—  SPECIALTY CONFERENCE  —

Infectious Disease Pathology

Case 1 - Post-Transplant Lymphoproliferative Disorder, Burkitt lymphoma type

Miguel Reyes-Mugica
Children's Hospital of Pittsburgh
Pittsburgh, PA





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Clinical History:
In 1995, 6 year-old girl presented with a large left neck mass at the Children's Hospital of Pittsburgh. Her past medical history was relevant for biliary cirrhosis secondary to extrahepatic biliary obstruction (biliary atresia), treated with a Kasai procedure. At one year of age, she underwent an orthotopic liver transplant (OLTx). At the time of her hospital admission, five years after the liver transplant, relevant laboratory results included: , Hb= 12.2; Ht= 35.1; WBC= 7.6K/DL: Plt.=296 K/dL; Neut.= 49%; Lymph.= 31%; Mon.= 9%; Eos.=10%; Bas./Band= 1%. SGTP/SGOT= 44/39 IU/L; ALKP/GGTP= 157/22 IU/L. Renal function tests, electrolytes and glucose were within normal limits. Uric acid= 3 mg/dL. The mass was removed and sent to pathology. Representative photomicrographs are presented for discussion.


Case 1 - Figure 1
Imprint taken from the excised mass. Cells are monomorphous, mid-sized, with a small amount of cytoplasm, focally vacuolated. Nuclei reveal fine, granular chromatin, and several inconspicuous nucleoli. There are numerous apoptotic bodies due to increased cell turnover. Diff-Quik®, 40X Diff-Quik
Case 1 - Figure 2
Low power photomicrograph (10X) showing the extensive effacement of the nodal architecture by a monotonous proliferation with a prominent "starry sky" pattern. The upper portion of the image shows partial preservation of the architecture.
Case 1 - Figure 3
Mid-power image (20X) featuring numerous macrophages with phagocytized cellular debris surrounded by a monomorphous proliferation of neoplastic lymphoid elements with intermediate size.

Case 1 - Figure 4
High-power photomicrograph (40X) revealing the very scanty cytoplasm, finely granular chromatin and multiple amphophilic nucleoli. Numerous apoptotic bodies and several mitotic figures are also shown.
Case 1 - Figure 5
Immunohistochemical staining is positive for CD20 in the proliferating lymphoid cells. CD20
Case 1 - Figure 6
Immunohistochemistry for Ki67 is positive in essentially all lymphoid neoplastic elements. Ki67

Case 1 - Figure 7
Another low power view of the architectural effacement with a prominent starry sky pattern.
Case 1 - Figure 8
The numerous tingible body macrophages, imparting the classic "starry sky" pattern reflect a high level of cell apoptosis and turnover.
Case 1 - Figure 9
Additional detail on the scavenging macrophages.

Case 1 - Figure 10
Panoramic view of the touch imprint to show the high cellularity and monotony of the proliferating lymphoid cells.
Case 1 - Figure 11
Immunohistochemistry for CD10 is ++ positive in lymphoid elements.
Case 1 - Figure 12
Immunohistochemistry for BCL6 is +++ positive.

Case 1 - Figure 13
In situ hybridization for EBER (10X).
Case 1 - Figure 14
In situ hybridization for EBER (20X).


Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The excised neck mass, represented by two rubbery lymph nodes with associated fascial connective tissue, measuring in total 4.5 x 2.5 x 1.5 cm was received in Pathology for examination. Histologically, the nodal architecture reveals extensive effacement by a population of proliferating, mid-sized lymphoid elements with scanty cytoplasm. The nuclear features include a finely granular, sometimes clumpy chromatin and several inconspicuous nucleoli. The proliferating cells feature a brisk mitotic activity and multifocal apoptosis. A prominent starry-sky pattern is evident, with numerous macrophages filled with cellular debris. The capsule exhibits fibrosis, and the neoplastic elements extend into the surrounding adipose tissue. The lymph node areas with architecture preservation show sinus histiocytosis and prominent follicular hyperplasia, with focal necrosis and occasional neutrophil infiltration. Relevant immunophenotyping shows ++++ positive staining for CD20, and λ restriction. CD3 and CD45RO (UCHL1) immunohistochemical stains are negative in the proliferating cells. Studies directed to detect Epstein-Barr virus (EBV) show positive staining with EBV-EZLF1 in multiple foci, and the in situ hybridization for EBER is also positive in an overwhelming majority of cells. Retrospective analysis performed in 2009, with additional immunohistochemical markers shows (+++) BCL6 staining, a +/++ positive stain for CD10 in most areas of proliferating lymphoid elements, and Ki67 in essentially all lymphoid cells within the areas of nodal involvement.

