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Lymphoid and histiocytic proliferations in HIV-positive patients: problems in diagnosis.

INTRODUCTION

HIV infects CD4-positive T-cells, monocytes and dendritic cells, and has profound immunological effects. The effects on the immune system include cellular and tissue manifestations throughout the 'lymphoreticular' system--lymph nodes (LN), spleen, extranodal lymphoid tissues, bone marrow and peripheral blood. These 'lymphoproliferative' disorders encompass pathologies of both neoplastic and non-neoplastic nature (infective or otherwise). Non-neoplastic lesions may precede or coexist with neoplasms [1]. To add to the diagnostic difficulties, there are morphological overlaps between neoplasms, infective pathologies and non-neoplastic/non-infective pathologies. This short review concisely states the situations that cause difficulties in diagnosis, and suggests some useful ways of tackling them.

REACTIVE LYMPH NODES THAT COULD BE MISTAKEN FOR NEOPLASMS

Frequently, diagnostic difficulties arise because the HIV infection itself is either not known at the time of LN biopsy or is not communicated to the pathologist. Early phases of HIV infection often present with generalised lymphadenopathy and a LN biopsy at this time often shows giant follicles predominantly composed of centroblasts with a starry-sky pattern. These follicles are usually deficient in mantle cells making identification of the follicles sometimes difficult. Such cases can be mistaken for high-grade follicular lymphoma or rarely diffuse large B-cell lymphoma. The later phases of HIV infection with follicular involution or lymphocyte depletion with paracortical expansion and increased vascularity can be mistaken for angioimmunoblastic T-cell lymphoma or other peripheral T-cell lymphomas. It Is Important to remember that most of the L-cells in these expansions are CDS positive whilst the majority of LN-based T-cell lymphomas are of CD4 type.

CD8-POSITTVE CYTOTOXIC T-CELL EXPANSIONS

Polyclonal or oligoclonal expansion of cytotoxic T-cells often occurs early In the disease process in HIV-positive patients. Diffuse Infiltrative lymphocytosis syndrome (DILS) typically affects viscera (salivary glands and lungs being the most common sites), but can also involve peripheral blood, LN and mucosal sites. The expansion can appear infiltrative and in some cases may show angiocentricity-mimicking features of NK/T-cell lymphomas. However, the cells are negative for Epstein-Barr virus (EBV) and CD56. CD8+ lymphocytosis syndrome without visceral infiltration is seen as an increased number of CD8+ large granular lymphocytes in peripheral blood. T-cell receptor gene rearrangement studies may suggest the presence of clonal expansion In some cases, however, these clonal expansions do not constitute a lymphoma [2,3].

HISTIOCYTIC PROLIFERATIONS

Histiocytic/epithelioid cell infiltrates often indicate an infective aetiology, which is further investigated by appropriate histochemical stains [Ziehl Neelsen, periodic acid Schiff (PAS), Grocott (silver) and mucicarmine stains]. The amount of necrosis is variable among the infective pathologies. In some cases the histiocytes can have the appearance of pseudo-Gaucher cells or have fibroblast-like featutes [4], Often these forms of histiocytes are heavily loaded with infective agents (Leishmaniasis, fungal infections and acid-fast bacilli). However, some neoplasms like classical Hodgkin's lymphoma (cHL) can present with prominent histiocytic/epithelioid cell infiltrates, and neoplastic cells can be extremely scanty. The neoplastic cells present may not have characteristic features of Reed Sternberg cells and usually resemble mononuclear Hodgkin cells. Furthermore, in the HIV setting, a proportion (~15-20%) of cHL presents at unusual sites such as liver or bone marrow, and in some cases, these maybe the only sites of documentable disease [5]. Apart from meticulous morphological evaluation, appropriate immunohistochemistry Is crucial. A panel of CD30, CD15, PAX5, CD20 and CD3 Immunostains along with in situ hybridisation (ISH) for EBV-encoded RNA (EBER) would usually suffice. All cases of cHL in the HIV setting are EBV-associated and hence, ISH for EBER Is a sensitive marker.

Another pathology associated with histiocytic proliferation in bone marrow trephine biopsies (BM I B) and splenic tissue is haemophagocytosis. This is more difficult to appreciate In H&E sections of BMTB compared with Giemsa-stained marrow aspirate films or PAS-stained BM LB sections. The presence of haemophagocytosis should prompt a work-up for HHV8 and EBV, as these viral Infections and associated lymphomas/lymphoproliferative processes can drive the haemaophagocytosis [6].

PLASMA CELL EXPANSIONS

Extensive plasma cell expansions in BMTB, mucosal lesions and LN biopsies are encountered in HIV patients [7,8]. The infiltrate can be variable in size, nucleolated and display mitoses. Light chain immunohistochemistry may show some degree of deviation from notmal kappa:lambda light chain tatio. Apart from an altered light chain ratio, Ki-67 expression can be higher. B-cell clonality studies for the presence of clonal IgH or Ig Kappa gene rearrangement would be useful in differentiating it from a plasmacytoma.

