Hodgkin's lymphoma, previously known as Hodgkin's disease, is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes. It was named after Thomas Hodgkin, who first described abnormalities in the lymph system in 1832 [1,2].

Hodgkin's lymphoma is characterized by the orderly spread of disease from one lymph node group to another and by the development of systemic symptoms with advanced disease. When Hodgkin's cells are examined microscopically, multinucleated Reed-Sternberg cells (RS cells) are the characteristic histopathologic finding. Hodgkin's lymphoma may be treated with radiation therapy, chemotherapy or hematopoietic stem cell transplantation, the choice of treatment depending on the age and sex of the patient and the stage, bulk and histological subtype of the disease. The disease occurrence shows two peaks: The first in young adulthood (age 15-35) and the second in those over 55 years old [3]. The 10-year overall survival rate is more than 90% for any stages, early stage may help more (stage I or II) Hodgkin's lymphoma. Since many patients are young, they often live 40 years or more after treatment. However, few studies follow patients as long as 25 years and those studies are of older treatments with more life-threatening adverse effects, so it is impossible to predict long-term outcomes of newer, less harmful treatments.

Radiation treatments and some chemotherapy drugs, pose a risk of causing potentially fatal secondary cancers, heart disease and lung disease 40 or more years later. Modern treatments greatly minimize the chances of these late effects [4]. Patients with a history of infectious mononucleosis due to Epstein-Barr virus may have an increased risk of HL.

Review of Literatures

Etiology and Epidemiology:

• Etiology is unknown

• Comprises 8.8% of all childhood cancers under the age of 20

• Incidence increases to 32 per million for adolescents 15–19 years

• Bimodal age-incidence curve with one peak at 15–35 years of age and the other above 50 years of age (incidence is highest among 15–19 year olds)

• Association with Epstein–Barr Virus (EBV)

• Incidence increased among consanguineous family members and among siblings of patients with HL [5]

The childhood form of Hodgkin lymphoma tends to increase with increasing family size and decreasing socioeconomic status. In contrast, the young adult form of Hodgkin lymphoma is associated with a higher socioeconomic status in industrialized countries [6].

Familial Hodgkin Lymphoma

Clustering of cases of Hodgkin lymphoma within families or races may suggest a genetic predisposition to the disease or a common exposure to an etiologic agent studies of affected families have suggested an increased association of Hodgkin lymphoma with specific Human Leukocyte Antigen (HLA) [7]. Hodgkin lymphoma is diagnosed more commonly in persons, whose immune system is abnormal, a finding that may reflect the slight increase in familial incidence [8].

The etiologic factors underlying the immune deficiency include genetic (e.g., ataxia-telangiectasia), infectious {e.g., Human Immunodeficiency (HIV) and iatrogenic agents [8].

Epstein–Barr Virus and Hodgkin Lymphoma

In the young adult form, delayed exposure to an infectious agent has been proposed as a risk factor for the development of Hodgkin lymphoma because its epidemiologic features are similar to that seen with paralytic poliomyelitis. Epstein-Barr Virus (EBV) has been implicated in the causation of Hodgkin lymphoma by both epidemiologic and serologic studies [9].

In cases associated with EBV, the virus is localized to the Reed-Sternberg cell, EBV latent gene products are expressed, ad the EBV infection is clonal. Hodgkin lymphoma that is EBV-positive at initial diagnosis is usually also positive for EBV at relapse with persistence of the same EBV strain, [10].

Pathology

Hodgkin lymphoma is characterized by a small number of clonal tumor cells {HRS cells, Lymphocytic and Histiocytic (L&H) cells and their variants}, surrounded by a polymorphous inflammatory cell population that constitutes the bulk of the tumoral tissue. These studies have shown that the HRS cells contain clonal Immunoglobulin (Ig) rearrangements and therefore are neoplasms of lymphoid origin [11]. In exceedingly rare cases, the HRS cells have been found to contain T-cell receptor gene rearrangement suggesting that some of these tumors may be of T-lymphoid lineage [12]. These cases are somewhat controversial [13] and remain to be further investigated. Thus, Hodgkin lymphoma is a unique type of B-cell neoplasm and hence the currently used World Health Organization (WHO) classification [14] has abandoned the term" Hodgkin disease" thought to reflect the lack of knowledge regarding the true origin of the HRS cells.

