appearing than non-Burkitt. Although a distinction has been made for years between Burkitt and non-Burkitt subtypes of diffuse SNCCL lymphomas, no clinical differences are found between these two subtypes.¹³⁵ Histologically, the cells of BL are medium sized with round nuclei containing two to five nucleoli, abundant basophilic cytoplasm, and cytoplasmic lipid vacuoles. Owing to its extreme rates of proliferation and spontaneous cell death, a number of macrophages are seen within this monomorphic field, consuming the dying cells and giving rise to the classic ‘starry sky’ appearance of BL.¹³⁶

Lymphoblastic lymphomas (LL) are distinguished by round or convoluted nuclei, finely dispersed chromatin, inconspicuous nucleoli, and scant cytoplasm. In the vast majority of these tumors, flow cytometry reveals the presence of the T-cell markers CD3 and CD7, with variable positivity for CD2 and CD5. These cells are typically Tdt positive, whereas BLs are Tdt negative. This subtype is classified as a precursor T-cell LL in the WHO classification. A small number of LL cases are B-cell precursor and express pre–B-cell antigen profiles.¹³⁴

Large cell lymphomas are a heterogeneous group of neoplasms. Histologically, approximately half are immunoblastic, 40% are large noncleaved cell, and fewer than 5% are large cleaved cell.¹³⁷ Flow cytometry shows relatively equal frequencies of B- or T-cell origin (36% and 33%, respectively) with 30% indeterminate.^138,139 A unique subset, identified by the immunophenotype CD30+ (the antigen identified by the Ki-1 monoclonal antibody),¹⁴⁰ is recognized morphologically by its anaplastic characteristics, including very large cells with abundant cytoplasm, atypical lobulated nuclei, and prominent nucleoli. These cells exhibit a cohesive pattern with lymph node sinusoidal invasion. In the WHO classification, this is referred to as ALCL. In the past, this subtype has also been referred to as malignant histiocytosis. The majority (60%) of these children have a T-cell immunophenotype.^138,141 Although it was originally thought to be uncommon in children, this subtype accounts for 40–50% of the large cell lymphoma cases.^{138,139,142,143}

Clinical Presentation

Diagnosis

Children initially suspected of having NHL should be evaluated immediately because of the high risk of either metabolic or anatomic complications before therapy begins. The rapid growth of these tumors may create a life-threatening complication overnight in a child who seemed relatively healthy the previous day (Box 69-2).

No clinical findings are pathognomonic for NHL. Ultimately, the diagnosis awaits the biopsy of involved sites, most commonly an excised lymph node or percutaneous needle biopsy. Fine needle aspirations do not provide enough tissue for the necessary subtyping, which is performed with flow cytometry, molecular genetics, and cytogenetics. It is critical for the excised tissue to be delivered quickly as a fresh specimen for processing.

Similar to HL, for patients critically ill at diagnosis, such as those with severe airway obstruction, diagnosis by alternative methods may be required. NHL is a systemic disease that requires chemotherapy so debulking operations or attempts at local control are not necessary. The one exception in which initial total resection may be considered are those patients with an abdominal mass in whom bowel resection is already required because of perforation or obstruction. In this case, total resection of the tumor should be considered. In this setting, resection reduces the stage of the patient’s disease, improves survival, and reduces the amount of therapy required.¹⁶⁵ For all other patients, resection of the mass provides no improvement in staging or long-term cure, and delays the time to initiation of chemotherapy. It should be remembered that most patients have disseminated disease at presentation. Also, it is important to note that with chemotherapy alone, more than 90% will achieve a complete remission.