MULTICENTRIC CASTLEMAN'S DISEASE AND RELATED DISORDERS

Morphological features of the follicles and the interfollicular area in multicentric Castleman's disease (MCD) are highly variable. The diagnostic feature is the presence of variable numbers of larger nucleolated cells with basophilic cytoplasm in the mantle zones (so-called plasmablasts), which infiltrate the follicles in some cases. These cells can be easily demonstrated by immunostaining for human herpes virus 8 (HHV8)--latent nuclear antigen 1 (LANA1). These cells express IgM and show lambda light chain restriction. Despite being monotypic for lambda light chain, the cells are polyclonal. Hence, the monotypic nature (with respect to light chain expression) of the HHV8-infected large lymphoid cells does not reflect a clonal expansion or a lymphoma [9,10]. As the morphological features may be subtle and variable, HHV8-LANA1 immunostain serves as a sensitive marker.

In a proportion of MCD, the HHV8-infected large nucleolated cells expand and form sheets either surrounding or involving the follicles (referred to as mictolymphomas). It is important to investigate all such cases by Ig rearrangement studies to demonstrate presence or absence of clonal B-cell expansion to guide further treatment. A small minority of MCD develop full-blown HHV8-associated large ceil lymphomas [9,10].

More than half of MCD harbour microscopic foci of Kaposi's sarcoma (KS) involving usually the capsule or the trabeculae and rarely the hilum of the LN [11], It is crucial to carefully evaluate the LNs of MCD for presence of microscopic KS. When patients with MCD and KS are treated with rituximab, there is often an exacerbation of KS, and it is important to forewarn the treating oncologist of this possibility by documenting the presence of microscopic KS [12].

MONOMORPHIC MALIGNANCIES with 'PLASMABLASTIC' MORPHOLOGY

Distinction between three somewhat overlapping morphologies, plasmablastic lymphoma, some cases of diffuse large B-cell lymphoma (DLBCL) of non-germinal centre (GC) type/immunoblastic type, and plasmacytoma can pose problems. Plasmablastic lymphomas are almost always EBV-associated: they are negative or weakly positive for CD20, PAX5 and CD45; always negative for CD56; and they are positive for CD138 and other plasma cell markers [13,14]. DLBCL-non-GC type with immunoblastic features is mostly associated with EBV, but is often positive for CD20 and negative for CD138. Plasmacytomas express CD138 and other plasma cell markers, are variably positive for CD56, and are negative for CD45 and EBV. Plasmablastic lymphomas frequently involve mucosal sites, particularly the oral cavity (LN involvement is extremely uncommon). The presence of skeletal lesions and a significant paraprotein is more characteristic of plasmacytoma. In addition to the above-mentioned entities; 'solid' or extracavitary forms of primary effusion lymphoma (PEL) may also have plasmablastic morphology. However, tumour cells in PEL are co-infected by EBV and HHV8 and most cases do not express Ig light chains [15].

DISTINCTION OF DIFFUSE LARGE B-CELL LYMPHOMA AND BURKITT'S LYMPHOMA

Nearly two-thirds of Burkitt's lymphoma (BL) in the HIV setting show plasmacytoid differentiation, a feature that is not seen in the immune competent setting. In addition, there is greater variability in the nuclear size and morphology, and most cases of BL in the HIV setting express MUM1. These features can make the distinction between BL and DLBCL more difficult [16]. Apart from CD10, BCL2, BCL6 and Ki-67 immunostains, CD38 and CD44 are often helpful for this distinction [17]. In difficult cases, fluorescent in situ hybridisation analysis for breakpoints in MYC, BCL2 and BCL6 loci should be undertaken.

BIOPSY TECHNIQUES

Many of the diagnostic difficulties arise not because of overlapping morphologies or immunophenotypes, but due to using needle core biopsies that are suboptimal for LN histology. While needle core biopsy is more beneficial than a fine needle aspirate and can be extremely helpful when dealing with surgically inaccessible sites, performing needle core biopsies on palpable LNs or easily accessible lesions should be discouraged.

References

(1.) Boutros N, Hawkins D, Nelson M et. al. Burkitt lymphoma and Leishmaniasis in [he same [issue sample in an AIDS patient. Hinopathology, 2006, 48, 880-881.

(2.) Franco-Paiedes C, Rebolledo p, Folch E et ol Diagnosis of diffuse CD8+ lymphocytosis syndrome in HIV-infected patients. AIDS Read, 2002, 12, 408-413.

(3.) Smith PR, Cavenagh JD, Milne T et al. Benign monoclonal expansion of CD8+ lymphocytes in HIV infection. J Clin Pathol, 2000, 53, 177-181.

(4.) Wannakrairot P, Leong TY. Leong AS. The morphological spectrum of lymphadenopathy in HIV infected patients. Pathology, 2007, 39, 223-227.