Macroscopic Features

The spread of HL occurs mostly by contiguity from one chain of lymph nodes to another.

Involvement of the left supraclavicular nodes often follows abdominal para-aortic node involvement with spread up the thoracic duct, whereas involvement of the right supraclavicular nodes tends to be associated with mediastinal adenopathy. Para-aortic node involvement commonly occurs in association with involvement of the spleen, which in turn is commonly followed by liver or bone marrow involvement, or both. The R-S cell is the hallmark of classical HL and is characterized by a binucleated or a multinucleated giant cell that is often characterized by a bilobed nucleus, with two large nucleoli, giving the classically described “owl’s eye” appearance. The R-S cells are embedded within a benign- appearing reactive infiltrate of lymphocytes, macrophages, granulocytes and eosinophils [5] (Figure 1).

Figure 1: Pattern of Lymph Node Spread and Histopathological Features of Hodgkin Lymphoma

Hodgkin lymphoma is characterized by a minority of malignant cells that account for 0.1 to 10% of the total cell population of the tumor [13]. The majority of the tumor is composed of an infiltrate of inflammatory cells (e.g. histiocytes, plasma cells, lymphocyte, eosinophils, neutrophils) and fibrosis, which develop as a result of cytokine release in its most typical forms, Hodgkin lymphoma must therefore be differentiated from several subtype of NHL with similar morphologic characteristics(i.e. T-cell rich large B-cell lymphoma and anaplastic large cell lymphoma) and from benign lymphoid hyperplasia with similar cellular composition (e.g. infectious mononucleosis, progressive transformation of germinal centers [15].

Immunophenotypic Features

Tumor cells in classic HL usually do not express B-cell antigens such as CD20 and CD79a, but virtually all express CD30 and most express CD15 [5].

Histological Classification

Hodgkin Lymphomas (HL) consist of two disease groups, as was proposed in the Revised European-American Classification of Lymphoid Neoplasms (REAL classification) and incorporated into the 2008 4th edition of the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues [5]. The current WHO histologic classification of Hodgkin lymphoma is largely based on the Rye modification of the Lukes and Bulter classification schema [16].

The WHO classification [15] recognizes two major subtypes of Hodgkin lymphoma cHL and nodular LPHL, based on their biologic and clinical features the cHL contains HRS cells with the classical morphology and immunophenotype.

Histologic Classification of Hodgkin Lymphoma According to the Who Classification:

• Nodular lymphocyte predominant Hodgkin lymphoma 

• Classical Hodgkin lymphoma:

• Nodular sclerosis subtype

• Mixed cellularity subtype

• Lymphocyte-rich subtype

• Lymphocyte-depleted subtype

In the nodular LP HL, the tumor has at least partially nodular architecture. The neoplastic nodules contain classic L&H cells and only rare classic HRS CELLS [16] Nodular LP HL affects 10-15% of patients, is more common among male and younger patients and usually presents as clinically localized disease affecting approximately 40% of younger patients and 70% of adolescents, Nodular Sclerosis (NS) cHL is the most common subtype [17]. In the MC subtype of cHL, HRS cells and their variants are often numerous (5 to 15 per high-power filed), this type is observed in approximately 30% of patients, is more common in children aged 10 years or younger and frequently presents as advanced disease with extranodal involvement. LD Hodgkin lymphoma is rare in children, but it is common in HIV-infected patients [18]. The Lymphocyte Rich (LR) variant of cHL is characterized by classical HRS cells and a cellular background that consists mostly of small B lymphocytes [19].

This subtype comprises approximately 5% of all Hodgkin lymphoma and closely overlaps with the nodular LP subtype in presenting clinical features and prognosis.

