Composite lymphoma with coexistence of diffuse large B-cell lymphoma and anaplastic large cell lymphoma: Diagnostic pitfalls

Meyyappa Devan Rajagopal; Rakhee Kar; Debdatta Basu; Sunu Lazar Cyriac

doi:10.4103/IJPM.IJPM_139_16

Home

About us

Instructions

Submission

Advertise

Contact

e-Alerts

Ahead Of Print

Users Online: 37419


CASE REPORT

Year : 2017 | Volume : 60 | Issue : 2 | Page : 275-278

Composite lymphoma with coexistence of diffuse large B-cell lymphoma and anaplastic large cell lymphoma: Diagnostic pitfalls

Meyyappa Devan Rajagopal¹, Rakhee Kar¹, Debdatta Basu¹, Sunu Lazar Cyriac²
¹ Department of Pathology, Section of Hematology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
² Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India

Click here for correspondence address and email

Date of Web Publication

19-Jun-2017

Abstract

Composite lymphoma is a rare tumor composed of two or more distinct lymphomas in the same topographic site or tissue. Several combinations of B-cell non-Hodgkin lymphoma (NHL), T-cell NHL, and Hodgkin lymphoma can occur with different prognoses and treatments. The coexistence of a B-cell NHL and a T-cell NHL is unusual. The exact etiology of composite lymphoma is unknown; however, few mechanisms have been proposed to explain its pathogenesis. The chemotherapeutic protocols are heterogeneous but are essentially targeted against the high-grade component. Most of the cases show worse outcome with a median survival of 12 months. In this article, we report a case of composite lymphoma which was initially diagnosed as diffuse large B-cell lymphoma, and the presence of CD3-positive atypical cells in the bone marrow urged us to re-evaluate the lymph node biopsy following which a focus of Alk-1-positive anaplastic large cell lymphoma was identified.

Keywords: Anaplastic large cell lymphoma, composite lymphoma, diffuse large B-cell lymphoma

How to cite this article:
Rajagopal MD, Kar R, Basu D, Cyriac SL. Composite lymphoma with coexistence of diffuse large B-cell lymphoma and anaplastic large cell lymphoma: Diagnostic pitfalls. Indian J Pathol Microbiol 2017;60:275-8

How to cite this URL:
Rajagopal MD, Kar R, Basu D, Cyriac SL. Composite lymphoma with coexistence of diffuse large B-cell lymphoma and anaplastic large cell lymphoma: Diagnostic pitfalls. Indian J Pathol Microbiol [serial online] 2017 [cited 2023 Sep 29];60:275-8. Available from: https://www.ijpmonline.org/text.asp?2017/60/2/275/208379

Introduction

Composite lymphoma is defined as the presence of two or more morphologically and immunophenotypically distinct types of lymphoma involving the same anatomic site or tissue which can occur concurrently or sequentially.^[1] It is a rare condition with the incidence varying from 1% to 4.7% according to different studies.^[2] The term composite lymphoma should not be confused with discordant lymphoma which indicates the presence of two or more different types of lymphoma occurring at different sites of the body. Similarly, transformation and progression of low-grade lymphoma into high-grade lymphoma precludes the diagnosis of composite lymphoma.^[3]

Composite lymphoma can have components of B-cell non-Hodgkin lymphoma (NHL), T-cell NHL, and Hodgkin lymphoma (HL) in various combinations. Most of the case reports in literature are classic HL with NHL, usually of the B-cell type.^[4] Composite lymphoma having both B- and T-lineage NHLs is an unusual event, and only few case reports have been documented.^[5] In this article, we report a case of composite lymphoma with components of diffuse large B-cell lymphoma (DLBCL) and Alk-1-positive anaplastic large cell lymphoma (ALCL) in a lymph node with emphasis on diagnostic challenges faced in arriving at the diagnosis.

Case Report

A 55-year-old male presented with complaints of fever and loss of appetite for 15 days. He was a known case of DLBCL involving bilateral inguinal lymph nodes diagnosed 6 months back with no bone marrow involvement at presentation and had taken six cycles of chemotherapy (Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisolone. On current examination, he was found to have bilateral inguinal lymphadenopathy and hepatomegaly. Contrast-enhanced computed tomography of thorax and abdomen showed 1.2 cm × 1 cm peripheral nodule with comet tail sign in the right lower lobe suggestive of hematogenous spread of lymphoma and mild hepatomegaly, respectively. His complete hemogram revealed pancytopenia with no atypical cells in peripheral blood smear. Bone marrow aspirate was particulate with preserved trilineage hematopoietic elements along with many scattered large atypical lymphoid cells, some of which had multilobate nucleus and prominent nucleoli [Figure 1]a. Bone marrow biopsy showed hypercellular marrow spaces infiltrated by similar cells in interstitial pattern [Figure 1]b. Immunohistochemistry (IHC) revealed a strong cytoplasmic positivity for CD3 in these large atypical cells. Careful search revealed occasional “Hallmark cells” with indented nuclei which were highlighted by CD3 immunostain [Figure 1]c. CD20 and CD79a were negative [Figure 1]d. Biopsy from the right inguinal lymph node showed extensive hyalinization with few residual mature B- and T-lymphocytes highlighted by CD20 and CD3 immunostains, respectively, which was consistent with postchemotherapeutic changes. No residual lymphoma was seen.

