Surgery in management of paediatric abdominal lymphoma:A traditional tool-revisited

Surgery in management of paediatric abdominal lymphoma:A

traditional tool-revisited

Ossama M Zakaria,a MD; Sherif  H Fa"ag,b MD; Tamer A Sultan,b MD; Magdy Lolah,c MD; Mohamed Y Daoud,c MD

a) Division of Paediatric Surgery and Oncology- Department of Surgery, Suez

Canal University, Ismailia, Egypt.

b) Department of Surgery, Menouy.fia University, Shebin El-Koum, Egypt.

c) Department of Surgery, Damnhour teaching Institute of Oncology, Bohairah, Egypt.

Co"espondence:e-mail: ossamaz2004@yahoo.com

Abstract

Background: The abdomen is one of the most frequent sites for lymphoma in children. The role of surgery has been limited to intra-abdominal respectable tumours or as a diagnostic procedure in case of disseminated disease. Laparotomy without total excision of the tumour does not improve survival; moreover, it may cause complications  and delays initiation of

chemotherapy.

Aim of the work: This study was undertaken to assess the role of surgery in the management of children and adolescents presenting with intra-abdomina/lymphoma in order to create certain criteria  to  select  the   proper  surgical  modality  for   managing  those   patients.

Patients and methods: This retrospective, descriptive study was done on 33 patients of

abdominal lymphoma over a period of seven years from 2000 to 2007. Patients' files were reviewed regarding the full clinical examinations, laboratory and radiological investigations as well as surgical and diagnostic procedures. Collected data were tabulated and statistically analyzed using SPSS program package.

Results: Patients' ages ranged from 2.5 to 16 years with a mean of6.7. They were 18females

and 15 males at FIM ratio 1.2: 1. In those patients who underwent surgery; seventeen (51.5%) presented with emergency complaints, 10 patients (30%) with acute abdominal pain and 7 patients (21.5%) with intestinal obstruction with surgical excision of the tumour mass. In the remaining 16 patients, 9 had huge pelvi-abdominal massesand 7 had generalized lymphadenopathy where  the intra-abdominal involvement  was discovered  following  further investigation.

Conclusion: Surgery still has a role in treatment of lymphoma whether non Hodgkin or Hodgkin's as complete resection does improve the survival rate, however, in disseminated metastatic disease, aggressive debulking of the tumour should be avoided as chemotherapy is to be instituted primarily. Surgical resection does not cause significant change in morbidity or mortality.

Key words: Abdomina/lymphoma in paediatrics, role of surgery.

Introduction:

Pediatric lymphomas are the third most common malignancy in children and accounts for 13% of all childhood cancers.Its incidence increases  with increasing  age in children.l Hodgkin (HL) and non-Hodgkin's lymphomas (NHL) constitute 10-15% of total cancer diagnoses in children in the more developed countries, after acute leukemia's and brain tumours.2,3

Approximately 60%  of paediatric lymphomas are NHL, with the remainder being Hodgkin's lymphomas (HL). Although age­ adjusted incidence rates ofNHL increase with age, the more aggressive lymphomas are seen more commonly in the younger population with a transition to low-grade, indolent subtypes as the population ages.4

According to the latest classification (2008) with the use of additional immunological and molecular markers, most paediatric NHL can be  grouped into   four  major histological subtypes:

a) Burkitt lymphoma.

b) Diffuse large B-celllymphoma. c) Anaplastic large cell lymphoma.

d) Lymphoblastic lymphoma. The most important subtype of  HL  is  nodular  sclerosis.5

Paediatric patients typically present with Burkitt lymphoma with extranodal involvement, specifically occurring in the abdomen in approximately 31% of the cases. Common presenting symptoms include abdominal pain, palpable mass, nausea and vomiting, intestinal obstruction due to bowel compression or intussusceptions, and acute appendicitis. Intussusceptions as a presenting feature of Burkitt lymphoma may be associated with early stage disease, which is curable with

less intensive therapy.1o

The appropriate role  of surgery in intra abdominal Burkitt's lymphoma although a controversial subject  became  more defined over  the  last  two  decades. Children with localized bowel tumour scan undergo gross total resection of the primary tumour, with low operational morbidity rate.ll-14

