Large Cell Lymphoma

Large B-cell lymphoma of thymus with extensive fibrosis and nodularity.

Definition

Distinctive form of lymphoma that occurs in the anterior mediastinum, often arising from the thymus, morphologically characterized by large cells containing vesicular nuclei with multiple distinct nucleoli and moderate to abundant cytoplasm.

Clinical Features

May present:
- as a thymic mass
- with lymph node involvement
- with superior vena caval syndrome1–6
Usually:
- young adult female
- restricted to intrathoracic region at presentation

Pathogenesis

Morphologic, immunohistochemical, and molecular attributes significantly different from those of large B-cell lymphoma at other sites:7
- postulated that:
  - represents a distinct type of lymphoma, possibly arising from subset of intrathymic lymphoid cells (asteroid B-cells)8,9
  - MAL (an integral membrane protein in glycolipid-enriched membrane microdomains, called lipid rafts) is a distinct molecular marker 10

Gross Pathology

Invasive, often into:
- pericardium
- pleura
- lung
- sternum
- chest wall5,11
Generally firm consistency (Fig. 1
Fig. 1: Gross appearance of large cell lymphoma with sclerosis of the thymus. There is distinct nodularity induced by the fibrous strands. This appearance is not too dissimilar from that of nodular sclerosis Hodgkin's lymphoma.
)
Frequent foci of necrosis

Histopathology

Wide bands of fibrosis:
- sometimes striking
- compartmentalize tumor cells (Fig. 2
  Fig. 2: Large B-cell lymphoma of thymus with extensive fibrosis and nodularity.
  )
Simulates an epithelial, germ cell, or neuroendocrine neoplasm5
Perivascular collections of lymphocytes (Fig. 3
Fig. 3: Perivascular cuffing by small non-neoplastic lymphocytes in large B-cell lymphoma. The formations should not be confused with the perivascular spaces of thymoma.
)
Artifactual clearing of cytoplasm induced by formalin fixation (not present in B5 or Zenker's fixed material) (Fig. 4
Fig. 4: Artifactual cytoplasmic clearing in a case of large B-cell lymphoma that has been formal-fixed.
)
Large number of reactive T cells12
Entrapment of thymic epithelium5,8
Sometimes abundant reactive histiocytic population
Diagnosis should be favored if:
- fibrosis in form of wide hyaline bands and as a fine network that entraps individual cells 13
Sometimes extreme cellular pleomorphism14
Exceptionally, tumor cells show tropism for germinal centers15

Special Stains and Immunohistochemistry

Invariably reactivity for CD45
Most are B-cell nature2,5,16–18
Occasionally T cell 19
Nearly 70% express CD3020
Also express bcl-6 and CD10:
- suggesting derivation from germinal center cells21,22

Diagnosis

Diagnosis may be suspected on basis of fine needle aspiration material 23

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Large Cell Lymphoma

Malignant thymoma
Seminoma (germinoma)
Large cell malignant lymphoma is correct diagnosis in most cases of a clinically and microscopically malignant mediastinal tumor in a young female

Causes Of Frequent Misdiagnosis

Simulates an epithelial, germ cell, or neuroendocrine neoplasm5
Perivascular collections of lymphocytes (see Fig. 3) may be misinterpreted as perivascular spaces of thymoma
Artifactual clearing of cytoplasm induced by formalin fixation (not present in B5 or Zenker's fixed material) (see Fig. 4)
Large number of reactive T cells12
Entrapment of thymic epithelium:5,8
- can create problems when examined ultrastructurally or immunostained for keratin 5
Abundant reactive histiocytic population may lead to misdiagnosis of true histiocytic lymphoma

Management

Radiation therapy and chemotherapy:
- usually excellent response3,24

Prognosis

Sometimes recurs within chest and spreads to other sites, including:
- central nervous system 25,26
Pleural effusion at presentation associated with poor outcome 27
Kidneys often involved in recurrent disease:5,28
- may be a ‘homing’ mechanism involved analogous to that hypothesized for MALT lymphoma

References

1 Abou-Elella AA, Weisenburger DD, Vose JM, Kollath JP, Lynch JC, Bast MA, et al. Primary mediastinal large B-cell lymphoma: a clinicopathologic study of 43 patients from the Nebraska Lymphoma Study Group. J Clin Oncol. 1999;17:784–790.

2 Addis BJ, Isaacson PG. Large cell lymphoma of the mediastinum. A B-cell tumor of probable thymic origin. Histopathology. 1986;10:379–390.

3 Aisenberg AC. Primary large cell lymphoma of the mediastinum. Semin Oncol. 1999;26:251–258.

4 Miller JB, Variakojis D, Bitran JD, Sweet DL, Kinzie JJ, Golomb HM, et al. Diffuse histiocytic lymphoma with sclerosis. A clinicopathologic entity frequently causing superior venacaval obstruction. Cancer. 1981;47:748–756.

5 Perrone T, Frizzera G, Rosai J. Mediastinal diffuse large-cell lymphoma with sclerosis. A clinicopathologic study of 60 cases. Am J Surg Pathol. 1986;10:176–191.

6 Trump DL, Mann RB. Diffuse large cell and undifferentiated lymphomas with prominent mediastinal involvement. A poor prognostic subset of patients with non-Hodgkin's lymphoma. Cancer. 1982;50:277–282.