Figure 1: (a) Bone marrow aspirate showing atypical lymphoid cell (Leishman stain; ×400). (b) Bone marrow biopsy showing infiltration by atypical cells in interstitial pattern (H and E; ×100). (c) Atypical cells positive for CD3 (IHC; ×400). (d) Atypical cells negative for CD79a (IHC; ×400)

Click here to view

In view of the present bone marrow biopsy showing infiltration by CD3-positive atypical cells, previous records were reviewed. The patient had two lymphnode biopsies. The first one was an outside block of a lymph node taken from the right superficial inguinal lymph node. It had shown a complete effacement of architecture predominantly by sheets of large lymphoid cells with prominent nucleoli [Figure 2]a. CD20 [Figure 2]b and Mum-1 immunostains were positive in those large cells with Ki-67 index of 80%. CD10, Bcl-2, Bcl-6, TdT, and CD38 were negative. In addition, scattered CD3- [Figure 2]c and CD30-positive medium-sized cells were noted. Hence, a repeat biopsy was advised. The repeat lymph node biopsy taken in our center from the same site had also shown sheets of CD79a-positive large cells confirming the diagnosis of DLBCL. On careful review of the morphology, it was observed that, in CD79a IHC, there were areas positive in sheets and areas relatively sparse in CD79a [Figure 2]d which were positive for CD3.

Figure 2: (a) Lymph node biopsy showing sheets of large lymphoid cells (H and E; ×200). (b) Sheets of CD20-positive large cells (IHC; ×200). (c) Scattered CD3-positive cells (IHC; ×400). (d) Sheets of CD79a-positive large cells along with a focus showing sparsely positive cells (IHC; ×40)

Click here to view

The morphology was meticulously studied with additional IHC markers emphasizing mainly on CD3-positive area. It showed heterogeneous population of lymphoid cells with scattered large bizarre cells resembling atypical cells in the bone marrow [Figure 3]a. Mitosis was prominent with few atypical mitotic figures [Figure 3]b. CD3 and CD30 were positive in these scattered large cells with focal Alk-1 positivity [Figure 3]c,[Figure 3]d,[Figure 3]e. Epstein–Barr virus (EBV)-latent membrane protein was also positive [Figure 3]f and CD15 was negative. A final diagnosis of composite lymphoma composed of DLBCL- and Alk-1-positive ALCLs was made. Meanwhile, the patient developed septicemia by Enterobacter species and succumbed to death during the course of treatment.

Figure 3: (a) Lymph node biopsy showing heterogeneous population of lymphoid cells with scattered large bizarre cells (H and E; ×400). (b) Atypical mitotic figure (H and E; ×400). (c) CD3 positive (IHC; ×400). (d) CD30 positive (IHC; ×400). (e) Alk-1 positive (IHC; ×400). (f) Epstein–Barr virus latent membrane protein-1 positive (IHC; ×400)

Click here to view

Discussion

The term “composite lymphoma” was first coined by Custer in the year 1954 which was later modified by Hicks et al. and Kim et al. as the presence of two distinct architectural and cytological subtypes of lymphoma occurring in the same anatomic site or tissue. This definition was used by the Working Formulation published in 1982 restricting the term to simultaneously occurring tumors.^[1],[6] The exact pathogenesis of composite lymphoma still remains unclear. However, several theories are being proposed to explain the pathogenesis of this uncommon entity which includes clonal selection with additional mutational accumulation, genomic instability with genetic predisposition, common precursor cell origin, immunosuppression, and the role of viral factor, mostly EBV. The different combinations of composite lymphoma that can occur are (i) two different NHLs of same lineage, (ii) B-cell and T-cell NHLs, (iii) B-cell NHL and HL, (iv) T-cell NHL, and HL (v) complex B-cell NHL, T-cell NHL, and HL. All morphologically consistent cases of composite lymphoma must be confirmed objectively using one or more laboratory tests. The diagnostic tests that can be used are (i) IHC and protein expression profile, (ii) flow cytometry, (iii) immunoglobulin and T-cell receptor gene rearrangement by polymerase chain reaction, (iv) cytogenetics and fluorescence in situ hybridization techniques for chromosomal translocations, (v) in situ hybridization for the detection of viral DNA, (vi) DNA sequencing for clonality studies, and (vii) cDNA microarray for gene expression profile.^[3],[7] These tests can be applied on tissue sections, cell suspensions, or DNA extract.^[8] The treatment of composite lymphoma is complex and directed mainly toward the high-grade component.^[3]

