Plasmablastic lymphoma following transplantation

Abstract

Posttransplant lymphoproliferative disorder is a serious complication following solid organ as well as hematopoietic stem cell transplantation due to prolonged immunosuppressive therapy. Plasmablastic lymphoma, although classically associated with HIV infection, has since been described in transplant patients as a variant of posttransplant lymphoproliferative disorder with varying clinical presentations. Here we add two additional cases to the literature: one following lung transplantation and one following pancreatic transplantation. In addition, the demographic, therapeutic, and immunophenotypic characteristics from prior reported cases are summarized.

Plasmablastic lymphoma was first described in 1997 as an oral mucosal lesion associated with HIV-positive individuals as a subtype of diffuse large cell lymphoma (1, 2). Since its initial description, it has now become well established as an entity seen in HIV-negative individuals as well, albeit rarely (3). In 2003, the first case of plasmablastic lymphoma in a posttransplant lymphoproliferative disorder (PTLD) was reported as a cutaneous leg ulcer (4). Since this original description, several additional cases have been reported following various solid organ and bone marrow transplantations. We present two cases of plasmablastic lymphoma, one following lung transplantation with subsequent immunosuppressive therapy (previously reported in the context of unusual clinical findings) (5) and another following pancreatic transplantation.

CASE 1

A 67-year-old man with idiopathic pulmonary fibrosis diagnosed at age 63 (2008) underwent sequential bilateral lung transplantation in October 2011. The patient had a complicated clinical course thereafter with repeated episodes of respiratory failure requiring reintubation and eventual tracheostomy. He subsequently developed bilateral pulmonary infiltrates and was placed on antibiotics. Biopsy showed acute lung injury, and the patient was placed on high-dose steroids for presumed acute rejection. The patient's respiratory status continued to decline, and he developed worsening pulmonary infiltrates. Repeat biopsy again showed acute lung injury with organization. He was again treated with high-dose corticosteroids as well as a 10-day trial of antithymocyte globulin (Atgam) for possible rejection. The patient began to recover clinically, and at the time of his discharge 45 days later, he was breathing room air and his tracheostomy site was healing. To modulate his posttransplant immune function, the patient was treated with tacrolimus, prednisone, and azathioprine.

In February 2012, the patient presented with facial swelling, numbness, right lower lip swelling, and mild erythema within the inner lip with corresponding numbness. He had macrocytic anemia with normal folate and vitamin B12 levels. Brain magnetic resonance imaging revealed multifocal patchy regions of marrow signal abnormality involving the calvaria, skull base, and visualized upper cervical spine. He had elevated copies of Epstein-Barr virus (EBV).

Histologic analysis of a bone marrow biopsy specimen disclosed scattered cellular sheets of a plasmacytoid infiltrate composed of medium- to large-sized cells with an abundant amount of basophilic cytoplasm, eccentrically located nuclei with a clock-faced chromatin, and a perinuclear hof. Many malignant cells displayed a large central nucleolus with finely dispersed immature chromatin consistent with a “plasmablast”-type morphology (Figures 1 and 2). Occasional cells showed bi- and trinucleated forms, and mitotic activity was increased with many atypical figures seen.

Figure 1.

Wright stain of bone marrow aspirate showing larger “blast”-like plasma cells with abundant cytoplasm, nucleoli, and open chromatin pattern. The cells also have vague perinuclear hofs and eccentrically placed nuclei. ×1000.

Figure 2.

(a) Hematoxylin and eosin staining of the aspirate clot preparation showing sheet-like infiltrate predominantly composed of larger “blast”-like cells with prominent nucleoli. ×400. (b) Epstein-Barr virus early RNA in situ hybridization showing strong nuclear positivity within the infiltrative cells. ×400.

Immunophenotypically, these cells were characterized by strong immunohistochemical staining to CD138 with patchy membranous positivity seen with CD56. CD30 and CD20 were negative in the plasmacytoid cells. Most malignant infiltrates were negative for both kappa and lambda in situ hybridization with rare scattered cells showing positivity. Additionally, most cells stained positively for EBV early RNA (EBER) by in situ hybridization (Figure 2).

