—  SPECIALTY CONFERENCE  —

Hematopathology

Case 4 - Plasmablastic Lymphoma (or diffuse large B-cell lymphoma, plasmablastic subtype)

Harald Stein
University Hospital Benjamin Franklin
Berlin, Germany


Click on each slide thumbnail image for an enlarged view
Clinical History:
A 66 year old patient presented with an ulcerated swelling of the maxillary gingiva and with enlarged cervical lymph nodes. An excision biopsy was taken from the lesion. Two paraffin blocks with representative slides were sent to our Lymphoma Reference Center in Berlin for consultation.


Case 4 - Figure 1
Case 4 - Figure 2


Case 4 - Figure 3
Case 4 - Figure 4

Diagnostic Studies:
4µm sections were stained with H&E, Giemsa, PAS and with a large panel of antibodies using the APAAP or the immunoperoxidase method.

Results of Diagnostic Studies:

  1. Histology:
    ulcerated gingival mucosa with a dense diffuse cohesive infiltrate consisting of large blastoid tumor cells with immunoblastic and plasmablastic features, i.e. demonstrating relatively broad basophilic cytoplasm, round to ovoid sometimes excentric nuclei with well defined to prominent central nucleoli. Numerous mitotic figures are present. No transitional cell forms between the tumor cells and mature plasma cells are seen. The tumor cells are intermingled with scattered large pale macrophages whereby a so-called "starry sky" pattern is produced in some areas. Admixture of only few reactive lymphocytes.

  2. Immunohistochemistry
    First round:
    CD45-, CD20-, CD79A-, PAX5-, VS38c-, CD138-, CD3-, CD30-, ALK-, Ki-67 >95%

    Second round:
    Pancytokeratin-, IgD+, Igλ+, j-chain+, MUM1/IRF4+, CD38+

  3. Diagnosis:
    Plasmablastic lymphoma (or diffuse large B-cell lymphoma, plasmablastic subtype)

  4. Differential Diagnosis:
    Morphology:
    • Diffuse large B-cell lymphoma
      • Common variant (mixed centroblastic-immunoblastic) with plasmacellular differentiation
      • Plasmablastic subtype
    • Anaplastic large cell lymphoma

    Following first round of immunohistochemistry:
    • Uncommon undifferentiated large cell carcinoma
    • Malignant melanoma
    • Undifferentiated mesenchymal large cell neoplasms
    • Transformed plasmacytoma with loss of plasma cell antigens
    • Diffuse large B-cell lymphoma with loss of B-cell markers
    • Plasmablastic lymphoma with loss of plasma cell markers

    Following second round of immunohistochemistry
    • Plasmablastic lymphoma with partial loss of plasmacell antigens

Discussion:
Since the second half of the 1980s the author of this handout received for consultation an increasing number of biopsies from the oral cavity that contained large round cell neoplasms. The submitted diagnoses ranged from undifferentiated carcinoma, melanoma and sarcoma to anaplastic large cell lymphoma with loss of lineage markers. Immunohistological and retrospective clinical studies revealed these neoplasms to have the following features in common (Delecluse et al 1997):

  • frequent occurrence of the neoplasm in HIV-positive patients
  • origin in extranodal tissues, most commonly in the oral cavity,
  • extremely large growth fractions (>95%),
  • consistent lack of lineage markers for B-cells (except CD79A which was partially positive in the majority of the cases), T-cells and histiocytes,
  • expression of cytokeratin in some cases,
  • strong expression of the plasma cell associated marker VS38c in all instances,
  • expression of light chain restricted cytoplasmic immunoglobulin in ca. half of the cases
  • clonal rearrangement of the immunoglobulin heavy chain gene in all cases
  • frequent infection of the tumor cells with EBV
  • no M-gradient in serum electrophoresis
  • usually no involvement of the bone marrow at the time of diagnosis, and
  • no history of prior malignancies including plasmacytoma or multiple myeloma

On the basis of the above findings my group and I concluded that the described neoplasms represent a new lymphoma entity. We proposed the name "plasmablastic lymphoma" since the tumor cells display the morphological features of large lymphoid blasts and the immunophenotype of plasma cells. The separation of plasmablastic lymphoma from common types of diffuse large B-cell lymphoma is clinically important since its prognosis is very unfavorable and the current treatment modalities applied for the treatment of diffuse large B-cell lymphoma are not efficient. Equally important is the separation of plasmablastic lymphoma from plasmacytoma/multiple myeloma since the clinical features are totally different.