Clinical Presentation

Lymphadenopathy (90% of All Cases):

• Painless swelling of one or more groups of superficial lymph nodes; rarely painful

• Cervical nodes involved in 60–80% of cases; associated with mediastinal involvement in 60% of cases

• Axillary, inguinal, mediastinal and retroperitoneal nodes also frequently involved

• Involved nodes are discrete, elastic, painless and usually “rubbery”; tenderness is rare

• The bulks of palpable lymph nodes are defined by the single largest dimension (in centimeters) of the single largest lymph node or conglomerate node mass in each region of involvement. A node or nodal mass 10 cm is defined as bulky. Abdominal nodal bulk is generally determined using CT (Figure 2)

Figure 2: Clinical Features and Distribution of Lymphadenopathy in Hodgkin Lymphoma

Mediastinal Adenopathy (60% of All Cases)

Approximately 20% of patients have bulky mediastinal disease defined as a large mediastinal mass (10 cm in maximum dimension) or which, on a posterior–anterior chest radiograph has a maximum width equal to or greater than one-third of the internal transverse diameter of the thorax at the level of the T5–6 interspace (mass to thoracic ratio >0.33).

Adolescents and young adults present with a mediastinal mass in 75% of cases, as opposed to children less than 10 years of age where mediastinal disease is present in only 35% of cases.

This is thought to be due to these younger patients having either mixed cellularity or lymphocyte predominant histology, where peripheral adenopathy is more common.

Splenomegaly

The spleen is commonly enlarged on physical examination or by 99mTc-sulfur colloid scan. However, its size is not indicative of splenic involvement with Hodgkin lymphoma.

In 13% of cases, the spleen is the only site of subdiaphragmatic disease. Spleen is involved in 26% of spleens resected in staging laparotomy.

Pulmonary Disease (17% of All Cases)

The mediastinal and hilar nodes are the pathway to the lungs for the spread of HL. Pulmonary HL does not occur without mediastinal or hilar disease. About two-thirds of patients with HD have intrathoracic involvement. There is a striking predilection of the nodular sclerosis type for mediastinal involvement.

Neurologic Manifestations

Neurologic dysfunction is usually a late manifestation. The disease can reach the nervous system in the following ways:

• Spread from paravertebral lymph nodes along nerve roots, blood vessels, or perineural lymphatics into the spinal canal by way of the intervertebral foramina and similarly into the intracranial region

• Hematogenous dissemination

Bone Disease (2% of All Cases)

Osseous HL typically presents with bone pain and the majority of patients have concurrent non osseous lesions detected at staging. The radiographic features of osseous Hodgkin lymphoma vary but indicate an aggressive malignant process.

Bone Marrow Involvement (5% of All Cases)

Symptomatic patients, particularly those with anemia, leukopenia, or thrombocytopenia, may have bone marrow involvement. Multiple biopsies are indicated, because HL tends to involve the marrow in a focal fashion.

Liver Disease (2% of All Cases) Mild Hepatomegaly Nonspecific abnormalities on liver scan and abnormal liver function tests do not correlate with actual histologic involvement of the liver. Liver biopsy is the only method for accurate diagnosis of liver involvement.

To Establish Liver Involvement, the Following Findings Should be Present:

• Evidence of discrete lesions that features one of the histologic subtypes of HL

• Conclusive evidence of a Reed–Sternberg cell or one of its variants

Renal Manifestations

HL may directly involve the kidney in 13% of cases. Renal involvement may be unilateral or bilateral and may be present as diffuse involvement, discrete nodules, or microscopic disease. Renal involvement with HL may result from ureteral obstruction and patients with HL may also have renal dysfunction related to renal vein thrombosis, hypercalcemia and hyperuricemia.

Hematologic Manifestations

• Blood count: Anemia-normocytic and normochromic, neutrophilia (50% cases), eosinophilia (50% cases), lymphocytopenia

• Myelosuppression in HL may be caused by hypersplenism or bone marrow infiltration

• A positive Direct Antiglobulin Test (DAT) may or may not be associated with overt hemolysis. Patients with a positive DAT test frequently have advanced-stage disease and systemic symptoms

• Immune thrombocytopenia may accompany HL in 1–2% of cases. Thrombocytopenia may develop before, concurrently with, or after the diagnosis of HL

• Autoimmune neutropenia has also been described in patients with HL. Neutropenia may occur before the diagnosis

• Eosinophilia is frequently associated with HL. This occurs in 15% of patients. The presence of eosinophilia is not related to stage or histology. IL-5 production by Reed- Sternberg cells, may explain the etiology of eosinophilia accompanying HL [5]

• The erythrocyte sedimentation rate and serum copper and ferritin levels may be elevated, reflecting activation of the reticuloendothelial system [20]

Constitutional B Symptoms

Approximately 20% of patients have associated B symptoms. B symptoms are defined as:

• Unexplained weight loss or more than 10% of body weight in the 6 months preceding the diagnosis

• Unexplained fever with temperatures .38_C for more than 3 days

• Drenching night sweats [5]

• Pruritus is another systemic symptom commonly observed in patients with Hodgkin lymphoma, which lacks the prognostic significance associated with fever, sweats and weight loss

Pruritus generally occurs more frequently in patients with advanced-stage disease, may accompany other systemic symptoms, may be more common in women and is usually generalized.