Patients with abdominal NHL can be divided into two surgical groups; in the first group the tumor  is localized anatomically within  the abdomen, in this case, the tumor often involves the bowel wall and many of those children present with  acute  abdominal symptoms suggesting appendicitis  or intussusceptions. The majority can undergo complete gross tumor resection, often with a simple bowel resection andre-anastomosis. In the second group; there is  extensive intra-abdominal tumor, and presentation with an abdominal mass without acute symptoms is more likely. The mesenteric root and retro peritoneum are heavily involved and attempts at complete excision are associated with a higher complication rate where surgery on   elective  basis is  for   debulking.12

Localized gastrointestinal lymphomas should be resected whether through laparotomy or  laparoscopically12,15 when  possible. Complete resection of non- Hodgkin lymphoma has been reported to reduce the tumour bulk and   to   have  a  favourable  impact  on

survival.16-I9

When patients present with extensive intra­ abdominal tumour, radical excision is contraindicated. The mesenteric root and retro peritoneum are heavily involved, and attempts at complete excision are  associated with a higher complication  rate.20,21 A recent study has stated that laparotomy  should be limited to cases presenting  with acute abdomen and limited resectable disease. In  cases of disseminated disease, bone marrow aspiration, cytological investigation of the ascite/pleural effusion, or ultrasound-guided-true-cut needle biopsy of the abdominal  mass were a better alternative, had less morbidity than laparotomy and allowed early initiation of chemotherapy.22

This study  was undertaken to assess  the role of surgery in the management of children and  adolescents presenting with intra­ abdominal lymphomas in our experience and to report our strategy management of abdominal lymphoma in order to reach certain criteria for selecting the  proper surgical modality.

Patients and methods:

A retrospective, descriptive study was done on 33 patients of abdominal  lymphoma who were treated over the period of 7 years from

2000 to 2007.

Inclusion criteria were  children and adolescents  aged 2-18 years, both males and females  who were suffering of generalized lymphadenopathy and got tissue biopsy revealing lymphoma  and evidence of intra­ abdominal involvement. Also, included were children  and adolescents of similar  age and sex who revealed intra-abdominal mass with tissue  biopsy  revealing  lymphoma.

Excluded of this study were patients out of the specified age range, or those without intra­ abdominal involvement. Those  who  had generalized lymphadenopathy or intra­ abdominal masses proven not to be lymphoma by tissue  biopsy  were excluded as well as patients with post-transplantation lymphoma or   severe immune-deficiency status.

After approval of the ethical  committee

patients' files  were  reviewed regarding demographic data, history taking, full clinical examinations including  general examination for the vital signs at presentation.Also reviewed were any  striking clinical features at presentation such as jaundice, cyanosis, pallor

and maller-flushes. Records of systemic clinical examination including thorough lymph node group's examination, abdominal examination, chest and cardiac examination were reviewed. Laboratory  and radiological  investigations were also reviewed. Surgical techniques were thoroughly studied  by reviewing all the operative details and fmdings. Post-operative sequence was also recorded in all patients with the fmal post-operative results.

Collected data  were  tabulated and statistically analyzed using SPSS program package.

Results:

The age ranged between 2.5 -16 years with a mean of 6.7 years; there were 18 females

and 15 males with F/M ratio of 1.2:1. The socio-demographic characteristics of  the patients are shown in Table(l).

Twenty  two patients presented with abdominal disease, 6 had intra-abdominal tumours and 5 had diffuse intra-abdominal spread. The remaining 11 patients presented with symptoms of an acute abdomen requiring emergent operation; 4 patients with complete intestinal  obstruction  secondary  to tumour matting, 5 with irreducible intussusceptions with tumour acting as the lead point, and 2 patients with suspected appendicitis.Moreover,

3 patients did show a pelvi- abdominal mass,

4 with generalized lymphadenopathy, 3 with acute  abdominal  pain,  and only 1 patient suffered of intestinal obstruction Table(2).

Table (1): Demographic characteristics of the studied patients.

Table (1): Clinical features of the studied patients.