Once NHL is suspected, a concerted and well-conceived plan of evaluation is important to achieve a diagnosis as quickly as possible. This should include laboratory examination to evaluate tumor burden and presence or risk of tumor lysis syndrome. The radiographic evaluation in these patients is extremely important.⁵¹ No procedures or sedation should be attempted until a mediastinal mass has been excluded. To identify the extent of disease, CTs of the neck, chest, abdomen, and pelvis are required. An examination of the head, either CT or MRI, should be obtained in those patients with CNS symptoms, with CSF pleocytosis, or in whom the primary lesions are parameningeal based. Bone scans should typically be obtained. ¹⁸FDG-PET or gallium scans are currently recommended. ¹⁸FDG-PET scans have gradually replaced gallium scans and are now considered an essential tool in the initial evaluation of patients with NHL. Advantages of PET over gallium include same-day imaging, improved resolution, and a higher target-to-background ratio.¹⁶⁶ Diagnostic PET scans are reliable (greater than 90% positive) in patients with DLBCL. Studies of patients with HL and NHL have found PET to be superior to gallium for diagnosing disease sites.⁶⁶ Also, PET has been shown to be more sensitive than CT or gallium scans in staging NHL.¹⁶⁷ PET may be fused with CT for improved imaging. PET is also an important component in evaluating response to treatment.

Histologic evaluation of the biopsy material should include general histochemical techniques to confirm the lymphoma and its subtype. Additional tests include flow cytometric analysis of cell-surface markers to determine the immunophenotype of the lymphoma, cytogenetic evaluation for diagnostic translocations, fluorescent in situ hybridization (FISH), and DNA analysis using either Southern blotting or the polymerase chain reaction (PCR) for detection of the pathognomonic oncogenes (gene rearrangements), even in the absence of identifiable cytogenetic translocations.¹⁶⁸ Examination of markers in tumor cells for EBV is important in the evaluation of PTLDs. Therapy differences between the subtypes of lymphoma are such that assignment to the wrong subtype due to a lack of adequate diagnostic material will adversely affect the chance of cure. These evaluations may be performed with biopsy material from any involved site, including the primary mass, enlarged lymph nodes, effusions, and bone marrow. Gene expression profiling, which uses DNA microarrays, has been shown to categorize patients further into specific histologic and genetic subsets of lymphoma, with much greater predictability of the clinical outcome.¹⁶⁹ This technique has revolutionized diagnostic and prognostic characterization for NHL.

Completing the diagnostic protocol is the determination of whether or not there is CNS or bone marrow dissemination. Lumbar puncture for cytocentrifuged CSF analysis should be performed in all patients. However, in those with localized abdominal BL, and those with large cell lymphoma, the benefit gained from this is arguable because of the low incidence of CNS disease in these subpopulations. Bone marrow evaluation should include bilateral iliac crest biopsies and aspirates.

Staging

Once the diagnosis of NHL is made, staging permits determination of the extent of disease at presentation. This provides direction in monitoring disease response to therapy. In contrast to HL, relapse does not necessarily occur at the site of initial or previous disease in NHL. Thus, this initial staging should not limit the extent of monitoring for relapse after therapy is completed.

Staging is important in the determination of therapeutic planning. The most widely used staging schema today is the St. Jude’s or Murphy system (Table 69-3).¹⁷⁰ This is an adaptation of the Ann Arbor scheme and is applicable to all types of childhood NHL. It divides patients into localized (stage I or II) and disseminated or advanced (stage III or IV) disease. Involvement of the CNS or bone marrow immediately places the patient in the stage IV category. Patients with more than 25% bone marrow involvement are, by definition, diagnosed with leukemia rather than with lymphoma. These include B-cell or Burkitt leukemia (L3 leukemia morphologic classification) and T-cell leukemia. The former patients are treated on B-cell NHL protocols with much better results than previously obtained on acute lymphoblastic leukemia (ALL) regimens. Many of the B-cell NHL protocol results reported in the literature include these patients in their stage IV populations. The T-cell leukemia patients remain on ALL protocols, but many similarities exist between these protocols and those used in T-LL therapy.