Differential Diagnoses:
The differential diagnosis is relatively narrow, but includes a primary lymphoid neoplasm and a post-transplant lymphoproliferative disorder (PTLD). Given the clinical history of OLTx, the second possibility is much more likely, and the documentation of EBV militates strongly in favor of this option. The morphological and immunophenotypical features of this proliferation are diagnostic of a Burkitt type PTLD.

Final Diagnosis:
Post-Transplant Lymphoproliferative Disorder, Burkitt lymphoma type.

Discussion
PTLD is an entity with a wide spectrum ranging from atypical lymphoid or plasmacytoid proliferations to malignant lymphomas. These growths arise as a consequence of immunosuppression in patients transplanted with a solid organ, bone marrow, or stem cell allograft. Pediatric transplant recipients are at increased risk of developing a PTLD because of their EBV-naïve status prior to transplantation ( many are EBV sero-negative at the time of transplantation), which makes them vulnerable to developing a primary EBV infection while on potent immunosuppressive medications. [1, 2]

The morphological picture of PTLDs ranges from early EBV-associated infectious mononucleosis-type to malignant lymphoma. [3] The majority of monomorphic PTLDs (M-PTLD) are composed of transformed B-cells that fit the criteria of a non-Hodgkin Lymphoma (NHL), predominately of the diffuse large B-cell type (DLBCL) and rarely as a Burkitt lymphoma (BL). While M-PTLDs have been thought to be histologically similar to their lymphoma counterparts arising in the immunocompetent patient, new molecular evidence is emerging to suggest that many of the B-cell M-PTLD are more closely related to other PTLDs rather than to B-cell NHL.4 The gene expression profiles of these PTLDs appear to be related to memory or activated B-cells, and share a non-germinal center phenotype. The exception is BL, which retains a germinal center phenotype and does not cluster with the other PTLDs.

Burkitt lymphoma is an aggressive, mature B-cell lymphoma, composed of a monomorphous population of small to intermediate-sized, non-cleaved lymphoid elements. It features high mitotic and proliferation rates, and a characteristic "starry-sky" pattern, imparted from the scattered tingible body macrophages engulfing apoptotic debris of the tumor. Ancillary immunophenotyping and cytogenetic analysis confirm the diagnosis, separating it from a diffuse large B-cell lymphoma (DLBCL). A majority of cases feature the classic translocation of the MYC gene, located at 8q24, to the 14q32 IG heavy chain region, although other, less common sites to which MYC translocates are the γ region at 22q11, or the κ region at 2p12. This translocation is a valuable adjunct in the diagnostic ancillary studies of BL using fluorescent in situ hybridization, although up to 10% of cases may render negative results by this methodology. [3] While the c-MYC rearrangements are not specific, the combination of CD10 positive, bcl-2 negative B-cells is considered diagnostic for BL.