Both ultrasound scanning and computed tomography were done for all the 33 patients. mtrasound scanning showed 4 (12.1%) patients with enlarged liver and 11 (33.3%) with enlargedspleen while lymph node enlargement was found in 10 (30.3%) and abdominal mass in  15  (45.5%)  and  intra  peritoneal fluid collection in 9 patients (27.3%).

Computed tomography (CT) reports revealed 6 (18.2.1%) patients with enlarged liver, 13 (39.4%) with enlarged spleen and para-aortic  lymph node enlargement  in 23 (69.7%) cases, with abdominal mass in 16 (48.5%)  cases, and intra peritoneal fluid collection in 11 (33.3%) cases Tables(3,4).

Table (3):Shows the ultrasonic findings in the studied patients.

sFishers Exact test.

Table (4): Computed tomography findings in the studied patients.

s Fishers exact test

*Results are statistically significant as the P value is <0.01.

Reviewed laboratory findings: 22 patients had elevated ESR 2-4 folds, 28 patients had elevated C-reactive protein. All the 33 patients showed elevated LDH; 15 had elevated lactate dehydrogenase (LDH)  (2 folds),  and in 18 cases elevated 3 folds. The complete blood count (CBC) showed normal blood picture in

5 cases, leucocytosis in 8 cases, 1 case with leucocytosis and lymphocytosis, 6 cases with leucopenia, 2  cases  with  leucopenia and lymphocytosis. Other laboratory findings were hypoalbunimia in 8 cases, elevated serum urea in 6 cases, elevated serum creatinine in 1case, and elevated liver enzymes (SGOT and SGPT) in 3 cases Table(5).

The operative records showed a total of 15 laparotomies. Out   of  them, 11  patients underwent  emergency  laparotomy for acute abdomen and 4 patients had elective abdominal exploration (EAE). Lymph node biopsies were taken in the remaining 7 patients. Moreover, urgent laparotomy procedures were performed in extra  3 patients as a diagnostic and  for appendectomy in 1 patient and resection of an intussusceptions mass in 2 patients. Out of the

total 33, the remaining 8 patients underwent laparotomy for  treatment of different pathologies Table(6A).

Laparotomy was performed in 15 patients, of  the  4 patients with  EAE,  total  tumour resection and  small bowel resection anastomosis were done in 1of them, 2 patients were splenectomised with para-aortic L.N. and liver  biopsy while  incisional biopsy was performed in 1 patient Inthe other 11 patients, urgent abdominal exploration was performed,

3 patients had ileocolic intussusceptions and resection anastomosis with lymph node biopsy (1 patient), debulking (1 patient), caecal perforation (1 patient) where right hemicolectomy was done with ileotransverse anastomosis. In 2 patients, splenectomy  was done with partial gastrectomy (1 patient) and resection anastomosis of small bowel  with partial excision of the mass (1 patient). In 4 other patients mesenteric mass was found with perforation  (3 patients), where debulking of the mass with resection anastomosis was done and 1 patient with an additional sigmoid volvulous which was untwisted with complete

debulking of the  mass. In the remaining 2 patients with urgent abdominal exploration, 1 patient had  ileoileal intussusception with lymphadenopathy where lymph node biopsy was done. I patient had intestinal perforation and resection anastomosis was done. The rest of patients underwent a diagnostic and therapeutic laparoscopy.One patient underwent

laparoscopic appendectomy; the remaining  8 patients underwent laparotomy for total tumour resection where small bowel resection anastomosis was done in 2 patients, debulking and splenectomy with para-aortic lymph node biopsy in 4 patients. The remaining 2 patients underwent  para-aortic L.N. and liver biopsy Table(6B).

Table (5): Laboratory findings in the studied patients.

*Results are statistically significant as the P value is<0.05.

# Montcalro Exact test.

Table (6A): Diagnostic method and surgical interventions in the lllparotomy group.

Table (6B): Diagnostic method and surgical interventions in the two groups.

Of the 15 patients who underwent abdominal exploration, the primary tumour sites were terminal ileum (n=7), caecum (n=l), ileum (n=2) colon (n=2) and lymph nodes /spleen (n=3).