Prognostic Risk Factors

When all patients are treated similarly, the stage of the lymphoma at diagnosis is a strong predictor of outcome.³ Prediction of a patient’s eventual outcome stratifies patients at high risk for relapse to more intensive or novel therapies and patients at low risk to shorter, more moderate therapies. Many prognostic factors have been evaluated over the years. All prognostic factors are dependent on the therapy subsequently given.³ It has been definitively shown that histology-based therapy is of critical importance in the successful outcome of these patients.¹⁵⁶

CNS involvement in both SNCCL and LL patients has predictably worse outcomes.¹⁵⁶ In patients with BL, the adverse effect of CNS disease on outcome has, in some studies, been more attributable to tumor burden at diagnosis than to the presence of CNS disease alone (i.e., those with greater tumor burden are more likely to have CNS disease).¹⁷¹ Patients with BL older than 15 years of age have a worse prognosis than patients younger than 15 years old. An LDH greater than 500 IU/L also predicts a worse outcome for patients with BL.¹⁷²

Treatment

Therapy for childhood NHL has evolved over the past several decades, and is based on the knowledge that this tumor is extremely chemosensitive. For BL and large cell lymphoma, the duration of therapy has become shorter as it became apparent that most, if not all, patients were experiencing relapse within the first 6 to 8 months of therapy.160,173 Despite reducing therapy to 6 months or less, no increase in relapse has been seen. Relapses for the most part have occurred within the first 6 to 8 months after diagnosis and virtually all have occurred within the first 2 years.^{154–156,173,174} Therapy for BL has shown a clear improvement as methotrexate and cytarabine doses have been increased. These two agents, in addition to cyclophosphamide, vincristine, doxorubicin (Adriamycin), and prednisone (and etoposide for the stage IV patients), now play a critical role in the successful outcome of these children.160,165,174,175 The addition of radiation has not shown improvements in DFS or OS.^142,144,176 The addition of rituximab (an anti-CD20 monoclonal antibody) is currently being studied.

For T-LL, the duration of therapy has been decreased to two years. The most effective regimens for LL have been ones similar to the intensive T-cell ALL protocols in current use. For patients with LL, irradiation to areas of bulky disease has been eliminated. However, for those patients with LL and CNS disease at diagnosis, irradiation remains an important part of their therapy. For ALCL patients, the use of T-cell regimens without much CNS-directed therapy has been efficacious.

Several additional points deserve mention. The use of corticosteroids should be avoided until the diagnosis is made. Steroids can induce rapid necrosis in the lymphoma, making subtype determination difficult if not impossible, and potentially jeopardizing the patient’s outcome. However, once adequate tissue has been obtained, chemotherapy including corticosteroids is an excellent method for rapid reduction of a life-threatening mass. Because of the extreme sensitivity of NHL, one can anticipate rapid reduction of tumor size once therapy is initiated. Radiation therapy is not necessary. It is not unusual to have symptoms completely resolve within 24 hours and have patients in complete radiographic remission within seven days. Many protocols now call for a period of reduced-dose chemotherapy for the first week to obtain a more controlled tumor reduction because of the severe tumor lysis that can accompany more rapid, therapy-induced necrosis.

NHL in immunodeficient individuals is most often a B-cell lymphoma, either small or large cell. Therapy for these patients has typically been directed toward these histologic types. For patients with ongoing iatrogenic immune suppression, a reduction in the immunosuppressive agent, with or without acyclovir, may be adequate to induce a remission in up to 75% of cases.132,177 In the past few years, for resistant disease, new methods using monoclonal antibody therapy, primarily rituximab, have been used with promising results alone, but these antibodies are most efficacious when combined with chemotherapy.¹⁷⁸

Results

When reviewing the outcomes of children treated for NHL, it is quickly apparent that considerable improvement in DFS and OS has occurred over the past several decades.³ Today, typically 90–100% of patients will achieve complete remission.^142,173,179 Five-year relative survival rates for children ages birth to 19 years, and diagnosed between 1996 and 2004, were 83.3%.¹³