Review of the literature and our own experience at CHP
Three main clinical variants of BL vary in their propensity to express EBV: Endemic predominately occurring in children of equatorial Africa, is strongly associated with EBV infection; Sporadic—presenting mainly in children and young adults less commonly expresses EBV (30%); and Immunodeficiency-associated—primarily associated with HIV infection has an intermediate EBV expression (25-40%). [5, 6] Case reports of BL occurring in the post-transplant setting seem to have an EBV expression profile intermediate between the endemic and immunodeficiency-associated types of BL. [4, 7, 8, 9, 10, 11, 12, 13, 14, 15]

As a PTLD, BL typically occurs later than other PTLDs (average 4.5 years) [16], presents at a higher stage than other M-PTLDs, and must also be clinically treated more aggressively, as decreased immunosuppression alone is inadequate therapy and immediate therapeutic regimens with alkylating chemotherapy agents must be used. [17, 18] While PTLD and BL are independently more commonly seen in children, BL as a PTLD is a rare entity within the pediatric transplant population. In the available medical literature, there are only a handful of case reports describing BL-in the post-transplant setting, [7, 8, 10, 11, 12, 19] and in large transplant studies there is a low incidence of BL-PTLD , ranging from 0.3 to 0.7% in heart and liver transplant patients. [20, 21, 22, 23] BL-PTLD is emerging as a distinct form of PTLD that needs to be more fully characterized in the pediatric population.

At the Children's Hospital of Pittsburgh, we have identified over a 28-year period, 10 cases that fit the diagnostic criteria of BL-PTLD, representing one of the largest series available (study approved by the University of Pittsburgh Institutional Review Board, number PRO09100103). Age at transplant ranged from 5 months to 16 years (median 3 y); 7 patients were boys (Table 1). Four patients had liver transplants [two of these had a second transplant (at 26 mo -case 6- and 20 mo -case 7) status post BL-PTLD diagnosis]; others included heart transplants (n=4), small bowel transplant (n=1), and kidney transplant (n=1, with a second kidney transplant 66 mo after BL-PTLD diagnosis). The BL-PTLD diagnosis was made 6 to 107 months after transplant (median 60 mo). The most frequent signs and symptoms included rapidly enlarging masses (abdominal masses; adenopathy) and abdominal pain. One case developed the BL-PTLD within the graft (case 10); the sites of involvement were the head and neck (n=4), and abdomen (n=4), including the small bowel; one case occurred in the kidney.

Table 1. BL-PTLD at Children's Hospital of Pittsburgh. Clinical data.

Sex Age at Tx Tx organ Site BL-PTLD TX-PTLD PTLD-outcome EBV donor EBV Pre-tx EBV @ PTLD Disease free (mo), Outcome
BL-1 M 7 mo heart Mandible, lymph node capsule, skull base, GI tract 56 127 POS NEG POS 127, Alive, no disease
BL-2 F 1 liver Neck lymph node 63 168 na na POS 168, Alive, no disease
BL-3 M 5 mo heart Kidney-right; *Kidney-bilateral 76 60 na NEG POS 60, Dead, complication of therapy, no disease at autopsy
BL-4 F 3 heart Abdominal mass 107 14 Equivocal NEG POS 14, Alive, no disease
BL-5 M 10 small bowel Neck lymph node 34 16 POS NEG POS 16, Alive, no disease
BL-6 M 16 liver/liver Small bowel 6 134 na na na 134, Dead, infection
BL-7 F 2 liver/liver Neck lymph node 101 199 na POS POS 199, Alive, no disease
BL-8 M 8 kidney/kidney Small bowel, abdominal mass 47 178 POS
(LRD) 		NEG POS 178, Alive, no disease
BL-9 M 9 mo heart Abdominal mass 29 86 NEG NEG POS 86, Alive, no disease
BL-10 M 10.5 liver Liver allograft, widespread metastasis 100 3 NEG NEG POS 3, Dead, graft failure and cardiac arrest

TX-PTLD indicates months from transplant to BL-PTLD; PTLD-outcome indicates months from initial PTLD to recurrence or last follow-up; *Recurrence; LRD=living related donor; LN=lymph node. Index case is BL-2 In all cases, the allograft biopsies immediately preceding the presentation of the BL-PTLD ranged from no rejection to mild cellular rejection. Donor EBV status was known in three cases (positive: cases 5 and 8; negative: case 10). Pre-transplantation EBV serology and/or titers were negative in 6 of 8 patients (75%) and were positive, post-transplant, for all known tested cases (9/9). Pre-transplant CMV serology and/or titers were negative in 6 of 9 tested patients.

