Introduction
Plasmablastic lymphoma (PBL) is a rare, aggressive lymphoma of B-cell lineage and
is frequently but not always associated with HIV and Epstein-Barr virus (EBV) infection.
Unlike diffuse large B-cell lymphoma, the most common aggressive lymphoma, PBL is
associated with a dire prognosis when treated using regimens commonly adopted for
diffuse large B-cell lymphoma. Most studies, albeit all small sample sizes, report
survival in the range of 3 to 12 months. Long-term survival for patients with relapsed
PBL is extremely rare, as the malignancy becomes highly resistant to chemotherapy.
PBL rarely involves skin. Our case describes a patient with nodal and extranodal involvement
of PBL, presenting in skin. Despite refractoriness to the initial combination chemotherapy,
the patient has achieved a durable remission.
Case report
A 47-year-old HIV-positive man on antiretroviral treatment with an undetectable viral
load a month prior, presented with persistent left leg swelling for 6 months, a 10-day
history of a rapidly enlarging right leg mass, and a 2-day history of a left foot
drop. The leg swelling began after a traumatic closed left tibial plateau fracture
that required open reduction and internal fixation. There was no evidence of pathologic
fracture.
On admission, he had a 6-cm round red/purple flat-topped tumor nodule with central
crusted depression on the right lateral shin (Fig 1). There was no lymphadenopathy,
and he denied a history of fevers, chills, night sweats, anorexia, or weight loss.
The left leg was larger in circumference than the right leg, and there was a left
foot drop. Computed tomography (CT) of the right lower leg showed an irregular subcutaneous
soft tissue lesion measuring 4.2 x 1.9 x 3.7 cm near the proximal calf. CT of the
left leg in the region of the thigh showed a 7.2 x 8.0 cm (anteroposterior x transverse)
lesion and a small subcutaneous enhancing lesion along the lateral aspect of the knee
measuring 1.0 x 0.9 x 1.3 cm.
Fig 1
Clinical photographs of cutaneous manifestation of PBL. A, A 6-cm round, red, nodular
flat-topped tumor with central crusted depression on the right lateral shin. B, Closer
view of same image.
The skin nodule in the right leg was biopsied at the outset. Results showed a diffuse
and dense dermal infiltrate of large plasmablastic tumor cells with irregular nuclei,
clumped chromatin, prominent nucleoli, and abundant basophilic cytoplasm, associated
with prominent mitoses and apoptotic bodies (Fig 2). Immunohistochemical analysis
(Fig 3) performed on formalin-fixed paraffin-embedded tissue sections found expression
of MUM-1, BCL-2, C-MYC, CD79a, CD138, CD38, and dim to absent expression of CD45.
The neoplastic cells were negative for PAX-5, CD19, CD20, CD56, BCL-6, and human herpesvirus
type 8. The proliferation rate as detected by the Ki67 antibody was greater than 90%
in the atypical cells. A λ light chain restriction was identified by in situ hybridization.
In situ hybridization for EBV-coded RNA was positive. These findings were consistent
with plasmablastic lymphoma. An EBV quantitative polymerase chain reaction performed
on the peripheral blood was 12,617 IU/mL. A concurrent test for HIV found a viral
load of 3183 copies/mL and a CD4 count of 331 cells/mm3.
Fig 2
Histologic images of PBL. A, Punch biopsy of right lower leg lesion shows a dense,
diffuse infiltrate in the dermis. B, Dense infiltrate of atypical cells with numerous
mitotic figures and tingible body macrophages imparting a starry sky pattern. C, Neoplastic
cells have a plasmablastic appearance with large nuclei, prominent nucleoli, and abundant
basophilic and often eccentric cytoplasm. (Hematoxylin-eosin stain; original magnifications:
A, x40; B, x200; C, x400.)
Fig 3
Immunostaining pattern of PBL. The neoplastic cells are negative for B-cell antigen
CD20 (A), positive for plasma cell markers CD79a (B) and CD138 (C), and positive for
MUM1 (D) and EMA (E). The neoplastic cells are also positive for EBV-encoded RNA by
in situ hybridization (F) and show restriction of λ light chain (G). The Ki67 proliferative
index exceeds 90%. (A through H, Hematoxylin-eosin stain; original magnification:
x400.)
Subsequently, the patient underwent surgical exploration of the left lower extremity,
which found diffuse infiltration by tumor with encasement of the hamstring muscles,
the posterior cutaneous nerve of the thigh, and the sciatic nerve. A soft tissue biopsy
was performed, and histologic and immunohistochemical analysis confirmed the presence
of HIV-associated, EBV positive plasmablastic lymphoma in the soft tissue of left
leg.
In subsequent staging workup, bone marrow biopsy showed 10% involvement by the plasmablastic
lymphoma. CT of the abdomen and pelvis found several enlarged left femoral lymph nodes,
the largest of which measured 21 x 12 mm.