The diagnosis of composite lymphoma is quite challenging, especially when two or more high-grade components are present since there can be a significant morphological overlap between some of the high-grade B-cell NHLs, T-cell NHLs, and HLs. In our case, infiltration of the bone marrow by CD3-positive large atypical cells in a known case of DLBCL urged us to review the previous lymph node biopsy. Careful morphological evaluation and application of additional IHC markers revealed a minor component of Alk-1-positive ALCL, based on which the final diagnosis of composite lymphoma having DLBCL- and Alk-1-positive ALCLs was made. This has to be differentiated from a reactive B-cell proliferation occurring in a T-cell NHL, in which the CD20-positive B-cells are seen scattered in T-cell area unlike our case where these large B-cells were seen in sheets and away from T-cell area. Both DLBCL and ALCL components have aggressive clinical course with a worse prognosis.

Our extensive search in literature revealed only two case reports of composite DLBCL and ALCL. The first case was reported by Rajappannair et al. in a 46-year-old female who presented with generalized lymphadenopathy and B-symptoms.^[9] The other case was a “Composite” posttransplant lymphoproliferative disorder in a 56-year-old male occurring 17 years after simultaneous kidney and pancreas transplant for diabetes mellitus.^[10] The occurrence of a B-cell NHL and a T-cell NHL is a rare and enigmatic phenomenon, most of which are associated with EBV infection. Wang et al. have reported the largest case series of composite B- and T-cell NHLs (14 cases). Although two cases of ALCL were documented in their study, none of them were seen in association with DLBCL. Clinical follow-up data were limited ranging from 3 to 44 months, with a median of 12 months. Most of the cases showed persistence, progression, or recurrence of the disease.^[5]

Conclusion

The diagnosis of composite lymphoma is quite challenging, particularly when two different high-grade components are present. Meticulous morphologic evaluation and ancillary tests such as IHC for confirmation will aid in accurate diagnosis. This rare coexistence of different lymphomas should be recognized because the disease subsets have different natural histories, prognoses, and treatments.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Ioachim HL, Medeiros LJ, editors. Composite lymphoma. In: Ioachim's Lymph Node Pathology. 4^th ed. Philadelphia: Wolters Kluwer/Lippincott Williams and Wilkins; 2009. p. 452-3.
2.	Thirumala S, Esposito M, Fuchs A. An unusual variant of composite lymphoma: A short case report and review of the literature. Arch Pathol Lab Med 2000;124:1376-8. [PUBMED]
3.	Mokhtar NM. Review article composite lymphoma. J Egypt Natl Canc Inst 2007;19:171-5.
4.	Altaf FJ, Al-Maghrabi JA. Composite lymphoma. JKAU Med Sci 2007;14:3-17.
5.	Wang E, Papavassiliou P, Wang AR, Louissaint A Jr., Wang J, Hutchinson CB, et al. Composite lymphoid neoplasm of B-cell and T-cell origins: A pathologic study of 14 cases. Hum Pathol 2014;45:768-84.
6.	Custer RP. Pitfalls in the diagnosis of lymphoma and leukemia from thepathologist's point of view. Proceedings of the Second National Cancer Conference. New York: American Cancer Society; 1954. p. 554-7.
7.	Demurtas A, Aliberti S, Bonello L, Di Celle PF, Cavaliere C, Barreca A, et al. Usefulness of multiparametric flow cytometry in detecting composite lymphoma: Study of 17 cases in a 12-year period. Am J Clin Pathol 2011;135:541-55. [PUBMED]
8.	Rabiller F, Belaud-Rotureau MA, Fitoussi O, Dubus P, Merlio JP, de Mascarel A, et al. Composite lymphoma: Association of a follicular lymphoma and a chronic lymphocytic leukemia. Ann Pathol 2008;28:41-4. [PUBMED]
9.	Rajappannair L, Lam E, Benson D, Racke F, Devine S, Zhao W. Collision anaplastic large cell lymphoma (T-cell/histiocyte-rich) and diffuse large B cell lymphoma: A pathologic and clinical evaluation. JCT 2012;3:1060-5.
10.	La Fortune K, Zhang D, Raca G, Ranheim EA. A unique “composite” PTLD with diffuse large B-cell and T/anaplastic large cell lymphoma components occurring 17 years after transplant. Case Rep Hematol 2013;2013:386147. [PUBMED]