Lymphoproliferative Disease


By Ramsey Hachem, M.D.

Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care

June, 2009

Unfortunately, cancer is one of the complications of chronic immunosuppression.  The immune system has an important role in detecting pre-cancerous lesions and limiting their growth.  In addition, certain viruses are carcinogenic and under the influence of immunosuppression, they may replicate unchecked, proliferating the cells they infect.  Indeed according to the International Society for Heart and Lung Transplantation Registry, 4% of lung transplant recipients develop cancer in the first year after transplantation, and 12% develop cancer in the first five years.  Skin cancers are the most common malignancies over the long-term, accounting for over 50% of cases.  However, in the first year after transplantation, post-transplant lymphoproliferative disease, or PTLD, accounts for approximately 45% of all cancers.  As the name implies, PTLD encompasses a spectrum of abnormal lymphoid tissue proliferation ranging from an infectious mononucleosis-like illness to malignant non-Hodgkin’s lymphoma.  Obviously, the seriousness of this complication depends on the underlying pathology.

Many cases of PTLD are related to Epstein-Barr virus infection.  In these cases, it is thought that under the right circumstances and immunosuppression, Epstein-Barr virus may replicate unchecked and infect a multitude of lymphocytes rapidly.  These may then mutate as they multiply rapidly, and a mutant clone of immortalized lymphocytes may emerge.  Additional mutations can result as these immortalized clones continue to grow and divide unchecked, ultimately causing PTLD.  However, not all cases of lymphoma after transplantation are related to Epstein-Barr virus infection.  In fact, some, especially cases arising beyond the first year after transplantation, are indistinguishable from non-Hodgkin’s lymphoma, a malignant lymph node cancer.

In general, PTLD after lung transplantation may fall into one of two categories.  Those isolated to the chest, including the transplanted lungs or the mediastinal structures, and those that are outside the chest, frequently involving the abdomen and pelvis.  Thoracic cases are more likely to appear in the first year after transplantation and usually have a more favorable prognosis.  These typically present radiographically without any symptoms.  Common findings on chest x-rays or CT scans include new pulmonary nodules, a mass, or enlarged mediastinal or hilar lymph nodes.  A biopsy is necessary to confirm the diagnosis and to determine the pathologic subtype for prognostic purposes.  A bronchoscopy is often the first diagnostic step because it is less invasive and has a high yield, however, surgery is sometimes necessary if bronchoscopic biopsies are non-diagnostic.  Extra-thoracic cases usually present later, often several years after transplantation.  These tend to present with clinical signs or symptoms related to their location.  Abdominal cases are common and may cause abdominal pain, gastrointestinal bleeding, and sometimes take the appearance of an ulcer in the stomach or small intestine.  Other common locations include the liver, spleen, abdominal lymph nodes, and the pelvis.  Multifocal cases involving multiple organs are usually more aggressive and portend a poorer prognosis.  In fact, most extra-thoracic cases are usually malignant and have a poorer prognosis than thoracic cases.

The cornerstone of treatment is de-escalation of the immunosuppressive regimen.  Generally, the tacrolimus or cyclosporine dose is adjusted to target levels approximately 50% of the previously targeted levels.   In addition, the dose of azathioprine or mycophenolate mofetil is reduced by 50% or the drug is stopped completely.  Historically, this approach has often been sufficient for thoracic cases.  However, the advent of rituximab, a lymphoma drug that is usually well tolerated, has improved the response rate when has used in conjunction with de-escalation of the immunosuppressive regimen.  In fact, most thoracic cases respond favorably to this combination therapy.  However, cases with more malignant pathology require the addition of conventional chemotherapy, which is often associated with multiple side effects.  Furthermore, the prognosis of these more malignant cases is typically worse because they tend to be less responsive to treatment.  Lastly, surgery, when the disease is focal and amenable to complete resection, can be curative when added to a reduction of the immunosuppressive regimen.

Both infection and rejection can further complicate the management of PTLD.  Conventional chemotherapy, when added to the maintenance immunosuppressive regimen, can result in profound immunosuppression that may predispose to serious infections.  Moreover, additional chemotherapy cycles may need to be postponed while infections are treated.  On the other hand, reducing the intensity of immunosuppression while managing PTLD can result in serious and sometime irreversible rejection.  This scenario is very challenging as re-intensifying the immunosuppressive regimen risks recurrence of progression of the PTLD.  Clearly, PTLD is a serious complication after transplantation that requires close collaboration with an experienced oncologist.