Out  of the  I5  patients  that  underwent

abdominal exploration; 4 cases were elective abdominal exploration and II cases were urgent abdominal exploration. In 6 cases, the intra operative  data  matched  with the previous

radiological investigations (abdominal CT & abdominal U/S) which were done before the surgical  intervention. In 9 cases the intra operative data did not match with the previous radiological investigations which were done before the surgical intervention. Surgery was also performed as laparoscopy in 3 patients and laparotomy in 8 patients. Operative data matched with  the previous imaging investigations in 8 patients that were done prior

to the surgical procedure, yet, they did not match in 3 patients Table(7).

Based on the pathological data; 15 patients were diagnosed as Non-Hodgkin's Lymphoma (NHL). As shown in Table(4),  according to the  American National Cancer  Institute

Classification, patients  had large B-cell lymphoma (n=8) where 3 cases were stage IVB, 4 cases were stage IR & 1 case was stage IIIB and small lymphocytic type, stage I (n=l), Burkitt's lymphoma type (4), stage IR {n=2) and stage IIIB (n=2) and MALT lymphoma,

stage NB (n=2). In group II, all of patients were ofNHL with small lymphocytic type in

2, Burkitt's lymphoma in 3, stage IR (n=2) and stage IIIB (n=l)  and MALT lymphoma in 1. On the other hand,  extra 7 patients were diagnosed as Hodgkin Lymphoma with nodular

sclerosis type who were diagnosed through CT and lymph node biopsy, lymphocytic predominant  (n=l), diagnosed  by staging laparotomy and another patient of lymphocytic depletion type who was also diagnosed via staging laparotomy Table(8).

Table (7):Showing the primary site of malignant involvement in studkd patients post abdominal exploration.

Table (8): Pathological and histological  results in the studied patients.

Inthe studied patients; 20 did not show any post-operative complications. 8 patients had wound infection. 4 patients were lost; 1 with renal failure, 2 as a result of wound infection and tumor lysis syndrome and 1 because of disseminated  metastasis  Table(9).

Records  of the histopathological data showed 26 cases diagnosed as Non-Hodgkin's lymphoma; 3 case with small lymphocytic type, stage I (according to American National Cancer  Institute  Classification), 11 cases

Burkitt's lymphoma type, stage IR in 2 cases and stage IIIB in 3 cases, 12 cases were large B-cell lymphoma where 3 cases were stage IVB, 5 cases were stage IR, lease was stage IIIB. In group II, all the 11 patients were diagnosed as Non-Hodgkin's lymphoma Table (10).

Seven cases were diagnosed as Hodgkin's lymphoma; 2 cases staged and diagnosed via staging laparotomy, other 5 cases were staged and  diagnose  by  LN  biopsy  and  C.T.

Table (9): Postoperative primary complications in the studied patients.

Table (10): Pathological results in the studied patients.

Discussion:

Despite the existing controversy in diagnosis and treatment of childhood and adolescent

lymphoma whether Hodgkin's or  non­ Hodgkin's the role of pediatric surgery in the management of these  diseases  is currently evoluting, with the  trend  towards  minimal involvement.23

For Hodgkin's disease staging, laparotomy remains undisputedly the most accurate method to delineate extent of disease precisely. Yet, for therapy of all Hodgkin's disease patients, young  and  old,  chemotherapy has  taken  a predominant role. Oncologists thus believe that the precise staging afforded by laparotomy has  come  to  have  academic value  and  no clinical importance.13,23-25

In our current study, surgical biopsy staging was performed inseven patients with Hodgkin's disease with no recorded complications in 5 patients  and wound  infection in 2 patients. Similar reports were recorded in the literature regarding the the superiority of pathologic staging.It was reported that most patients with an equivocal staging should undergo staging laparotomy.13

This is contradicted by other  data in the literature supported  by the concept  that the

main  purpose of  staging  laparotomy is to identify patients who should be treated with chemotherapy, and because current protocols are mostly chemotherapy-based, laparotomy is unnecessary. Staging  laparotomy is used less frequently now.25