Proposed explanations of Hodgkin- associated prurites include cholestatic liver disease and peripheral sensory neuropathy pruritus typically resolves when the Hodgkin lymphoma is treated [21].

Prognostic Factors

Several pretreatment factors have been associated with an adverse outcome in one or more studies and these include:

• Advanced stage of disease (Stage IIB, IIIB, or IV disease)

• The presence of B symptoms

• The presence of bulk disease

• Extranodal extension

• Male sex

• Elevated erythrocyte sedimentation rate

• White blood cell count 11,500/mm³ or higher

• Hemoglobin less than 11.0 g/dL

• The combination of B symptoms and bulky disease are inferior prognostic indicators. Histology has been noted to be an important prognostic indicator as well. Patients with Nodular Lymphocyte Predominance HL (NLPHL) appear to have an overall better prognosis than those with classical HL (cHL)

• Serum markers are currently being studied as prognostic indicators; those associated with poor prognosis include: tumor necrosis factor, soluble CD30, beta 2 macroglobulin, transferrin and serum IL-10 level. Favorable outcomes have been noted with high levels of caspase 3 in Reed–Sternberg cells

• Other prognostic indicators include initial response to chemotherapy. Early response assessment is based on volume reduction of disease, functional imaging status or both. Significant reduction in disease volume and PET negativity after two cycles of chemotherapy is associated with a favorable outcome in children and adolescents and failure to achieve this has been associated with an unfavorable outcome in adults

This therapeutic response may permit titration of therapy based on early response and this paradigm is being studied in cooperative group and consortium trials [5].

Differential Diagnosis

Hodgkin lymphoma must be differentiated from other inflammatory causes of lymphadenopathy, particularly those with an indolent course (e.g., atypical mycobacterium infections and toxoplasmosis).

NHL may have similar presenting signs & symptoms, but the growth rate of the affected lymph nodes is often more rapid than in hodgkin lymphoma. The cervical lymphadenopathy of Hodgkin lymphoma must also be differentiated from metastatic adenopathy of other primary tumors (e.g., nasopharyngeal carcinoma and soft tissue sarcoma).

A more difficult problem is that of a mediastinal mass that must be differentiated from normal thymus in an otherwise asymptomatic patient, the thymus is maximal in size in children aged approximately 10 years and may be differentiated from tumor on thoracic Computed Tomography (CT) scans by its texture [22].

Staging

The Ann Arbor Classification was originally adopted in 1971 and was up dated in 1989; it has also been called the Cotswald Classification [5]. Hodgkin lymphoma appears to spread along contiguous lymph nodes until late in the course of disease [23] the currently used Ann Arbor staging system, adopted in 1971, is based on this observation the sub stage classification A, B and E amend each stage based on defined clinical features. Sub stage A indicates "asymptomatic" disease. B symptoms include fever exceeding 38c for 3 consecutive days, drenching night sweats and an unexplained loss of at least 10% of body weight over 6 months, sub stage E denotes minimal extralymphatic disease (Figure 3).5

Figure 3: A Modified Ann Arbor Classification of Hodgkin lymphoma (Continued) Symptoms and Presentation

Disease limited to the spleen or splenic hilar or porta hepatic nodes has been said to have a more favorable prognosis relative to other stage III A disease and is designated III A1 (Table 1) [24].