After a diagnosis of posttransplant plasmablastic lymphoma was made, the patient was started on a cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin), and prednisone/prednisolone (CHOP) chemotherapy regimen. After 1 cycle of treatment, the patient elected to receive palliative care only.

CASE 2

In 2008, a 45-year-old woman received a pancreas transplant for brittle diabetes mellitus type I. Over the next year, the patient was hospitalized multiple times with abdominal pain, which was attributed to pancreatitis. In May 2009, the patient was hospitalized for abdominal pain, again with a failed pancreatic transplant. She underwent a planned pancreatectomy. During the procedure, a 16-cm loop of small bowel was identified wrapping around a 6.0 × 5.0 × 4.0 cm soft tissue mass within the abdomen, and it was resected.

Histomorphologically, the mass was composed of large round to oval-shaped cells with finely dispersed immature chromatin and prominent nucleoli consistent with a “blast”-type morphology (Figure 3). Immunohistochemically, the cells had a positive stain for CD138 and CD56 and were positive for EBER by in situ hybridization, confirming the diagnosis of plasmablastic lymphoma. Postoperatively, the patient had a complicated course and died 7 days following the procedure due to overwhelming gram-negative sepsis.

Figure 3.

Hematoxylin and eosin staining of the mesenteric mass showing large cells with open chromatin and prominent nucleoli consistent with a “blast”-type morphology. ×400.

DISCUSSION

PTLD is a heterogenous disease seen in patients who have undergone solid organ or hematopoietic stem-cell transplantation. It was first described in 1968 in association with renal transplantation. In patients who have received a transplant, the risk of lymphoma is increased 20% to 120% compared with the general population (6). Additionally, several risk factors have been shown to increase the risk of PTLD, including immunosuppression (6–8), EBV (9–12), genetic susceptibility (13), and a host of other miscellaneous factors including Caucasian race (14), hepatitis C, cytomegalovirus, and human herpes virus-8 infection (15–17). PTLD is classified into four categories based on immunophenotype, morphology, and molecular criteria. These include early lesions, polymorphic, monomorphic, and classical Hodgkin lymphoma (18).

Traditionally, plasmablastic lymphomas have been described in HIV-positive individuals, typically occurring in the mucosa of the oral cavity. The lesion is characterized morphologically by blastic cells with a plasma cell immunophenotype. In recent years, this entity has also been described in individuals who have previously undergone a transplantation procedure, including kidney, heart, heart/lung, liver/small bowel, and bone marrow (Table 1) (4, 19–24). To our knowledge, the present report is the first describing plasmablastic lymphoma following pancreatic transplantation.

Table 1.

Reported cases of plasmablastic lymphoma in transplanted patients

Study	No.	Sex	Age (years)	Transplant	Location	Treatment	Status (months)
Nicol et al, 2003 (4)	1	F	68	Heart	Cutaneous	Local radiotherapy	Alive (9)
Teruya-Feldstein et al, 2004 (19)	1	M	73	Kidney	Cutaneous	Chemotherapy	Alive (7)
Verma et al, 2005 (20)	1	F	38	Kidney	Cutaneous	Resection and radiotherapy	Alive (32)
Borenstein et al, 2007 (21)	4	M	27	Kidney	Prostate	Not reported	Not reported
	M	46	Heart	Oral cavity
	M	48	Bone marrow	Lymph node
	M	57	Kidney	Cutaneous
Apichai and Hernandez et al., 2009 (22, 23)	1	F	14 mo	Small bowel, liver	Cutaneous	IR	Progression (<1)
Zimmermann et al, 2012 (24)	8	F	30	Heart, lung	Disseminated	IR + chemo	Progression (<1)
	M	37	Heart	Nasal cavity	IR + chemo + radiation	Alive (48)
	F	42	Kidney	Disseminated	None	Progression (<1)
	M	44	Heart	Disseminated	IR + chemo	Progression (4)
	M	49	Kidney	Subcutaneous	IR + chemo + radiation	Alive (14)
	M	54	Heart	Disseminated	Chemo	Progression (6.5)
	M	62	Heart	Disseminated	IR + chemo	Alive (29.5)
	M	67	Kidney	Disseminated	IR + chemo	Progression (10)
Present study (including Shahriar et al, 2012 [5])	2	M	67	Lung	Bone marrow	Limited chemo	Alive (<1)
	F	42	Pancreas	Mesenteric	Resection	Progression (<1)