7 Tsang P, Cesarman E, Chadburn A, Liu Y-F, Knowles DM. Molecular characterization of primary mediastinal B cell lymphoma. Am J Pathol. 1996;148:2017–2025.

8 Davis RE, Dorfman RF, Warnke RA. Primary large-cell lymphoma of the thymus. A diffuse B-cell neoplasm presenting as primary mediastinal lymphoma. Hum Pathol. 1990;21:1262–1268.

9 Eichelmann A, Koretz K, Mechtersheimer G, Möller P. Adhesion receptor profile of thymic B-cell lymphoma. Am J Pathol. 1992;141:729–741.

10 Copie-Bergman C, Plonguet A, Alonso M, Boulland ML, Marquet J, Divine M, et al. MAL expression in lymphoid cells: further evidence for MAL as a distinct molecular marker of primary mediastinal large B-cell lymphomas. Mod Pathol. 2002;15:1172–1180.

11 Levitt LJ, Aisenberg AC, Harris NL, Linggood RM, Poppema S. Primary non-Hodgkin's lymphoma of the mediastinum. Cancer. 1982;50:2486–2492.

12 Dunphy CH, Babich AD, Borson RA. Primary mediastinal large cell lymphoma with sclerosis containing a large number of T-cells: differential diagnosis. AIMM. 1999;7:48–51.

13 Paulli M, Strater J, Gianelli U, Rousset M-T, Gambacorta M, Orlandi E, et al. Mediastinal B-cell lymphoma: a study of its histomorphologic spectrum based on 109 cases. Hum Pathol. 1999;30:178–187.

14 Suster S, Moran CA. Pleomorphic large cell lymphomas of the mediastinum. Am J Surg Pathol. 1996;20:224–232.

15 Suster S. Large cell lymphoma of the mediastinum with marked tropism for germinal centers. Cancer. 1992;69:2910–2916.

16 Al-Sharabati M, Chittal S, Duga-Neulat I, Laurent G, Mazerolles C, Al-Saati T, et al. Primary anterior mediastinal B-cell lymphoma. A clinicopathologic and immunohistochemical study of 16 cases. Cancer. 1991;67:2579–2587.

17 Menestrina F, Chilosi M, Bonetti F, Lestani M, Scarpa A, Novelli P, et al. Mediastinal large-cell lymphoma of B-type, with sclerosis. Histopathological and immunohistochemical study of eight cases. Histopathology. 1986;10:589–600.

18 Yousem SA, Weiss LM, Warnke RA. Primary mediastinal non-Hodgkin's lymphomas. A morphologic and immunologic study of 19 cases. Am J Clin Pathol. 1985;83:676–680.

19 Waldron JA, Dohring EJ, Farber LR. Primary large cell lymphomas of the mediastinum. An analysis of 20 cases. Semin Diagn Pathol. 1985;2:281–295.

20 Higgins JP, Warnke RA. CD30 expression is common in mediastinal large B-cell lymphoma. Am J Clin Pathol. 1999;112:241–247.

21 de Leval L, Ferry JA, Falini B, Shipp M, Harris NL. Expression of bcl-6 and CD10 in primary mediastinal large B-cell lymphoma: evidence for derivation from germinal center B cells?. Am J Surg Pathol. 2001;25:1277–1282.

22 Pileri SA, Gaidano G, Zinzani PL, Falini B, Gaulard P, Zucca E, et al. Primary mediastinal B-cell lymphoma: high frequency of BCL-6 mutations and consistent expression of the transcription factors OCT-2, BOB.1, and PU.1 in the absence of immunoglobulins. Am J Pathol. 2003;162:243–253.

23 Silverman JF, Raab SS, Park HK. Fine-needle aspiration cytology of primary large-cell lymphoma of the mediastinum. Cytomorphologic findings with potential pitfalls in diagnosis. Diagn Cytopathol. 1993;9:209–214.

24 Lones MA, Perkins SL, Sposto R, Kadin ME, Kjeldsberg CR, Wilson JF, et al. Large-cell lymphoma arising in the mediastinum in children and adolescents is associated with an excellent outcome: a children's cancer group report. J Clin Oncol. 2000;18:3845–3853.

25 Bishop PC, Wilson WH, Pearson D, Janik J, Jaffe ES, Elwood PC. CNS involvement in primary mediastinal large B-cell lymphoma. J Clin Oncol. 1999;17:2479–2485.

26 Lazzarino M, Orlandi E, Paulli M, Strater J, Klersy C, Gianelli U, et al. Treatment outcome and prognostic factors for primary mediastinal (thymic) B-cell lymphoma: A multicenter study of 106 patients. J Clin Oncol. 1997;15:1646–1653.

27 Kirn D, Mauch P, Shaffer K, Pinkus G, Shipp MA, Kaplan WD, et al. Large-cell and immunoblastic lymphoma of the mediastinum. Prognostic factors and treatment outcome in 57 patients. J Clin Oncol. 1993;11:1336–1343.

28 Todeschini G, Ambrosetti A, Meneghini V, Pizzolo G, Menestrina F, Chilosi M, et al. Mediastinal large-B-cell lymphoma with sclerosis. A clinical study of 21 patients. J Clin Oncol. 1990;8:804–808.

Last updated: 27 Mar 2006