Post Transplant Lymphoproliferative Disorder (PTLD ...



California Tumor Tissue Registry

Case of the Month

July, 2003

A 63-year-old male presented with a persistent sore throat and was noted to have an enlarged right tonsil. A four cm oval tonsil was excised. The patient’s history was noteworthy for his having received a kidney transplant five years earlier. Up to this time his immunosuppressant treatment had been uneventful.

Fig. 1: Tonsillar tissue showed architectural distortion by sheets of eosinophilic structures.

Fig. 2: The structures were be variably sized, consisting of homogeneous eosinophilic material in both cytoplasmic and nuclear locations. The cytoplasmic structures were felt to represent Russell Bodies and the rarer nuclear ones were felt to be Dutcher Bodies.

Fig. 3: A CD79a immunostain highlighted a population of plasma cells.

Fig. 4: Kappa (left, 4a) was negative while Lambda (right, 4b) was positive.

PAS and CD138 stains were positive. A CD117 was positive in a few of the plasma cells. Negative stains included CD20/CD3, Congo red, and Crystal violet.

Diagnosis:

“Post Transplant Lymphoproliferative Disorder - Plasmacytoma Type, With

Prominent Russell Body and Dutcher Body Formation”

Sajjad P Syed, MD(, Jung Wang, MD(, William P Illig, MD((, and

Donald R Chase, MD(

( Loma Linda University Medical Center, and California Tumor Tissue

Registry, Loma Linda, California, USA.

(( Midwest Pathology Consultants, P.C., Oklahoma, USA.

Since 1969, it has been well established that organ transplant recipients have an increased incidence of neoplasms, especially skin and lip carcinomas, as well as lymphoid lesions. The latter conditions are usually B-cell proliferations, with many being Epstein Barr Virus (EBV) related. They cover a complex spectrum ranging from reactive lymphoid hyperplasia to lymphoma (1). The clinically and histologically heterogenous group of EBV-driven lymphoid proliferations that arise following solid organ transplantation are collectively referred to as post-transplantation lymphoproliferative disorders (PTLD). Twenty percent (20%) of these, however, have been found to be EBV-negative, and among renal allograft recipients up to 50% may not be associated with EBV. EBV-negative cases tend to occur later than EBV-positive cases (usually > 5 years after transplant) (9). Using serology, 93 percent of post-transplant patients in the University of Pittsburgh study had EBV (3). PTLDs occur more frequently in children than in adults (2). Patients who have undergone heart-lung transplantation are reported to have the highest incidence and shortest interval of development of PTLD (9.4 %), whereas patients receiving kidney transplants have the lowest incidence and longest interval of development (approx. 1%) (3). Donor origin PTLDs appear to be most common in liver and lung allografts (9). The variable incidence of PTLD has been attributed to the different intensities of immunosuppression needed for the different types of allografts. Patients who have undergone more than one transplant have a higher likelihood of developing PTLD. Agents associated with the development of PTLD include: cyclosporine A (6), tacrolimus, OKT3 antibody, and azathioprine or antilymphocyte globulin (3). The interval between transplant and development of PTLD is relatively short with a mean interval of 48 months having been described in literature. Some cases have been reported as early as 0.7 months (3).

The majority of PTLDs occur in extranodal locations. The patients generally fall into three categories:

• those with head and neck disease, who present with either as a mononucleosis-like illness with fever, sore throat with tonsillar enlargement and lymphadenopathy, or a localized mass (5),

• those with abdominal disease, usually secondary to involvement of the gastrointestinal tract with ulceration or perforation, and

• those with single organ involvement, the central nervous system being the most common site (3).

According to the WHO classification, PTLD is categorized from ‘early lesions’ to ‘overt lymphomas’(9):

1. Early lesions

Reactive plasmacytic hyperplasia

• Infectious mononucleosis-like proliferations

2. Polymorphic PTLD

3. Monomorphic PTLD (classified according to lymphoma classification)

B-Cell neoplasms

• Diffuse large B-cell lymphoma (immunoblastic, centroblastic, anaplastic)

• Burkitt/Burkitt-like lymphoma

• Plasma cell myeloma

• Plasmacytoma-like lesions

T-Cell neoplasms

• Peripheral T-cell lymphoma, NOS

• Other types

4. Hodgkin lymphoma (HL), and Hodgkin-like PTLD

The presence of plasmacytic elements is considered a hallmark of PTLD, and in a transplant recipient a predominance of these cells within an infiltrate should suggest PTLD rather than a nonspecific inflammation of another cause (1). The rare PTLD plasmacytoma-like lesion is characterized by a proliferation of monomorphic B-cells and morphologically is similar to plasmacytomas which arise in non-transplantation settings. In general, plasmacytomas may be subclassified into four groups based on location:

• extramedullary (extraskeletal),

• solitary plasmacytoma of bone,

• multiple myeloma, and

• plasma cell leukemia (4).

Post transplant plasmacytoma-like lesions are almost always extramedullary, usually occurring in the gastrointestinal tract, extranodal locations, lymph nodes, or other sites (9).