IR indicates immunosuppressant reduction.

Morphologically, PTLD plasmablastic lymphoma is characterized by larger immature cells with abundant cytoplasm, nucleoli, and an open chromatin pattern. Immunophenotypically (Table 2), previously reported cases have been predominantly positive for CD138 and VS38 and usually display either a kappa or lambda restriction. B-cell markers, such as CD20 and CD79a, are typically negative, and the proliferative index (Ki-67) is invariably high, usually above 80%. The preponderance of reports demonstrates positivity for EBER through in situ hybridization, with one other case demonstrating an EBV and human herpes virus-8 coinfection (20).

Table 2.

Immunophenotypes in reported cases of plasmablastic lymphoma in transplanted patients

Study	VS38c	CD79a	CD20	κ	λ	EBER	CD138	CD56	IgG	IgM	CD30	EMA	LCA	HHV-8	Ki-67
Nicol et al, 2003 (4)	1/1	0/1	0/1	0/1	–	–	0/1	0/1	1/1	–	–	0/1	–	–	–
Teruya-Feldstein et al, 2004 (19)	–	0/1	0/1	–	–	1/1	1/1	–	–	–	–	–	Weak	1/1	–	>80%
Verma et al, 2005 (20)	–	1/1	0/1	0/1	1/1	1/1	–	1/1	–	–	0/1	–	–	1/1	–
Borenstein et al, 2007 (21)	4/4	Weak	4/4	0/4	2/4	1/4	3/4	2/3	0/3	–	–	1/2	1/3	–	–	70%–90%
Apichai and Hernandez et al, 2009 (22, 23)	–	Weak 1/1	0/1	0/1	1/1	–	1/1	1/1	–	–	0/1	–	–	–	>90%
Zimmermann et al, 2012 (24)	–	–	0/7	4/7	2/7	5/8	6/8	1/6	–	–	–	–	–	–	80%–100%
Present study (including Shahriar et al, 2012 [5])	–	–	0/2	0/2	0/2	2/2	2/2	2/2	–	–	0/2	–	–	–	–

κ indicates kappa; λ, lambda; EBER, Epstein-Barr virus early RNA; EMA, epithelial membrane antigen; LCA, leukocyte common antigen; HHV-8, human herpes virus-8.

The role of EBV in the development of PTLDs (including plasmablastic lymphoma) is well established. EBV preferentially infects B cells, where its genome can lay dormant as an episome (25). In healthy immunocompetent individuals, activated T cells play an important role in controlling the proliferation and elimination of infected B cells. Due to immunosuppressive therapy severely impairing T-cell activity, immunosuppressed patients are at risk for uncontrolled proliferation of the infected B cells.

The treatment for PTLD has many modalities with varying degrees of effectiveness. Antiviral therapies, particularly ganciclovir, have been used as prophylactic agents to prevent EBV-related PTLD, although the data are not definitive. Donor-derived EBV-specific cytotoxic T-cell lymphocyte infusions (adoptive immunotherapy) have also been shown to play a role in PTLD prophylaxis in both adult and pediatric populations (26, 27). Treatment modalities of diagnosed PTLD have included reduced immunosuppression as well as CHOP-based chemotherapy with or without rituximab. A recent study looking at treatment options for PTLD plasmablastic lymphoma by Zimmermann et al found that immunosuppression with systemic chemotherapy (CHOP-21) achieved a more lasting and complete remission than immunosuppression with local therapy (24).