Table 1: Modified Ann Arbor Classification of Hodgkin lymphoma [5]

Diagnostic Workup

• Recommended for children with equivocal infra diaphragmatic imaging if expertise is available at center

• Recommended for all children except those with stages IA/IIA

• Recommended for children with Bone pain and elevated alkaline phosphates

• Recommended in selected cases only (Figure 4)

Figure 4: Diagnostic Evaluation for Children with Hodgkin Lymphoma

The chest radiograph provides preliminary information about mediastinal involvement and intrathoracic structures patients with "bulky" mediastinal lymphadenopathy measurement greater than or equal to 33% of the maximum intrathoracic cavity may benefit from a combined-modality treatment approach [25].

Positron Emission Tomography (PET) has been used with increasing frequency over the last decade and will likely replace gallium as the preferred functional imaging modality for lymphoma staging [26].

In PET scanning, uptake of the radioactive glucose analogue 18-Fluoro-2-Deoxyglucose (FDG) correlates with proliferative activity in tumors undergoing anaerobic glycolysis [27].

Bone marrow involvement at the time of initial presentation of Hodgkin lymphoma is uncommon and rarely occurs as an isolated site of extranodal disease.

A bone marrow aspirate alone is not adequate to assess the marrow for disease. A bone marrow biopsy should be performed in any patient with clinical stage III to IV or B symptoms or in any patient at the time of disease recurrence.

A technetium -99 bone scan with corresponding plain radiograph of abnormal areas aids in the assessment of skeletal metastases and should be reserved for the child who has bone pain, a serum alkaline phosphate concentration elevated beyond that expected for age, or extranodal disease identified by other staging studies [28].

Treatment

In general, the use of combined chemotherapy and Low-Dose Involved Field Radiation Therapy (LD-IFRT) is considered standard of care.

This allows for maximal therapy with reduction of individual drug-related or radiation-related toxicities. The volume of radiation and the intensity/duration of chemotherapy are determined by prognostic factors at presentation and include:

• The presence of B symptoms

• Initial stage of disease

• Presence of bulky disease [5]

Combination of Chemotherapy

Current effective multi drugs regimens for Hodgkins and other pediatric malignancies combine non-cross-resistant agents with following properties:

• Each agent should be individually active against the tumor

• The agents should differ in the mechanism of antineoplastic activitiy, there by targeting different cellular or biochemical events and preventing development of resistance

Toxicities of the agents should not overlap, so that each drug can by an administered at full single-agent dose [29] (Table 2).

Table 2: Lists some of the Regimens used in Hodgkin Lymphoma [29]

Radiation

Hodgkin lymphoma is a radiosensitive disease. Treatment for HL in children and adolescents employs radiation therapy in the context of multimodality therapy. Most newly diagnosed children and adolescents are treated with risk-adapted chemotherapy alone or in combination with LD-IFRT. In general, doses of 15–25 Gy are used with modification based on patient’s age, the presence of bulk disease, normal tissue concerns and potential acute and long-term effects [5].

Prognosis

Treatment of Hodgkin's disease has been improving over the past few decades. Recent trials that have made use of new types of chemotherapy have indicated higher survival rates than have previously been seen.

In one recent European trial, the 5-year survival rate for those patients with a favorable prognosis was 98%, while that for patients with worse outlooks was at least 85% [30].

A Progression/Relapse of the Disease

• Progression if it occurs until three months after the end of therapy (last day of chemotherapy application (including Prednisone/ prednisolone) or last day of radiotherapy respectively)

• Early relapse if it occurs between three and twelve months after the end of therapy

• Late relapse if it occurs later than twelve months after the end of therapy [31]

Treatment for Relapsed and Progressive Disease

Treatment failure in children and adolescents with HL can be divided into:

• Relapsed disease, or

• Primary progressive disease

Relapsed patients can still be cured even if relapse occurs after initial treatment. Relapse usually occurs within the first 4 years following treatment. The presence of B symptoms and extra nodal disease at the time of relapse are poor prognostic features. A study conducted by the Society for Pediatric Oncology. 

Hematology (GPOH) showed the Following Results:

• Patients with an early relapse had a 10-year Event-Free Survival (EFS) of 55% and Overall Survival (OS) of 78%

• Patients who had a late relapse had a 10-year EFS and OS of 86 and 90%, respectively [5]

Most relapse in patients with Hodgkin lymphoma occur within the first 3 years, although some patients may relapse as long as 10 years after initial diagnosis.

As many as 50% to 80%; of patients who relapse after radiation therapy alone can be salvaged with chemotherapy or combined-modality therapy [32].