In non-immunocompromised patients who develop plasmacytoma de novo, the median age is 50-70 years. Men are affected three to four times as often as women. Although extramedullary plasmacytomas have been reported in almost every organ (including skin), primary involvement of a lymph node is rare (4). Between 80-90% of extramedullary plasmacytomas occur in the head and neck, primarily in the upper respiratory tract, especially the nasal cavity (25–30 %), paranasal sinus (20–25 %), nasopharynx (20–25 %), tonsil (5–10 %), larynx (5 %), and oral cavity (5 %). The latter includes the gingiva, submaxillary and parotid gland, and the roof of the mouth. In the setting of organ transplant, findings of masses in the Waldeyer’s ring or an excessive number of cervical nodes should increase the index of suspicion of PTLD (7). Children without previous EBV exposure may develop PTLD localized to the tonsils/adenoids, and biopsy of these tissues may permit early diagnosis and clinical intervention (8). Post transplant plasmacytoma of the heart is reported to have the worst outcome (10).

When involving the G.I. tract, PTLD is usually submucosal, and is from two to five cm in greatest diameter. It is usually red, soft or firm, and either sessile or pedunculated. It tends to bleed easily. Extraosseous tumors rarely show destruction of adjacent bone (4).

Histologically, PTLDs are fairly uniform, consisting of a dense, homogenous infiltrate of plasma cells. These plasma cells have been shown to be clonal, though polyclonal proliferations exist. They may demonstrate varying degree of atypia, including prominent nucleoli, dispersed chromatin, irregular nuclei, and multinucleation (4). Three variants have been described:

• The plasmacytic (well-differentiated) variant consists of plasma cells having clumped chromatin and little cytologic dysplasia.

• The plasmablastic (moderately differentiated) type, consists of plasma cells having more dispersed chromatin and more prominent nucleoli. The cytoplasm is more amphophilic than a normal plasma cell.

• The anaplastic (poorly differentiated) type has more nuclear immaturity and dysplasia (4).

Immunoglobulin inclusions in the cytoplasm (Russell bodies) or nuclear psuedoinclusions (Dutcher bodies) can be present in all more-differentiated types of plasmacytomas. In our presentation case, the most striking feature was the remarkably overwhelming presence of immunoglobulin inclusions (Russell bodies), which nearly completely replaced the native cells. Rarely, amyloid or amorphous deposits of immunoglobulin, sometimes accompanied by a foreign body reaction, may be seen (4).

Immunohistochemistry shows the plasma cells to be surface immunoglobulin negative. They do, however, contain immunoglobulin in their cytoplasm. Most B-cell antigens are negative (CD19, CD20, CD22), but CD79a may be positive. Other markers which are variably positive include CD45, HLA-DR, CD38, EMA, CD43, and CD56 (4). Immunoglobulin heavy-chain and light-chain genes have been shown to be rearranged or deleted, and to show variable regional mutations similar to post-germinal center cells (1). In recent molecular studies, EBV does not appear to be of major importance in the pathophysiology of extramedullary plasmacytoma(4).

If untreated, PTLDs of either polyclonal and monoclonal type often have a rapid progressive, even fatal clinical course (3), with overall mortality in solid organ allograft recipients being approximately 60%. If progression occurs, the tumor is usually treated as a lymphoma, with standard therapies such as irradiation and chemotherapy being utilized (3). Acyclovir, a drug that inhibits EBV DNA replication, has sometimes been given with varying success, but its use in extramedullary plasmacytoma is not clear. Radiotherapy has been shown to be an effective treatment for primary extramedullary plasmacytomas. To prevent PTLD from developing in patients who will receive bone marrow transplant, pre-transplant depletion of B cells from the donor marrow prior to infusion may be considered (1). Of some interest is that if immunosuppressive therapy is withdrawn or substantially reduced, some PTLDs have been shown to completely regress.

With early diagnosis, prompt reduction of immune suppression, and careful administration of chemotherapy or radiation therapy, the prognosis for all types of PTLD has improved (9).

References

1. Neoplastic Hematopathology, 2nd Ed. Knowles. Pgs.117, 524, 579-595, 702, 720-721, 1048-1052, 1217-1218, 1292-1292, 1339-1341

2. Immunodeficiency Disorders. Pediatric Hematopathology, Collin & Swerdlow. Pgs.48-57

3. Surgical Pathology of the Lymph Nodes and Related Organs, 2nd Ed. Jaffe. Pgs.325-330, 527

4. Surgical Pathology of the Head and Neck, Vol 2, 2nd Ed. Leon Barnes. Pgs.1323-1329

5. Hague et al. Posttransplant Lymphoproliferative Disease Presenting as Sudden Respiratory Arrest in a Three Year Old. Ann Otol Rhinol Laryngol 1997 Mar;106(3):244-7.

6. Nalesnik et al. The Pathology of Posttransplant Lymphoproliferative Disorders Occurring in the Setting of Cyclosporine A – Prednisone Immunosuppression. Am J Pathol 1988 Oct;133(1):173-92.

7. Loevner et al. Posttransplantation Lymphoproliferative Disorder of the Head and Neck: Imaging Features in Seven Adults. Radiology 2000 Aug; 216(2):363-9.

8. Lones et al. Changes in Tonsils and Adenoids in Children With Posttransplant Lymphoproliferative Disorder: Report of Three Cases With Early Involvement of Waldeyer’s Ring. Hum Pathol 1995 May;26(5):525-30.

9. Tumors of Haematopoietic and Lymphoid Tissues. Elaine S. Jaffe, Nancy Lee Harris, Harold Stein, and James W. Vardiman. WHO, 2001. Pgs.264-271

10. Fernandez LA, Couban S, Sy R, Miller R. An Unusual Presentation of Extramedullary Plasmacytoma Occurring Sequentially in the Testis, Subcutaneous Tissue, and Heart. Am J Hematol 2001 Jul;67(3):194-6.

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