However, the debate regarding the benefits of  staging laparotomy still  exist  as  many complications are related  to the procedure, although surgical mortality is rare.In a literature review, it was reported that atelectasis, wound infection, intestinal obstruction, left-sided pleural effusion, retroperitoneal hematoma, sub-diaphragmatic abscess, transient pancre­ atitis, and  thrombotic episodes have  been observed  in 6% to 7% of patients. The most common complication is intestinal obstruction

{2% to 4% of patients), which is usually a late event that often occurs more than 6 months postoperatively.26

In  our  current study, the  incidence of complications after  surgery for Hodgkin's lymphoma was 9.1%. It has been reported that long-term complications of staging laparotomy are related to the asplenic state. The incidence of post splenectomy sepsis in patients  with Hodgkin's  disease  was 11 % to 13 % before the development of polyvalent pneumococcal,

hemophilus, and meningococcal vaccines and use of peri  operative and prophylactic antibiotics.24

In the last few years, chemotherapy has evolved to be the primary modality of treatment for all types of non-Hodgkin's lymphomas. Role of radiation therapy and surgery have been regulated to that of symptomatic relief. The  dramatic improvement in  survival of childhood non-Hodgkin's  lymphomas can be attributed  to multi-agent chemotherapy and improved supportive care. Event free survival of these lymphomas is exceedingly good and thus the current emphasis is to identify newer treatment modalities.6

For  practical purpose, patients with abdominal non-Hodgkin's  lymphoma can be divided into two surgical groups, in the first group  the  tumor  is localized anatomically within the abdomen.  In this case; the tumor often involves the bowel wall and many of these children present with acute abdominal symptoms suggesting appendicitis or intussusceptions. The majority  can undergo complete gross tumor resection, often with a simple bowel resection and re-anastomosis. In the second  group;  there  is extensive intra­ abdominal  tumor,  and presentation with an abdominal mass without acute symptoms is more  likely. The  mesenteric root and  retro peritoneum are heavily involved and attempts at complete excision are associated with a higher  complication rate where  surgery on elective basis is for debulking.l2

In our current  study,  patients with  non­ Hodgkin's lymphoma huge pelvi-abdominal mass were  recorded  as 9 (27.3%) patients. Moreover, other abdominal complications due to lymphoma with the need for an emergent surgical intervention were recorded as irreducible intussusceptions in 5 patients, appendicitis in 3 patients with a total percentage of 15.2% and 9.1%, respectively.

In a study of 62 patients  with abdominal

lymphomas treated at Texas Children's Hospital over a 40-year period, 26 underwent complete resection. Only 2 complications (small-bowel obstruction, wound infection) occurred although a primary anastemosis was performed in  all.  Of  a  total  of  138  published cases involving  complete  resection,  only  6

complications (5%) were reported.  Patients with extensive abdominal disease should undergo a biopsy only followed by the early initiation of chemotherapy.17

This data can be compared to our study results  that  showed an elective abdominal exploration in a total of 6 out of 26 patients with non-Hodgkin's lymphoma with incisional biopsy for pelvi-abdominal mass in 1 patient, splenectomy + para-aortic L.N & liver biopsy in 4 patients, and 1 patient of total resection of pelvi-abdominal mass  + small bowel resection anastomosis.

On the other hand, an urgent abdominal exploration was performed in 21 patients who were  divided as 1 reduction Lymph  node biopsy, 1 perforation+ right hemicolectomy and ileo transverse anastomosis, and debulking in 5 patients.

Other  literature reported an  intestinal

obstruction in only 4 of 146  staging laparotomies, all of which took place over 1st year  postoperatively. Furthermore, serious bacterial infections occurred in 1.4% of children who underwent a splenectomy and in 2.8% of children who did not. These infections were attributed to functional asplenia following splenic  radiation. Subsequent exposure to chemotherapy increased the  incidence of infection 9-fold in both groups.24

Other reports noted the role of surgery in non-Hodgkin's lymphoma based on an extensive experience with  patients having Burkitt's lymphoma, suggesting that surgical reduction of tumour  bulk had a favourable impact on survival. There were  several problems with their conclusion. First, extent of disease at diagnosis was not evaluated for its predictive effect on outcome. Second, only