Standard multi agent chemotherapy and radiation therapy may salvage 40% to 50% of children with 1 year or longer initial remissions, but subsequent treatment sequelae, including second malignancies, may reduce ultimate survival [33].

Patients who develop refractory disease during or within 1 year of completing therapy respond poorly to conventional salvage therapy, as does patient with multiple relapses.

For these high-risk patients, consolidation with myeloablative therapy followed by Hematopoietic Stem Cell Transplantation (HSCT) provides the best opportunity for a durable remission.

Several studies support the feasibility and efficacy of this approach, which produce overall survival rates ranging from 30 to 60% in children and adolescents with relapsed Hodgkin lymphoma [34].

Transplant–associated mortality occurs in approximately 10% of patients and most commonly results from infection, cardiopulmonary, or neoplastic complications [33]. Patients have been reported to be at risk for relapse as late as 5 years after HSCT, emphasizing the need for heightened surveillance to ensure continued remission status and monitor for late treatment sequelae.

Autologous HSCT has been preferred for patients with relapsed Hodgkin lymphoma because of the historically high transplant-related mortality associated with allogeneic transplantation [35].

Other novel therapeutic approaches for relapsed Hodgkin lymphoma are currently under investigation. immunotoxin therapy targeting antigens expressed by HRS cell include CD25(the IL-2 receptor) and CD30 (the Ki-1 antigen) clinical trials to date have included only small numbers of patients [36].

Long-Term Complications

Survivors of HL are at risk for numerous late complications of chemotherapy and radiation therapy. Late effects include secondary malignancies, organ dysfunction and psychosocial sequelae.

Secondary Malignancies

The incidence of secondary malignancies in survivors is 7–18 times higher than the general population. Many of these patients had received high-dose alkylating agents and radiation.

Cardiac Toxicity

HL survivors exposed to doxorubicin or thoracic radiation therapy are at an increased risk for long-term toxicity.

Pulmonary Dysfunction

Pulmonary fibrosis is a late complication of HL following radiation therapy. Bleomycin associated pulmonary fibrosis with decreased diffusion capacity.

Thyroid Dysfunction

Primary hypothyroidism is noted following radiation therapy to the neck for HL; though hyperthyroidism, goiter, or nodules have also been noted.

Gonadal Dysfunction and Infertility 6- Growth Dysfunction

Long-term effects on bone and soft-tissue growth among survivors of childhood HL are related to the dose and volume of radiation received, as well as the age of the child when the radiation was received.

Psychosocial Problems

Six percent of HL survivors have symptoms of depression and 15% have somatic distress higher than that for other malignancies or when compared to sibling cohorts. Risk factors associated with increased risk for somatic distress include female gender, lower household income, less than a high school education and lack of current employment [5].

Aim of the Study

• To study the clinico-pathological features of Hodgkin Disease in Iraqi children

• To compare the results of our study with other studies done inside and outside Iraq

• To assess the response to treatment, outcome and survival

Patients and Methods

Over 6-year period, from January 1st 2003 to December 31st 2009 a retrospective study was done for 86 children with Hodgkin’s lymphoma who were admitted to the pediatric oncology unit in Children Welfare Teaching Hospital.

The information's regarding (age, sex, residence, clinical presentation, diagnostic procedure, staging investigation, treatment modality and its complications, outcome) were taken from hospital registry (Inpatient and outpatient) in addition to own patient’s records.

Pretreatment studies included complete blood count, serum electrolyte, hepatic and renal profile, bone marrow aspirate and biopsy, incision or excision biopsy , Fine needle aspirate, radiography (chest x-ray, abdominal ultrasound, CT scan and/or MRI to the primary site).

Because of lack of the facilities, several investigations were not done like bone scan, serum LDH, immunohistochemical studies, cytogenetic and molecular analysis.

In 8 cases; the paraffin blocks were sent to Pathology department/Sapienza Rome University and re-evaluation was done.

Presenting Features

A total 86 children with Hodgkin disease were seen at CWTH from January 1st 2003 to December 31st 2009. Patients' data were analysed.

The patient were referred to CWTH from 11 governorates, nearly half of them were from Baghdad 42 (48.8%) patients followed by Diala 9 (10.5%) patients, Wasit 8 (9.3%) patients, as shown in Table 3.