(5.) Ponzoni M, Fumagalli, Rossi C, et al. Isolated bone marrow manifestation of HIV-associated Hodgkin lymphoma. Mod Pathol, 2002, 15, 1273-1278.

(6.) Stebbing J, Ngan S, Ibrahim H et al. The successful treatment of haemophagocytic syndrome in patient with human immunodeficiency virus-associated multi-centric Castleman's disease. Clin Exp Immunol, 2008, 154, 399-405.

(7.) Burke AP, Anderson D, Mannan P el al. Systemic lymphadenopathic histology in human immunodeficiency virus-1-seropositive drug addicts without apparent acquired immunodeficiency syndrome. Hum Pathol 1994, 25. 248-256.

(8.) Karcher DS, Frost AR. The bone marrow in human immunodeficiency virus (HIV)-relarcd disease. Morphology and clinical correlation. Am J Clin Pathol, 1991, 95, 63-71.

(9.) Dupin N, Diss TL, Kellam P et al. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood, 2000, 95, 1406-1412.

(10.) Du MQ, Liu H, Diss TC et al. Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders. Blood 2001, 97,2130-2136.

(11.) Naresh KN, Rice AJ, Bower M. Lymph nodes involved by multicentric Castleman disease among HIV-positive individuals are often involved by Kaposi sarcoma. Am J Surg Pathol, 2008, 32, 1006-1012.

(12.) Bower M, Powles T, Williams S et a!. Brier communication: rituximab in HIV-associated multicentric Castleman disease. Ann Intern Med 2007, 147, 836-839.

(13.) Delecluse HJ, Anagnostopoulos I, Dallenbach F et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood, 1997, 89, 1413-1420.

(14.) Colomo I, Loong F, Rives S et al. Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities. Am J Surg Pathol, 2004, 28, 736-747.

(15.) Chadburn A, Hyjek E, Mathew S et al. KSHV-positive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma. Am J Surg Pathol 2004, 28, 1401-1416.

(16.) Davi F, Delecluse HJ, Guiet P et al. Burkitt-like lymphomas in AIDS patients: characterization within a series of 103 human immunodeficiency virus-associated non-Hodgkin's lymphomas. Burkitt's Lymphoma Study Group. J Clin Oncol 1998, 16, 3788-3795.

(17.) Rodig SJ, Vergilio JA, Shahsafaei A, Dorfman DM. Characteristic expression patterns of TCL1, CD38, and CD44 identify aggressive lymphomas harboring a MYC translocation. Am J Surg Pathol 2008, 32, 113-122.

KIKKERI N NARESH, JUSTIN STEBBING AND MARK BOWER

Departments of Histopathology and Oncology, Hammersmith Hospital and Imperial College, London, UK, and Department of HIV Medicine and Medical Oncology, Chelsea and Westminster Hospital, London, UK

Correspondence to: Kikkeri Naresh

Department of Histopathology, Hammersmith Hospital

Du Cane Road, London W12 OHS, UK

(email: k.naresh@imperial.ac.uk)
Table 1: Common 'lymphoid' pathologies encountered in tissue
samples of HIV patients.

'Reactive' lymph nodal alterations
 Florid follicular hyperplasia and acute viral lymphadenitis-like
 changes
 Follicular involution
 Depleted lymph node
 Castleman-like changes

T-cell expansions
 Diffuse infiltrative lymphocytosis syndrome and HIV-associated
 CD8+ lymphocytosis syndrome

Histiocytic infiltrates
 Infective granulomatous diseases--mycobacterium tuberculosis,
 atypical mycobacteria, various fungal infections etc.
 Histiocytic pseudo-tumours
 Parasites--Leishmaniasis, toxoplasma lymphadenitis etc.

Plasma cell infiltrates
 Florid plasma cell expansion in lymph nodes, tissues and bone
 marrow with polyclonal hypergammaglobulinemia

HHV8-associated pathologies
 MCD
 MCD with so-called microlymphoma
 MCD with lymphoma
 MCD with Kaposi's sarcoma
 MCD with HHV8 associated haemophagocytic syndrome

Lymphomas specifically occurring in HIV-positive patients
 Plasmablostic lymphoma
 Primary effusion lymphoma--classical and 'solid' forms
 Lymphomas orising in MCD

Lymphomas occurring In other immunodeficient states
 Lesions similar to polymorphic post-transplant
 lymphoproliferative disorder

Lymphomas also occurring In immune competent patients
 Classical Hodgkin's lymphoma
 Burkitt's lymphoma
 Diffuse large B-cell lymphoma

MCD, multicentric Castleman's disease.
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Title Annotation:EDITORIAL
Author:Naresh, Kikkeri N.; Stebbing, Justin; Bower, Mark
Publication:Journal of HIV Therapy
Article Type:Report
Geographic Code:4EUUK
Date:Jun 1, 2009
Words:2019
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