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Coexistence of acute cellular rejection and lymphoproliferative disorder in a lung transplant patient.

Lung transplantation is an established and increasingly available therapeutic intervention for end-stage pulmonary disease. (1) Acute cellular rejection (ACR), with an incidence of 67%, (2) and infections are frequent complications in the first 2 to 3 months following transplantation. During the later posttransplantation period, progressive deterioration of graft function secondary to obliterative bronchiolitis (OB) develops in about 10% to 54% of lung recipients. (3) Obliterative bronchiolitis resulting from chronic rejection usually cannot be successfully treated once it is clinically manifest. For this reason, it represents the most critical threat to the long-term survival of lung recipients. (4) The other main complication that may appear in the postoperative period, especially in patients with cystic fibrosis, (5) is posttransplant lymphoproliferative disorder (PTLD), which has an incidence of 8% in lung transplant recipients. (2) The pathophysiologic mechanisms of ACR and PTLD seem to be in opposition to each other. Posttransplant lymphoproliferative disorder results from an expansion of the pool of Epstein-Barr virus (EBV)-infected B cells that are able to evade specific cytotoxic T-lymphocyte control, secondary to immunosuppressive therapy. Acute cellular rejection, on the other hand, is primarily a consequence of alloreactive cytotoxic T-lymphocyte-mediated endothelial or bronchiolar epithelial damage. Thus, ACR is treated by increasing immunosuppression, while PTLD responds to the opposite therapy, which is a decrease in immunosuppression. (2)

In this article, we describe an unusual case of likely coexistent ACR and PTLD found by transbronchial lung biopsy (TBB). We also describe the surprising finding of fibrotic lesions of the large bronchi, which is usually restricted to membranous and respiratory bronchioles, in the context of chronic rejection with OB.


A 37-year-old white man underwent bilateral lung transplantation in May 1997 for end-stage cystic fibrosis. The EBV serology was positive on pretransplantation evaluation. He received an immunosuppressive maintenance regimen of cyclosporine, azathioprine (Imurel), and cortancyl. Ten days later, he developed a clinical ACR, which was treated with a bolus of methylprednisolone (Solumedrol). This resulted in rapid clinical and radiographic improvement. Two and a half months later, a computed tomographic scan showed multifocal nodules with ill-defined margins in both lungs. The left superior lobe was spared. The largest nodule measured 15 mm in diameter. The bronchoscopy revealed a thickened and inflamed wall at the bifurcation of Nelson's bronchus. A B-cell PTLD was diagnosed by endobronchial biopsies, while a perivascular lymphoid infiltrate was found by TBB.

Complete radiographic and histologic regression of the PTLD followed a decrease in the maintenance dose of immunosuppression and anti-interleukin-6 treatment. Perivascular lymphoid infiltrates, however, persisted on successive TBBs and were finally considered to be mild ACR (grade 2). Three boluses of methylprednisolone were administered, and the initial immunosuppressive regimen was reintroduced. Successive TBBs showed an initial disappearance of perivascular infiltrates and subsequent reappearance of these lymphoid infiltrates without obvious infectious cause. Six months later, the patient presented with a deterioration in pulmonary function leading to a rapid course of severe OB. One year after his lung transplantation, the patient died and an autopsy was performed.



Paraffin-embedded tissues from endobronchial biopsies, TBB, and postmortem lung samples were studied histologically using hematoxylin-eosin, Giemsa, and periodic acid-Schiff stains.

Immunohistochemical and In Situ Hybridization Analyses

Immunohistochemistry was performed on paraffin slides using a streptavidin-biotin peroxidase method (BIOSPA kit, Abcys, Milan, Italy). Specific antibodies studied included CD20 (L26, 1:100, Dako, Trappes, France), CD79a (JCB117, 1:50, Dako), CD3 (polyclonal, 1:50, Dako), latent membrane protein 1 (LMP1) (CS1/4, 1:50, Dako), and [kappa] (polyclonal, 1:4000, Dako) and [lambda] (polyclonal, 1:4000, Dako) light chains. In situ hybridization was performed following the manufacturer's instructions using EBV-encoded RNA (EBER) oligoprobes (BioGenex, San Ramon, Calif) to detect EBV transcripts.