Patients with localized disease have an overall excellent prognosis, regardless of histologic subtype, with DFS typically exceeding 90–95%. BL patients with advanced disease have experienced DFS exceeding 80% in the recent trials. Patients with LL with disseminated disease are not faring as well, but DFS for these patients is exceeding 65–70% in most trials. Overall, when they occur, treatment failures typically happen within the first two years after diagnosis. Patients with BL who experience relapse primarily do so within the first 6 to 8 months. LL patients will have an occasional late failure after two years, although even in this group of patients the vast majority of failures will occur early.¹⁷⁹ The prognosis for patients with DLBCL is excellent with three-year EFS of ≥90% in a recent trial.¹⁸⁰ Patients with advanced-stage ALCL have 2-year EFS of approximately 70%.¹⁸¹

Early Complications

Depending on the tumor burden at diagnosis, patients may initially have a constellation of significant metabolic derangements known as tumor lysis syndrome.152,153 These problems include hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia. Recognition of this syndrome is critical to prevent life-threatening complications, including acute renal failure. Without treatment, the incidence of acute renal failure may be as high as 30%.¹⁸² Tumor lysis syndrome is the result of the rapid turnover of cells within the tumor. The fraction of tumor cells in S phase at any given time can approach 27% in some patients.¹⁸³ These tumors have a high degree of spontaneous lysis at the time of diagnosis because they rapidly outgrow their blood supply. Any manipulation, including transfusion or operation, may induce a sudden worsening of this syndrome.

Therapy is primarily based on preventing hyperuricemia. For those at high risk, determined by the presence of an elevated LDH, creatinine, or uric acid value, intervention is important. For most patients with little or no elevation in these values, adequate hydration (>3000 mL/m²/day) and pH monitoring (maintain between 7.0 and 7.5) is adequate, along with the initiation of allopurinol to reduce the production of uric acid through inhibition of xanthine oxidase.¹⁸⁴ Rasburicase cleaves uric acid into allantoin, a soluble by-product. This agent, administered daily for one to five days, dramatically reduces measurable uric acid levels to immeasurable levels, thus allowing the clinician to focus on prevention or treatment of hyperphosphatemia, which requires maintaining acidic urine.^185,186 Despite these measures, it may be necessary to place patients on dialysis either to treat oliguria/anuria or to prevent it in the presence of rapidly increasing uric acid, phosphorus (typically >10 mg/dL), or potassium (>7.5 mEq/L) levels.^160,187 In an effort to avoid this complication, an initial low-dose therapy (usually 1 week) to more slowly reduce the tumor burden is used in some treatment regimens.

As a result of the much more myelosuppressive protocols required in NHL therapy, infection is a much greater risk for NHL patients as compared with HL patients.¹⁵⁶ In one recent study, 63% of the deaths were due to infection. Most patients require transfusion support during treatment because of the myelosuppression. The chemotherapy itself may cause acute complications, including severe chemical burns due to extravasation of certain vesicant agents (vincristine, anthracyclines). As most children require the placement of right atrial catheters to facilitate their therapy, thrombosis of this area and the surrounding vasculature has become more frequent.¹⁸⁸ Mucositis is seen in a significant number of patients during therapy for Burkitt lymphoma as well.

Long-Term Sequelae

As long-term survival has improved, the concern over lifelong sequelae has increased in these patients. With current therapy, these complications include cardiac toxicity,¹²² infertility as a result of the alkylating agents used,¹⁸⁹ and secondary leukemias due to epipodophyllotoxins (etoposide, tenoposide) and the alkylating agents used in the NHL regimens.¹⁹⁰ The risk for developing cardiac toxicity is related to several factors, including the irradiation dose, cumulative anthracycline dose, and age at exposure. Patients are at an increased risk for anthracycline-related cardiomyopathy if they are female, have received doses greater than 200–300 mg/m², and were younger when given anthracyclines.¹⁹¹

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