The summary of Pathology results is shown in Table 2.

Table 2. Summary of Pathology results.

Histology Immunophenotype EBER Cytogenetics Previous PTLD
BL-1 SNC-BL, vacuolated cytoplasm CD20,10,79a, 43, bcl-6,cK; neg: TdT POS 25.8% of cells c-MYC - RA (BAP)
BL-2 SNC-BL CD20, Lambda, bcl6 POS NA yes; Mono-like
BL-3 atypical cells with hi N/C ratio, apoptotic bodies *CD20,19,22,10,79a,bcl6,DR,cK; negTdT POS;
POS 		t(8;14) yes;P-PTLD
BL-4 SNC-BL CD20,79a, CD10,bcl-6; neg:TdT POS NA
BL-5 Medium-large atypical lymphoid cells, with GC-type BL phenotype CD20,19,10,bcl-6; neg:TdT NEG;
rare+(x2) 		NEG c-Myc/IgH; 200/201 Neg (1-8q24+) yes;P-PTLD
BL-6 Diffuse NHL B-cells NA NA NA
BL-7 Monomorphic Large lymphoid cells; malignant lymphoma IgM,K,L, rare bcl6 POS t(8:14), complex karyotype yes;P-PTLD
BL-8 Monomorphous, BL-vacuoles, starry sky IgM kappa, bcl6 POS t(8:14) and +c-myc
BL-9 Monomorphic, BL morphology-vacuoles, apoptosis, necrosis CD79a,10,bcl6,cK+; neg Tdt POS (50-80%) t(8;14) yes;Monolike
BL-10 intermediate non-cleaved-BL, TBM, apoptosis,mitosis *CD20,19,10,79a,bcl-6,38,cK,DR+; neg: TdT NEG (rpt) t(8;14) and c-myc

SNC=small noncleaved cell; *Immunophenotype from concurrent Bone Marrow. RA= rearrangement; BAP= break-apart probe.
Index case is BL-2.

At our institution, BL-PTLD represented 15% of PTLD for pediatric heart, lung, heart/lung transplants from 1982-present (1.1% incidence-unpublished data); 14% of all pediatric renal PTLD cases from 1989-1995 (1.6% incidence-unpublished data); and 6% of all liver PTLD cases from 1989-1991 (0.76% incidence). [21] Our case-series showed that 78% (7/9) of cases were EBV+, which is similar to the frequency of BL-PTLD (72%) that we extracted from case series for both pediatric and adult cases in the literature. [4, 7, 8, 9, 10, 11, 12, 13, 14, 15] This frequency is similar to EBV expression in other PTLDs [13, 24, 25, 26] but is higher than the one shown by both sporadic and immunodeficiency-associated BL (primarily HIV-associated BL). [3] The majority of our cases (75%) had negative EBV serology and/or titers prior to transplant but all cases were positive post-transplant, prior to or at the diagnosis of the BL-PTLD. EBV seronegative recipient status is the single most important risk factor in the development of PTLD [1]and appears to also be important in BL-PTLD, despite its later onset and more aggressive clinical presentation, as compared to other PTLDs.

The relationship of EBV infection/expression with PTLD and BL is intriguing in regards to the interplay between this virus and the oncogenic transformation furnished by the MYC gene. While endemic BL has a high expression of EBV, sporadic and immunodeficiency-BLs have a much lower EBV prevalence. The role of EBV in the pathogenesis of BL is not as well understood as it is in PTLD, in which virally infected resting B-lymphocytes become immortalized by the interaction of the virus with cell cycle control and the bcl-2 gene to prevent apoptosis. [27] In the post-transplant immunosuppressed host, cytotoxic T-lymphocytes (CTL) are inhibited in order to prevent cellular rejection, impairing their ability to kill the EBV-infected B-lymphocytes. These EBV infected cells continue proliferating and can then manifest as an early, polymorphous, or a monomorphous PTLD. [7] The interplay between EBV and the MYC oncogene in BL-PTLD may occur by the virus contributing to the dysfunction of the MYC gene altering specific breakpoint patterns [28] Existing data show that certain MYC breakpoint locations (in which the c-MYC regulatory region remains intact) are more common in EBV+ than in EBV(-) BL. This suggests that EBV proteins may influence the regulatory regions of the c-MYC gene and thus could play a specific pathogenic role in certain types of EBV+ BL, including BL-PTLD. [28]