A diagnosis was made of stage IV PBL, involving the lymph nodes, skin, bone marrow,
and nerves. He received 4 cycles of etoposide, prednisone, vincristine, cyclophosphamide,
and doxorubicin hydrochloride (EPOCH regimen) given every 3 weeks, and additionally
received intrathecal treatments. The patient achieved a complete response after 4
cycles of EPOCH, confirmed by positron emission tomography (PET) and bone marrow biopsy.
He received 2 more cycles of planned EPOCH for consolidation. However, within 4 weeks
of completing cycle 6 of EPOCH, a restaging PET scan found several fluorodeoxyglucose
(FDG) avid masses in the left lower extremity and relapse was confirmed by biopsy.
He subsequently received dexamethasone, high-dose cytarabine, and cisplatin (DHAP
regimen) with bortezomib and daratumumab for 3 cycles and again achieved complete
remission. He then received carmustine, etoposide, cytarabine, and melphalan (BEAM
regimen) prior to autologous stem cell transplantation, which he underwent approximately
9 months after his initial diagnosis. Because of the high risk of relapse and the
proven activity of lenalidomide in plasma cell tumors and certain lymphomas, the patient
was placed on lenalidomide, 15 mg/d using a 3-weeks-on 1-week-off schedule. Approximately
1 year later, after missing 2 to 3 weeks of maintenance lenalidomide, a new FDG-avid
right groin lymphadenopathy was found. He responded clinically to restarting lenalidomide
at a higher dose (25 mg) and was eventually switched back to 15 mg/d for better tolerance.
His most recent CT scan showed complete remission. The patient has survived 46 months
since his initial diagnosis and remains in remission (Fig 4).
Fig 4
Timeline of the clinical course. Timeline of the patient's clinical course from time
of fracture to present. ORIF, open reduction internal fixation; CR, complete remission;
DHAP, cisplatin, cytosine arabinoside and dexamethasone.
Discussion
Plasmablastic lymphoma is an aggressive lymphoma of the B-cell lineage, which usually
presents with fever, weight loss, and night sweats in a patient with HIV infection
or AIDS. In a recent meta-analysis of 277 patients with plasmablastic lymphoma, 50%
were found to be HIV positive and 66% of the biopsies performed on these patients
were EBV positive.
1
Extranodal presentation is most frequent, with the oral cavity and gastrointestinal
tract being the most common sites of disease. Primary cutaneous PBL is rare, accounting
for approximately 6% of HIV-associated cases, but a large ulcerative or infiltrative
multinodular tumor mass on the legs is a common pattern.
2
,
3
Histopathologic examination shows a tumor with a dense and diffuse growth pattern
and a “starry sky” appearance, imparted by the presence of frequent mitoses, apoptosis,
necrosis, and tingible body macrophages. The tumor cells resemble both B-immunoblastic
lymphoma cells with large nuclei and prominent nucleoli and plasmacytoma cells with
an abundant, basophilic, and often eccentric cytoplasm. The tumor cells are CD45–
(our case showed dim to absent positivity), express plasma cell markers (CD79, CD138,
and CD38, with a restriction of a light-chain λ noted in our case) and are B-cell
antigen (CD19, CD20, PAX-5) negative. This antigen profile indicates a differentiation
stage in between immunoblasts and plasma cells, hence, the term plasmablastic lymphoma.
EBV can be detected in up to 75% of cases and HHV-8 in less than 50% of cases. MYC
gene rearrangements have been identified in 40% to 50% of patients.
4
PBL presents with advanced-stage diseases in most patients and has a very poor prognosis
with death occurring within the first year of diagnosis. For systemic PBL, there is
no standard therapy that is proven to be highly effective. The most commonly used
regimen for first-line treatment of PBL is cyclophosphamide, doxorubicin, vincristine,
and prednisone (CHOP) or CHOP-like. More intense regimens, including high-dose chemotherapy
and autologous stem cell rescue in first remission, have been reported in small studies,
but the long-term benefits of dose intensification in PBL has yet to be confirmed.4,
5, 6 However, antimyeloma agents such as daratumumab and proteasome inhibitor bortezomib,
alone and in combination with chemotherapy, have produced responses in some patients
with PBL.
4
,
6
Lenalidomide, an immunomodulatory agent, has also shown efficacy in some patients
with relapsed PBL. Our patient had refractory PBL, which is associated with a poorer
prognosis than those with relapsed PBL. Fortunately, the patient has responded very
well to the treatments given so far, including chemotherapy and 3 drugs active in
plasma cell tumors. He remains lymphoma free 46 months from the initial diagnosis.
The case shows that in carefully selected patients with PBL it is feasible and likely
beneficial to incorporate bortezomib, lenalidomide, and daratumumab into chemotherapy
regimens, and such treatments may produce long-term survival even in refractory PBL.
This strategy warrants further study in clinical trials.