Subsequently to our first description of plasmablastic lymphoma in 1997 (Delecluse 1997) we have collected 70 additional cases. The investigation of these cases confirmed that plasmablastic lymphoma arise most often in extranodal tissues. Approx. 50% of these patients presented - in contrast to our first series - with a manifestation in the abdomen. The incidence of an association with HIV proved to be much lower in our second series. Morphologic and immunohistochemical studies confirmed the blastoid feature and the extremely high proliferative activity of the tumor cells, the loss of B-cell antigens and the presence of plasma cell associated antigens. Clinical studies confirmed consistent absence of an M-gradient and the lack of a prior malignancy (including plasmacytoma/multiple myeloma) in plasmablastic lymphoma patients.

The description of plasmablastic lymphoma as a new disease entity evoked criticism. It was argued that the plasmablastic lymphoma represented a transformed plasmacytoma or multiple myeloma rather than a new entity. This is, however, unlikely, since there was no history of a prior plasmacytoma or multiple myeloma or a detectable M-gradient in all the cases studied in the first series (Delecluse et al 1997). This also proved to be the case in our second larger series of patients (manuscript in preparation).

Since the first description of plasmablastic lymphoma in 1997 more than 100 publications about this subject have appeared. These publications revealed that the criteria for the diagnosis of plasmablastic lymphoma are not generally understood. In contrast to the strict definition given in our original paper (Delecluse et al 1997), many authors included diffuse large B-cell lymphomas which expressed CD45 and B-cell markers, and which showed features of plasmacellular differentiation into the category of plasmablastic lymphoma. Apart from the possibility that the latter cases also represent a special subtype of diffuse large B-cell lymphomas, they are distinct from plasmablastic lymphoma in terms of both clinical presentation and behavior. Further, the B-cell antigen-positive diffuse large B-cell lymphomas with plasmacellular differentiation do not significantly differ clinically from B-cell antigen-positive diffuse large B-cell lymphomas without signs of plasmacellular differentiation.

The case presented here displays a peculiarity when compared with our previously reported plasmablastic lymphomas. Two plasma cell antigens VS38c and CD138 are not expressed by the tumor cells. This finding prompted us to systematically investigate lymphomas with plasmacellular differentiation. We found that absence of VS38c and CD138 can also be encountered in plasmacellularly differentiated tumor cells of other lymphomas such as lymphoplasmacytic lymphoma and MALT-lymphoma. In this study MUM1/IRF4 and CD38 proved to be the most consistent plasma cell associated antigens.

The relation of the herein presented plasmablastic lymphoma to diffuse large B-cell lymphoma with the expression of full length ALK and to the HHV8-positive plasmablastic lymphoma of primary effusion (body cavity) type and Castleman type will be discussed.

References

  1. Delecluse HJ, Anagnostopoulos I, Dallenbach F, Hummel M, Marafioti T, Schneider U, Huhn D, Schmidt-Westhausen A, Reichart, PA, Gross U, Stein H (1997). Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood 89: 1413-1420.
  2. Brown RS, Campbell C, Lishman SC, Spittle MF, Miller RF (1998): Plasmablastic lymphoma: a new subcategory of human immunodeficiency virus-related non-Hodgkin's lymphoma. Clin Oncol (R Coll Radiol) 10:327-329.
  3. Dupin N, Diss TL, Kellam P, Tulliez M, Du MQ, Sicard D, Weiss RA, Isaacson PG, Boshoof C (1999). HHV8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV8-positive plasmablastic lymphoma. Blood 95:1406-1412.
  4. Gatter KC, Warnke, RA (2001). Diffuse large B-cell lymphoma. In Tumors of the Haematopoietic and Lymphoid Tissues edited by Jaffe ES, Harris NL, Stein H, Vardiman JW. IARCPress: Lyon 2001.
  5. Banks PM, Warnke R (2001). Primary effusion lymphoma. In Tumors of the Haematopoietic and Lymphoid Tissues edited by Jaffe ES, Harris NL, Stein H, Vardiman JW. IARCPress: Lyon 2001.
  6. Colomo L, Lopez-Guillermo A, Perales M, Rives S, Martinez A, Bosch F, Colomer D, Falini B, Montserrat E, Campo E (2002): Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma. Blood, prepublished online August 8, 2002.