The Role of Laparoscopic Techniques in Children with Suspected Post-Transplantation Lymphoproliferative Disorders

Introduction

Post-transplantation lymphoproliferative disease (PTLD) is known to be a severe complication of immunosuppressive therapy after solid organ transplantation.^1–5 Its development is a result of compromised antiviral and antitumor immunosurveillance due to iatrogenic immunosuppression causing significant morbidity and mortality.^2,3 To start consecutive treatment, there is consensus to evaluate possible PTLD as promptly as possible via several biopsy techniques.^4,5 To date, there is extensive literature on the potential risk factors for development of PTLD,^2–4 as well as the current treatment strategies, including reduced immunosuppressive therapy as tolerated, monoclonal antibodies, and chemotherapy combined with cytotoxic agents.^2,4,5 However, with regard to the increasing number of reports on minimally invasive techniques for biopsy or resection in pediatric malignancy, there is no study to date focusing in particular on the role of laparoscopic biopsy in children with suspected PTLD, especially if no endoscopically reachable or superficially located lesions are present.

Thus, the aim of this retrospective study was to evaluate the number of patients with exclusive intraabdominal manifestation of suspected PTLD cases, which were scheduled for laparoscopic biopsy to assess its safety and accuracy in the diagnosis of PTLD.

Materials and Methods

With agreement of the local ethics committee, we performed a descriptive, retrospective study based on medical files and biopsies of 34 children and adolescents (20 male, 14 female), who underwent solid organ transplantation from May 1992 to November 2008. Clinical and follow-up data were supplemented with data from the German Ped-PTLD registry. The mean age at solid organ transplantation was 66 months (range, 5–277). Distribution of solid organ transplantation included 14 patients with former liver transplantation, 14 kidney, 3 heart, 2 lung, and 1 patient with former heart and lung transplantation. The biopsies for suspected PTLD were taken between May 1993 and September 2009. The time point of onset and type of PTLD was assessed in all patients and compared in nonlaparoscopic and laparoscopic biopsy groups.

Results

The mean time interval between transplantation and biopsy for suspected PTLD was 39 months (range: 1–136). Comparing mean time intervals between groups revealed that the onset of PTLD was significantly later in patients requiring intraabdominal biopsy (81 ± 6.3 months versus 28 ± 5.3 months; P < .001) as shown in Table 1.

Twenty-four of 34 patients (70%) had surgical biopsies of superficial lymph nodes (n = 9), oropharyngeal biopsy (n = 5), gastrointestinal endoscopy or bronchoscopy (n = 5), ultrasound-guided biopsies (n = 3), and biopsy of the bone marrow (n = 1) or of the orbita (n = 1) as shown in Table 2. No data of the technique used were retrospectively available in 3 cases (9%). Due to lack of superficially located lesions, 6 of 34 patients (18%) had laparoscopic biopsy for suspected PTLD, of whom 4 had former abdominal organ graft (liver = 2, kidney = 2).

Patients scheduled for laparoscopic biopsy were placed in a supine position and a 3-trocar technique was used. After subumbilical insertion of a 5-mm optic trocar, a CO₂ pneumoperitoneum limited to 8 mm Hg was created. Subsequently, two 3-mm working trocars were placed in the right and left mid-abdomen under videoscopic guidance. In 5 of 6 cases (83%), a laparoscopic biopsy was successfully performed with endoscopic scissors and subsequent monopolar coagulation with negligible blood loss. Adhesions were mild and easily cut with the monopolar hook and did not affect the applicability of the minimally invasive approach. Intraabdominal manifestation of PTLD concerned the mesenterium of the small bowel in 4 (former liver transplantation = 2; former kidney transplantation = 2) and the retroperitoneal space at the left iliac fossa in 1 case with former heart transplantation. Mean operation duration was 72 minutes (range, 55–105). Laparoscopy was converted in 1 patient due to limited visibility with abscess formation at area of former kidney transplantation. Easy access to a huge mass from the liver porta to the abdominal wall led to a primary biopsy via a mini-laparotomy in another case. One patient with abdominal Burkitt's lymphoma developed a trocar metastasis, which was successfully treated by systemic chemotherapy. No other complications were observed after laparoscopic biopsy.

Distribution of PTLD histopathology is presented in Table 3 and did not show significant differences of PTLD type distribution comparing groups of nonlaparoscopic and laparoscopic biopsies. Accuracy of minimally invasive surgery (MIS) biopsies was 100%. Morbidity and mortality were not influenced by biopsy technique or time point of PTLD onset.

Ten of 34 patients (29%) died during follow-up until September 2009. In 1 patient, death was unrelated to PTLD; 9 patients died of disease progression (n = 3), treatment-related complications (n = 4), or a combination thereof (n = 2), respectively. All patients were part of the nonlaparoscopic group with monomorphic non-Hodgkin-type PTLD. Twenty-four (70%) patients demonstrated full remission without death related to PTLD or treatment until September 2009, at a mean follow-up of 99 months (range, 17–220) after initial solid organ transplantation.