While there is a low incidence of BL-PTLD in the literature, it appears to be different than other PTLDs, both in clinical presentation and through molecular studies. BL in the post-transplant setting is a more aggressive type of PTLD since it does not respond to decreased immunosuppression alone, requiring immediate chemotherapy.

In this pediatric population, the time from transplant to the initial development of BL-PTLD was also much longer than other types of pediatric PTLD. In our case-series, the median time to presentation was about 60 months post-transplant, compared to about 10.2 to 23 months for other PTLD in pediatric liver and heart patients, respectively. [20, 22] Our reported time interval is similar to other published pediatric case reports for BL-PTLD, ranging from 24-72 months post-transplant. [7, 8, 9] One hypothesis to explain this longer lag time in BL-PTLD points towards a more complex pathophysiology or an increased number of alterations needed to induce the genetic dysregulation of the MYC oncogene that accumulates over time, in contrast to the immediate CTL immunosuppression and subsequent EBV B-cell proliferation for other PTLDs. Four cases did have some type of PTLD proliferation prior to the BL-PTLD presentation; however, no real conclusion can be made as to whether an early-type or polymorphous PTLD predisposes or impacts the development of BL-PTLD, as there was a wide time range both in the initial PTLD and subsequent BL-PLTD presentations.

Lastly, gene expression data suggest that many of the M-PTLD are more related to other early and P-PTLD than to their NHL counterparts, with the exception of BL and a minority of DLBCL, which retain a germinal center phenoptype. [4, 29] Capello et al. suggests that there are many PTLD with a non-germinal center phenotype that have a nonfunctional IgVH or IgVL, crippling gene rearrangements that lead to B-cell receptor (BCR) loss; however, rescue from apoptosis may occur through EBV-LMP1 antigen expression that induces bcl-2 expression. It may be suggested that BL-PTLD, through its c-MYC dysregulation and persistence of a GC-phenotype, has a singular molecular profile that is more genetically similar to its immunocompetent counterpart than other M-PTLDs.

Conclusion(s):
BL-PTLD is an emerging, aggressive subtype of M-PTLD that needs to be recognized and accurately diagnosed as such in order to establish immediate therapy, not only decreasing immunosuppression, but also administering alkylating agents. It shares some features of other PTLDs, like high expression of EBV, which likely plays an additional role in the pathogenesis of MYC dysregulation. However, features such as a more aggressive clinical presentation with higher stage, longer interval between transplant and presentation, and a GC-phenotype, segregate BL from other M-PTLDs. Awareness of BL as a PTLD is necessary because a different clinical management is needed for proper treatment. Further work to understand the genetic expression profile of this PTLD subtype is needed to fully characterize its biology, since only a handful of cases have been studied with current molecular methods, only a minority of them in pediatric patients. The patient discussed here is currently 20-years-old and continues in good health, with no evidence of rejection or PTLD. Acknowledgements: I want to thank specially Dr. Jennifer Picarsic, YPG3 of the AP/CP program at UPMC, for her excellent job in reviewing the data and preparing the manuscript draft on which much of this presentation is based. I also thank my colleague, Ron Jaffe, for sharing with us cases collected by him through many years. Finally, I thank Drs. George Mazariegos, Steve Weber, Michael Green and Demetrius Ellis, our clinical colleagues at CHP, for providing clinical information derived from their transplant patients.

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