Introduction

Hodgkin’s lymphoma, also known as Hodgkin’s disease is characterized by progressive enlargement of lymph nodes in the patients. It was first reported by Hodgkin’s in 1832 A.D and was described as some morbid appearances of the absorbent glands and spleen. 1 Sternberg in 1898 and Reed in 1902 are generally credited with the first definitive and thorough description of multinucleated giant cells in the disease. 2, 3.
Initially the disease was considered to be of infectious or autoimmune origin however successful cultivation of Reed Sternberg cells (RS) which is the hallmark of disease, led to the confirmation of its malignant nature. 4 The cause is still unknown but three factors are said to interplay in its causation;
Viral: Herpes virus 6, cytomegalovirus and Epstein Barr Virus (EBV) have been responsible. EBV has been associated in epidemiological and serologic studies especially with mixed cellularity Hodgkin’s disease [58% had EBV genome fragments (EBNA)]. EBV is more frequent in children less than 10 years Genetic: Hodgkin’s disease is associated with systemic lupus erythematosus (SLE), rheumatoid arthritis, ataxia telengiectasia and Swiss type agamma globulinemia. 5,6 Clustering of cases within families or races may suggest a genetic predisposition. Studies have pointed its association to specific HLA antigens. 7
Environmental: It is speculated that herbicides, environmental carcinogens and pesticides play a role in predisposed patients with certain HLA antigen/immune deficient states with infection probably of viral origin.

Materials and Methods

The study was carried out at Oncology unit of Children Hospital, Pakistan Institute of Medical Sciences (PIMS) Islamabad. The data was primarily retrieved from records of patients registered at tumor registry maintained at the unit. The Children Hospital is about 250 bedded Hospital founded in 1985. Since its early days Oncology services had been provided on regular basis. The current oncology unit has a day care facility with over 400 visits per month, of which 80% receive chemotherapy. The inpatient facility is comprised of a 6 bedded room in west medical ward.  A proper tumor registry was founded in November 2005 and till date it has registered 204 patients with various types of cancers. In this study all patients diagnosed with Hodgkin’s disease on the basis of excisional biopsy from November 2005 to October 2007 were included. Children less than 14 years of age were included and a detailed Performa was filled in for each patient, which was later transferred on to Excel Sheet (Microsoft). Each patient’s sex, age, residence, presenting complaints, histological type, nutritional status, previous drug history and outcome at the time of study was entered. The lab support included histopathology, ultrasound abdomen (for abdominal lymphadenopathy and splenic deposits), chest X-ray, C.T scan chest, neck and abdomen and bone marrow trephine biopsy. Baseline tests of liver functions, renal functions, hepatitis profile and echocardiogram were also performed in all patients. Bone scan was not done in all patients due to non-availability. Patients received treatment with Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) /Cyclophosphamide, oncovin, prednisolone and dacrbazine (COPD) protocol initially at first presentation. However relapse (on/off treatment) were switched to EPIC regimen. 

Results

Hodgkin’s disease was diagnosed in 33(16%) patients out of 204 newly registered patients. Male patients were 29(88%) and female patients were 4 (12%). Male to female ratio was 7:1.  The age ranged from 2 years to 14 years. The mean age (1st peak) at presentation was between 6 to 8 years. A second peak was observed between 10 to 11 years. The patients were mainly referred from upper Punjab (42%) and North-West Frontier Province (NWFP) (24%). However some patients were referred from far-flung areas such as Gilgit, Sikardu and Chitral.15% of patients had a previous history of receiving anti tuberculous drugs for varying length of time. The disease was primarily observed in cervical region in 26(78%) patients. However some patients presented with involvement of unusual sites, for example isolated inguinal lymph nodes or cortical bone. Among the four known histological types; 18 (54%) had mixed cellularity, 10(30%) had nodular sclerosis, 2 (6%) had lymphocytic predominance and 3 (9%) had lymphocytic depletion. B symptoms were reported in 14 (42%) patients. The disease was staged according to Ann Arbor classification with sub classification using presence or absence of B symptoms. Majority of patients presented in stage III 15(45%) followed by stage II 6(18%). Bulky disease /stage III se was present in 5(15%) of patients. Bone marrow involvement was present in only 3 (9%) patients.
The outcome of patients was calculated at the time of study. 23 (70%) patients had successfully completed their treatment; one patient expired at home while on active protocol due to status asthmaticus or questionable pneumonia. Whereas 2 patients expired following relapse of the disease and failed to respond to second line protocol (EPIC). The overall mortality was 9%.  6 (18%) patients were receiving treatment at the time of study. Only one patient was referred to another hospital upon personal request. (Graph 1)