Table 3: Referral Area of Patients to CWTH

There were an increment in referral of the patients with Hodgkin disease to our hospital in 2003 as compared to 2009 (1.2 Vs 25.6%), as shown in Table 4.

Table 4: Years of Diagnosis

There were 63 (73.3%) males and 23 (47.8%) females; male to female ratio was 2.7:1 as shown in Table 5.

Table 5: Sex Distribution

Male: Female ratio 2.7:1

Fifty eight (67.4%) patients presented with age group between 6-10 years, 15 (17.4%) patients presented with age group between 11-14 years and 13 (15.1%) patients presented below 5 years, with median age was 8 years; the mean age was 7.8 years, ranged from 2 years to 12.4 years, as shown in Table 6.

Table 6: Age Distribution

The median age was 8 years; The mean age was 7.8 years

Neck swelling was the most common sign observed in 42 (48.4%) patients. Neck swelling and fever were present in 16 (18.6%) patients; axillary swelling was present in 3 (3.5%) patients, as shown in Table 7.

Table 7: Presenting Signs

Regarding lymphadenopathy, cervical lymph node enlargement was found in 64 (74.4%) patients, followed by supraclavicular lymph node enlargement which was found in 8 (9.3%) patients, generalized lymph adenopathy was found in 6 (7%) patients, axillary lymphadenopathy in 4 (4.7%) patients, inguinal lymphadenopathy in 4 (4.7%) patients, as shown in Table 8.

Table 8: Site of Involvement

B symptoms (weight loss, fever and night sweating), were found 37/80 patients (43%). The mean duration of illness was 7.57 months.

Diagnosis

Chest X-ray reports were seen in the records of all cases; it was normal in 49 (57.0%) patients, mediastinal mass in 26 (30.2%) patients and hilar lymphadenopathy in 11 (12.8%) patients as shown in Table 9.

Table 9: Radiological Findings

Ultrasound reports were found in 85 cases; it was normal in 44 (51.2%) patients, splenic involvement was found in 23 (26.7%) patients, hepatosplenomegaly was found in 12 (14%) patients, mesenteric or para-aortic lymphadenopathy was found in 3 (3.5%) patients, pleural effusion was found in 2 (2.3%) patients, pancreatic involvement was found in 1 (1.2%) patient and one (1.2%) patient has no record of abdominal ultrasound.

CT chest records were found in 10/86 cases; it was normal in 4 (4.7%) patients, hilar lymphadenopathy was found in 6 (7%) patients and 76 (88.4%) patients had not done CT chest.

CT abdomen records were found in 4 cases; it was normal in 2 (2.3%) patients and splenic involvement was shown in 2 (2.3%) patients as shown in Table 9.

Staging

Stage III was the commonest; recognized in 42 (48.8%) patients, followed by stage II in 33 (39.5%) patients and stage I in 10 (11.6%) patients, while no patients presented with stage IV as shown in Table 10.

Table 10: Staging

Histopathology

All pathological specimens were evaluated in Iraq; 8 cases re-evaluated in Rome (in 4 cases the diagnosed was changed to Hodgkin’s lymphoma after being diagnosed and treated as non-Hodgkin’s lymphoma).

Mixed cellularity was found to be the commonest histopathological group in 71 (82.6%) patients, followed by lymphocyte predominant in 12 (14%) patients, nodular sclerosis in 2 (2.3%) patients and lymphocyte depleted was found in 1 (1.2%) patient as shown in Table 11.

Table 11: Histopathology

Treatment Outcome

Seven patients were excluded from the outcome analysis (4 patients were treated as non-Hodgkin’s Lymphoma, 1 died before treatment, 1 refused treatment by the family and 1 treated in another institute).

Till February 10^th 2011; 71 (89.9%) patients alive, 2 (2.5%) died and 6 (7.6%) lost follow up during therapy.

From 79 patients who received chemotherapy; fifty six (70.9%) patients finished treatment and remained free of disease till time of last follow up, 1 (1.3%) patient died during treatment, 12 (15.2%) patients relapsed after finishing treatment (all of them received rescue treatment with more intensive protocols; 11 patients remained alive free of disease and one patient got second relapse and abandoned further treatment), 4 (5%) patients abandoned treatment and never came back and 6 (7.6%) patients got progressive disease during treatment (one died, one abandoned further treatment and 4 received rescue treatment and remained free of disease till time of last follow up), as shown in Table 12.