On the endobronchial biopsies taken 2 1/2 months after lung transplantation, hematoxylin-eosin-stained sections revealed a diffuse dense infiltrate of polymorphic lymphoid cells involving the bronchial lamina propria under a focally ulcerated bronchial epithelium. Areas of coagulative necrosis were present within this infiltrate, which consisted of small to large lymphoid cells. Large lymphoid cells, consisting of immunoblasts and centroblasts, predominated (Figure 1, A). The immunopheno, typic profile of the endobronchial biopsies confirmed the diagnosis of a PTLD, since the large lymphoid cells were positive for CD20 and CD79a. As there was no intracytoplasmic immunoglobulin light chain staining, the monoclonality or polyclonality of the infiltrate could not be determined. These large lymphoid cells expressed LMP1 and EBER transcripts (Figure 1, A). A minority of small lymphocytes and a few large lymphoid cells expressed CD3. Transbronchial lung biopsy revealed several perivascular polymorphic lymphoid infiltrates composed of numerous small and rare large immunoblastic cells (Figure 1, B). Most of the lymphoid cells expressed CD3, whereas the rare large lymphoid cells expressed CD20 but not LMP1 or EBER transcripts.


After the decrease in dosage of maintenance immunosuppression, the persistence on successive TBBs of several perivascular lymphoid infiltrates composed of predominantly small-sized lymphoid cells was interpreted as a sign of mild ACR (grade 2), according to the pulmonary allograft rejection classification. (6) The immunophenotypic profile of the perivascular lymphocytic infiltrate was similar to the one previously described, and no EBV proteins (LMP1) or EBER transcripts were present.

Postmortem examination of hematoxylin-eosin-stained sections revealed OB lesions of the bronchioles with partial or total obliteration of the lumen with granulation tissue infiltrated by a few lymphocytes, plasma cells, and some neutrophils (Figure 2, A). This fibrous scar tissue was focally associated with fragmentation of the smooth muscle wall. These OB lesions were associated with mild perivascular mononuclear cell infiltrates surrounding venules and arterioles and limited to the vascular adventitia. The infiltrates consisted of small round lymphocytes and medium-sized and large lymphoid cells. Mononuclear cells frequently infiltrated the subendothelium. These lesions were diagnosed as mild ACR, and they displayed an immunophenotypic profile similar to that previously observed on TBB. Surprisingly, large airway fibrosis partially obstructing the bronchial lumen was observed (Figure 2, B). This fibrosis contained some small to medium-sized lymphoid cells. The lymphoid cells expressed mainly CD3 for small and some large lymphoid cells and CD20 for a few large lymphoid cells. The latter were positive for EBV by in situ hybridization and by immunohistochemistry (Figure 2, C).



We report the unusual observation of a likely coexistent ACR and PTLD on TBB. According to Rosendale and Yousem, (2) the histologic distinction between ACR and PTLD can be difficult on TBB because histologic patterns similar to ACR can be seen at the periphery of a PTLD. Although it is difficult to confirm the existence of ACR lesions associated with PTLD in our case, several arguments can be put forward to support this hypothesis. First, the treatment of PTLD, which consisted of a decrease in the dose of maintenance immunosuppression, allowed the total regression of PTLD but had no effect on the perivascular mononuclear infiltrates on successive TBBs. Second, the treatment of ACR temporarily induced the disappearance of these perivascular infiltrates. Third, EBV expression was detected only in lymphoid cells of the PTLD. According to Rosendale and Yousem, (2) the presence of EBV LMP1 is the most consistent and significant difference between the extension of PTLD and ACR, which was always negative for EBV LMP1 in this study. (2) Finally, we found OB lesions on postmortem histologic findings with absence of PTLD. The exact cause of OB is unknown. Many reports in the literature outline the fact that ACR is the main risk factor for the subsequent development of OB. (7) Therefore, we can hypothesize that the OB lesions in this case may have resulted from ACR.