Discussion

Hodgkin’s disease is a relatively less common form of lymphoma i.e. 1 out 5 lymphomas. It is characterized by its distinct involvement of lymph nodes and other lymphoid glands (e.g. spleen, liver and bone marrow). The lymph nodes have particular rubbery texture are discrete and non-tender and over overlying skin is freely mobile. However when they grow to massive size they tend to coalesce.
In this study children with Hodgkin’s disease formed a sizable fraction of malignancies presenting to our O.P.D (16%). In developed countries Hodgkin’s disease is rarely diagnosed in less than 5 years of age. 8 However in developing world this does not hold true and patient under 5 years with Hodgkin disease is seen especially with mixed cellularity Hodgkin’s disease (MCHD)9. This may be attributed to its causation/ etiology i.e. viral infection at an early age especially before 10 years of age. This may be the reason that 5 (15%) of our patients were 5 years or less at the time of diagnosis.
Over all incidence of Hodgkin’s disease has a slight male predominance. This difference is more marked in patients less than 10 years. In our study there was a significant male predominance (88% Vs 12%). It was observed in all ages i.e. less then 5 years, 5-10 years and in adolescent age group This can be a true reflection of disease pattern.  However other factors may also be playing a certain role e.g. distance of health facility from native place. As Children Hospital is a tertiary care hospital and patients were referred here from far flung areas i.e. upper Punjab (42%) NWFP (24%), Kashmir (9%) and Gilgit. Only 20% of patients belonged to twin cities of Rawalpindi and Islamabad. Due to traditional taboos female child is usually not taken to distant health care facilities for treatment.

Fig 1. A 10 year old child presenting with Hodgkin’s lymphoma after six years of diagnosis

Another important observation seen in this study was of previous history of receiving anti tuberculous therapy (ATT). Most of our patients presented with cervical disease i.e. cervical lymph nodes (78%). These patients were clinically diagnosed as tuberculous lymphadenitis and were started on ATT. 15% of our patients received ATT for varying length of time before being referred to a tertiary care facility for further evaluation. This can be attributed to the fact that tuberculosis is rampant in our society. However there are certain clinical and laboratory criteria which have to be met before starting a child on ATT.
The diagnosis of Hodgkin’s disease is clinical but it is confirmed on excisional biopsy. 
In this disease diagnosis is often missed and reactive hyperplasia and unresponsive tuberculosis is confused with Hodgkin’s lymphoma. On the other hand suspected Hodgkin’s disease may also turn out to be benign reactive condition especially if central most node is not biopsied. The characteristic and hallmark malignant cell in Hodgkin’s disease is classic Reed-Sternberg (R-S) cell that is required at least for initial and primary diagnosis.
The R-S cell is a large cell and contains abundant weakly eosinophilic cytoplasm

Figure 2:  Typical Reed-Sternberg Cell with owl eye and mirror image nuclei (H& E x 1000)