Table 12: Treatment Outcome

At median follow up period of 36months, ranged from 1 month -82 months; Event free survival is 70.9%, as shown in Figure 5.

Figure 5: Event Free Survival is 70.9%

Overall survival was 89.9%, as shown in Figure 6.

Figure 6: Overall Survival for 36 Months is 89.8%

This study described outcomes of patients with Hodgkin disease in our institution. Patients had male to female ratio of 2.7:1, comparable to3:1that mentioned in literature [5], Olapuram Jose B study in USA 2004 of 2.6:1 [37] and two previous studies done in the same hospital (1991-1995) of 4:1 and (1997-2003) of 3.1:1[38,39] but lower than 9.6:1 in Arya et al. [40]  study from India 2006.

Median age at presentation was 8 years, comparable to previous studies in the same hospital of (8 and 7.5 years) respectively [38,39] and Arya et al. [40], study of 8 years but lower than 14 years in Olapuram Jose B study in USA 2004 although 3% of their patients were above 15 years of age [37], the lower median age in our study might be due to overcrowding and subsequent infection.

Cervical lymphadenopathy was the commonest presentation in our study in 64 (74.4%) patients, similar to literature and previous Iraqi studies [5]; [38,39].

Table 13 shows comparison between 3-study periods in the same hospital; there was a trend towards increasing number of referrals to CWTH over the last 2 decades and in the number of early stages of the disease rather than advanced stages, this might reflect better awareness of the disease by the families, health paramedics and physicians which led to early seeking of medical advice and relatively earlier diagnosis.

Table 13: Overall Survival

Comparing with other studies; still our study series showing more advanced stages than other studies in developed countries [37,41], but less than studies India and South Africa [40,42] as shown in Table 14. This might be due to increased family sizes, poor socioeconomic status, less awareness of the disease and poor diagnostic facilities in resource limited countries.

Table 14: Comparison between 3 Studies done to Patients with Hodgkin’s Lymphoma’s in the Children Welfare Teaching Hospital

In the current study, mixed cellularity was the commonest histological subtype (82.5%), differ from Hesseling PB study in South Africa 1997 [42], in which nodular sclerosis was the commonest histological subtype (59%) and from Hung study in Taiwan [43] in which the commonest histological subtype was nodular sclerosis (57%). This might be explained by higher incidence of EBV infection in the developing countries, which contribute to the pathogenesis of younger age in Hodgkin’s lymphoma and M.C. subtype (Table 15).

Table 15: Comparison between Current Study and other Studies Analyzing Patients with Hodgkin’s Lymphoma

In the current study, splenic involvement was found in 23 (26.7%) cases, which was different from that mentioned in Arya et al. study in India [44], in which splenic involvement was found in (15.6%).

In the current study; B symptoms were found in (43%), which was different from that mentioned in Arya et al. study in India [40], in which B symptoms were found in (54.5%).

Event free survival was 70.9% better than (48.3%) in the previous study in CWTH (1997-2003).

Overall survival in the current study was 89.9%, better than 74.1% in the previous CWTH (1997-2003) but lower than 98% in European studies and that mentioned in Fadoo et al. study in Pakistan 2010 [45], in which overall survival was 94%.

There is no follow up system in our setting to detect those who lost to follow up during therapy or post therapy taking in consideration that Hodgkin’s Lymphoma needs follow up beyond five years after finishing therapy.

• Male affected more than female
• Presentation in younger age groups
• Advanced stages are less than the previous two studies in the same hospital
• Mixed celluarity is the most common histopathologiacl type
• High rate of patients presented with B symptoms
• Overall survival better than previous studies in CWTH but still below the standard in developed countries

Recommendation

• Education of general practitioners for early referral of patients
• Improve diagnostic facilities for accurate diagnosis.
• Improving medical health services by establishment of trained full time team of physicians and nurses, provision of nurses with specialized training in oncology
• Comprehensive treatment with all modalities, chemotherapy and radiotherapy in well-equipped specialized center

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