On the subject of the association of PTLD and ACR, we propose that 2 different subpopulations of T cells are involved: EBV-specific T cells implicated in PTLD and allospecific T cells directed toward donor alloantigens in ACR. Montagna et al (8) pointed out this possibility in in vitro studies of independently controlled allogenic and antiviral reactions, thus suggesting 2 distinct processes. In our observations, the presence of persistent ACR lesions with decreasing antiviral immunity is probably the reflection of a higher number of allogenic rather than specific anti-EBV cytotoxic precursors.

The other original finding in this case was the presence of fibrosis partially obstructing large bronchial lumens on postmortem lung sections. Such lesions, which to our knowledge have not been reported previously in autopsies of transplant patients, do not belong to the classic morphologic description of OB. Because of the morphologic similarities between such lesions and OB, these lesions may result from the same pathologic process and could be the result of tissue repair and remodeling in response to graft injury that was caused by repeated cycles of rejection or ongoing subclinical alloreactivity. These fibrotic lesions could also be a consequence of PTLD, which was diagnosed on endobronchial biopsies. Immunohistochemical study of postmortem lung sections revealed some large lymphoid B cells expressing EBV transcripts within these fibrotic lesions.

In conclusion, we report the coexistence of ACR and PTLD lesions. Although we do not have markers to identify T-cell specificity (alloreactive or anti-EBV T cells), our observations support the possibility that these 2 lesions may coexist and that pathologists and clinicians should consider both for diagnosis and treatment purposes.

The authors thank Serge Bain, Francis Devez, and Veronique Ducruit for their technical assistance, Lionel Poursac for the illustrations, and Jennifer Chow for the translation.


(1.) Ward C, Snell GI, Zheng L, et al. Endobronchial biopsy and bronchoalveolar lavage in stable lung transplant recipients and chronic rejection. Am J Respir Crit Care Med. 1998;158:84-91.

(2.) Rosendale B, Yousem SA. Discrimination of Epstein-Barr virus--related post-transplant lymphoproliferation from acute rejection in lung allograft recipients. Arch Pathol Lab Med. 1995;119:418-423.

(3.) Kramer MR, Stoehr C, Whang JL, et al. The diagnosis of obliterative bronchiolitis after heart-lung and lung transplantation: low yield of transbronchial lung biopsy. J Heart Lung Transplant. 1993;12:675-681.

(4.) Al-Dossari GA, Kshettry VR, Jessurun J, Bolman RM III. Experimental large-animal model of obliterative bronchiolitis after lung transplantation. Ann Thorac Surg. 1994;58:34-40.

(5.) Cohen AH, Sweet SC, Mendeloff E, et al. High incidence of post-transplant lymphoproliferative disease in pediatric patients with cystic fibrosis. Am J Respir Crit Care Med. 2000;161:1252-1255.

(6.) Youssem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: lung rejection study group. J Heart Lung Transplant. 1996;15:1-15.

(7.) Hirt SW, You XM, Moller F, et al. Development of obliterative bronchiolitis after allogeneic rat lung transplantation: implication of acute rejection and the time point of treatment. J Heart Lung Transplant. 1999;18:542-548.

(8.) Montagna D, Yvon E, Calcaterra V, et al. Depletion of alloreactive T cells by a specific anti-interleukin-2 receptor p55 chain immunotoxin does not impair in vitro antileukemia and antiviral activity. Blood. 1999;93:3550-3557.

Accepted for publication March 30, 2001.

From the Departments of Pathology (Drs Longchampt, Tissier, Audouin, and Molina) and Pulmonology (Drs Achkar and Rabbat), Hotel Dieu University Hospital, Paris, France.

Reprints: Thierry Molina, MD, Department of Pathology, Hotel Dieu, 1 place du parvis de Notre Dame, 75131 Paris cedex, France (e-mail: thierry,
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Author:Longchampt, Elisabeth; Achkar, Antoine; Tissier, Frederique; Rabbat, Antoine; Audouin, Josee; Molina
Publication:Archives of Pathology & Laboratory Medicine
Date:Nov 1, 2001
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