Two or more nuclear lobes with distinct mirror image nuclei are present.The nuclei contain large prominent eosinophilic nucleoli with peri-nucleolar halo giving rise to owl eye appearance. (Figure 2). The cell is surrounded by inflammatory cells and fibrosis. In the disseminated disease the criteria for R-S cell is slightly relaxed.
Haque et al have described the gradual changes in the sinusoidal cells finally changing into frank Reed-Sternberg cells. Malignancy begins gradually in a stepladder fashion from mild, moderate and severe dysplasia to carcinoma in situ and then frank invasive malignancy. When the malignant cells are sufficiently dysplastic and ready to spill over the barriers but have not yet invaded the surrounding tissue, the stage is called carcinoma in situ.When they actually infiltrate into the surrounding areas invasive malignancy is the result. 10, 11 They have also described the mechanism of lacunar cell formation due to cytoplasmic and nuclear degeneration. As granulomas are formed from activated macrophages (epithelioid cells) and R-S cells also have the same origin it is not surprising that granulomas do occur in Hodgkin’s disease  and in those countries where tuberculosis is very common e.g. Pakistan, a mistaken diagnosis of tuberculosis is not infrequent. They have claimed that fibrosis results from necrotic changes which could in turn result from hemorrhages or exuded plasma due to damaged endothelial cells.
The histological sub types after seeing classical Reed-Sternberg cells were also assessed. As elsewhere in developing world, our study also showed that mixed cellularity Hodgkin’s disease was the most common sub type which has high association with EBV infection.   96% of the cases with mixed cellularity have been reported to contain genome or EBV associated antigen in cells of Hodgkin’s disease with mixed cellularity. 12 Other forms were also seen e.g. nodular sclerosis and lymphatic predominance. The rare entity of lymphocytic depletion was seen in 2 (6%) patients. Since the advent of highly curative treatment regimens, however histological features have had less prognostic significance.

   

The systemic symptoms commonly known as B-symptoms may be present in 30% of patients. These include fever; which was previously night sweats and unexplained weight loss of about 10% in last six months. In our study B-Symptoms were present in 42% of patients, especially in those who had illness for more than 4 months.
As compared to the developed countries where disease is diagnosed earlier and hence there is less tumor burden, our patients presented to a tertiary care center much late. Most of the patients were in advanced stage. 45% had stage III at presentation with lymph nodes on both sides of diaphragm being involved. 15% had bulky disease with involvement of abdominal lymphoma or splenic deposits. The staging laparotomy is no longer routinely performed since the advent of better imaging technique e.g. C.T. Scan and MRI. Splenectomy which was also performed at laparotomy is also now avoided due to long term adverse effects of splenectomy.13 The surprising finding in our study was involvement of bone marrow in our patients; 9% of our patients had metastasis to bone marrow which is 10 times more as reported in Western literature which reports it to be less then 1%. This also can be attributed to late diagnosis and referrals
Prognosis is stage dependent as with any other cancer, However Hodgkin’s disease is one of the cancers of childhood which is considered as saving grace of oncologist because of its excellent response to treatment. With combined treatment modalities of neoadjuvent  chemotherapy and local radiotherapy to involved field after chemo has over all survival of 95%. However, long term complications of radiation e.g. bone/secondary cancers e.g. acute myeloid leukemia (AML), Osteosarcoma, Non Hodgkin's Lymphoma (NHL) cause late morbidity and mortality.
Chemotherapy apart from having febrile neutropenia also has a long term sequlae of decreased pulmonary reserve, dilated cardiomyopathy and secondary cancers like AML. The outcome calculated at the time of study was fairly encouraging in the constraint resources that oncology is practiced in developing country especially in a Government sector hospital. 70% were off treatment and 20% patients were receiving chemo therapy. The over all mortality was 9% 3 Out of these 3 patients, one patient died because of poorly controlled asthma at home. Where as two patients died because of relapse and failure to respond to second line chemotherapy of EPIC. These patients were referred for autologous bone marrow transplantation but because of constraint resources they could not avail it.

Conclusion

 Hodgkin’s disease is a highly curable cancer and a fairly common form of lymphoma in Pakistan. Its sub group, mixed cellularity which has association with EBV is common and occurs at an early age. However most of our patients presented at an advanced stage III, IIIse or IV thus  jeopardizing the survival. The overall survival is however very encouraging but steps are to be taken to ensure the availability of autologous bone marrow transplantation for poor patients at no or low costs.

References

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