9 of the 68 patients reported (13%)  actually underwent  total resection  (defined  as >90% resection). The vast majority had biopsy alone (63%) or subtotal resection (24%). Their data strongly suggested a biologic selection for the patients undergoing total  resection. They reported surgical mortality rate in their series to be 10% that would seem excessive under present circumstances.l6

Moreover, the role of surgery both in the primary tumour and  in  treatment of complications for  patients with  a miracle

Burkitt's lymphoma was evaluated suggesting an advantage to complete resection but point out that extent of disease was not analyzed as an independent variable. A role for surgical intervention in  the supportive therapy  of non-Hodgkin's lymphoma was  also suggested.27-29

Similarly, the surgical committee of the Children's Cancer Group (CCG) evaluated the role of surgical therapy in 68 patients with non-Hodgkin's lymphoma in the CCG-551 study. Sixty three variables were analyzed included extent  of disease at diagnosis; completeness of surgical resection (complete gross  resection); radiation  therapy  to the primary site; and  sex,  age,  and  race. Laparotomy  was performed  in 67 children (99%)  with  complete gross  resection accomplished in 28 (42%). Age at diagnosis, sex, and race had no effect on event-free survival. Tumour  burden  was the most important prognostic factor. Complete resection was also a significant predictor of event-free survival but not as important as tumour burden. Their data agreed with our current study data supporting a role for complete surgical resection in the setting of localized disease, especially when confined to bowel. Resections performed under these circumstances positively affect outcome by reduction of tumour cell burden and prevent certain complications, such as bowel  perforation. Because extensive retroperitoneal dissection with the possibility of significant hemorrhagic or septic complications is avoided, chemotherapy can be initiated promptly.l7

Nevertheless, attempts  at resection  of massive retroperitoneal masses or large hepatic lymphomas are associated with an increased complication rate and serve to postpone essential chemotherapy. This is particularly deleterious because  undifferentiated lym­ phomas grow so rapidly.In patients presenting with extensive abdominal disease, diagnosis can often be made by bone marrow aspiration because at least 20% of all patients have obvious marrow involvement (symptoms, positive bone scan), and an additional I0% have microscopic involvement that is unsus­ pected  clinically. Additional sources  of

effusions, peripheral lymph nodes, or local­ ized bone lesions, which can sometimes be biopsied by needle. Tumour may invade bowel wall and undergo subsequent necrosis resulting in free perforation and peritonitis or severe hemorrhage. Often, Burkitt's lymphoma is localized to the right lower quadrant in the region ofPeyer's patches; and symptoms may mimic acute appendicitis. In this situation, resection of the ileocoecal segment and adjacent mesentery often results in complete gross resection.29

Through the study of our patient's record, complete blood picture and platelet count were done preoperatively  based on the fact that significant bone marrow infiltration may cause thrombocytopenia, this  was supported  by published data suggesting that the production of serum clotting factors may also be affected by hepatic infiltration, and a full coagulation screen should be performed in preparation for surgery.12

The data of our current study showed 3 patients with tumour lysis syndrome that results in hyperuremic nephropathy and renal shut down. This syndrome was also reported in the literature.30,31

We recommend that in patients presenting with extensive intra-abdominal tumour, radical excision is to be contraindicated as the mesenteric  root  and retro-peritoneum are heavily involved. Attempts at complete excision are associated with a higher complication rate and may lead to a delay in initiation of chemotherapy.

It is also recommended  that laparotomy should be limited to cases presented with acute abdomen and limited resectable disease.Inthe condition of disseminated disease,  other alternatives should be applied including bone marrow aspiration, cytological investigation of ascitis/pleural effusion or ultrasound-guided­ true- cut needle biopsy of the abdominal mass in order to have less morbidity than laparotomy and allow early initiation of chemotherapy. Despite the benefits of staging laparotomy, many  complications are related to the procedure, although surgical mortality is rare.

It can  also  be  concluded that  a multi disciplinary approach should be applied for

laboratory, imaging techniques as well  as surgical  biopsy  in selected  cases  to reach a proper diagnosis. After a proper diagnosis the treatment  options can be planned; including chemotherapy, radiotherapy and surgery in limited cases in order to deal with complications.

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