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

Stay updated, free articles. Join our Telegram channel

Join