Discussion

PTLD as a severe complication after pediatric solid organ transplantation typically may arise in regions where resident lymphoid tissues and aggregations are present due to overproliferation under immunosuppression.^1–5 Epstein–Barr virus infection after transplantation has been noted to be a major risk factor for PTLD,^2,5 especially in pediatric recipients due to anticipated less Epstein-Barr virus (EBV)-specific immunity at the time of transplantation compared to adults, thus leading to a higher PTLD incidence in children, which varies with the type of organ transplanted.^2,5

In our presented study, clinical characteristics and PTLD outcomes among several types of solid organ transplantation corresponded well to data of other reports.^1–5

Several studies revealed an excellent accuracy of laparoscopic biopsy performed for lymphoproliferative disease and other pediatric malignancy,^6–9 but not in particular for PTLD.

With regard to the role of laparoscopic biopsy for anticipated intraabdominal PTLD in children, which had so far not been investigated, we were able to show for the first time that MIS techniques were feasible and safe with 100% accuracy in detecting PTLD in case of absent, more superficial, or endoscopically reachable lesions. The 20% of PTLD cases requiring an intraabdominal biopsy in our series, due to explicit intraabdominal manifestation, underlines the importance of our investigation.

The accuracy of laparoscopic biopsy in the diagnosis of PTLD in our series was as high as in reported series for minimally invasive biopsy procedures for other pediatric malignant entities.^7–9 Presenting only 1 case with need of a conversion due to lack of overview, the low conversion rate of laparoscopic biopsy for PTLD corresponded well with low conversion rates reported for other pediatric malignant diseases.^7–9 Therefore, we believe that laparoscopic biopsy is a safe tool for diagnosing pediatric PTLD.

In addition, laparoscopic biopsy was feasible in the majority of cases after prior abdominal organ transplantation, which corresponded well with a recent study postulating consecutive laparoscopy as the first choice approach after prior abdominal operation irrespective of the approach in a wide nonmalignant spectrum of pediatric disease. ¹⁰

In contrast to Tai et al., ⁵ who reported that abdominal involvement increased the risk of mortality in heart and lung transplant recipients with PTLD, our data additionally included liver and kidney transplantation recipients, and showed no higher mortality related to intraabdominal involvement of PTLD compared to groups with extraabdominal manifestation. However, data should be taken with care regarding the retrospective and heterogenic patient group.

Apart from a report on a trocar metastasis after thoracoscopic resection of a lung metastasis of an osteogenic sarcoma ¹¹ and our recent description of a trocar metastasis after laparoscopic biopsy of suspected PTLD in a child with former heart transplantation, ¹² there are no further reports on port-site metastasis after minimally invasive procedures for pediatric malignancies.^7–9,13 In the latter patient, who is included in our presented series, we speculate that the extent of the PTLD was underestimated because histopathological examination of the first biopsy failed to detect c-myc translocation,^8,14 which was then found at the time of the second biopsy of the trocar metastasis. Certainly, detection of c-myc translocation at first biopsy would have led to polychemotherapy, instead of single rituximab therapy, after which there was a complete remission. Nonetheless, it remained unclear whether the progress of the PTLD in this case was additionally facilitated by use of a minimally invasive technique for the first biopsy. Therefore, in case of inadequate chemotherapy due to underestimated intraabdominal post-transplant lymphoma, port-site metastasis can develop after laparoscopic biopsy. However, all other cases of laparoscopic biopsy for PTLD had no postoperative complications related to MIS.

Like others, we did not find any correlation between early or late PTLD onset after several types of pediatric solid organ transplantation. ² However, with regard to exclusive intraabdominal PTLD manifestation, we found a significantly later onset compared to nonintraabdominal lesions. It is known that PTLD cases represent a highly diverse spectrum of disease, which varies with respect to behavior and clinical presentation with and without symptoms.^14,15 With regard to our findings, it could be speculated that explicit intraabdominal PTLD manifestation might have caused less clinical symptoms compared to nonintraabdominal PTLD manifestation and thus could have led to investigations diagnosing PTLD at a later time point. Tai et al. ⁵ compared 8 abdominal and 8 nonabdominal cases of PTLD manifestation out of 134 pediatric patients, who had undergone heart, lung, or heart and lung transplantation, and confirmed that patients with abdominal PTLD involvement on average were also diagnosed later. There was no information available on the type of biopsy used confirming abdominal PTLD.

Conclusions

In the majority of cases with suspected pediatric PTLD, the diagnosis can be established without abdominal or thoracic access. However, in 20% of pediatric PTLD cases an intraabdominal biopsy is required, due to explicit intraabdominal manifestation. As laparoscopic surgery was even feasible in the majority of patients after prior abdominal organ transplantation, we suggest laparoscopic biopsy as a safe tool in diagnosing pediatric PTLD.