Common variable immunodeficiency

* Anaplastic large cell lymphoma is a unique diagnostic subcategory of the T-cell lymphomas in the current World Health Organization classification. Representing approximately 3% of adult and 10% to 30% of childhood nonHodgkin lymphomas, anaplastic large cell lymphoma classically consists of CD30+ large lymphoid cells with abundant cytoplasm and pleomorphic, often horseshoe-shaped or kidney-shaped nuclei. Among the reported nodal and extranodal sites of occurrence, the gastrointestinal tract and central nervous system have rarely been noted. We report a case of primary anaplastic lymphoma kinase-negative anaplastic large cell lymphoma in the brain of a 46year-old patient with acquired immunodeficiency syndrome. T-cell lineage was confirmed by T-cell receptor [gamma] chain gene rearrangements using polymerase chain reaction, and extra copies of the anaplastic lymphoma kinase gene of chromosome 2 were demonstrated by fluorescence in situ hybridization analysis. To our knowledge, primary anaplastic large cell lymphoma of the brain has not previously been reported in acquired immunodeficiency syndrome.

(Arch Pathol Lab Med. 2004;128:324-327)

Lymphomas arising in human immunodeficiency virus (HlV)-positive individuals are heterogeneous and may be the initial manifestation of acquired immunodeficiency syndrome (AIDS).1,2 Most lymphomas are aggressive B-cell neoplasms, mainly Burkitt lymphoma or diffuse large B-cell lymphoma, which frequently occur in the central nervous system (CNS).1 Primary effusion lymphoma and plasmablastic lymphoma of the oral cavity are considerably less frequent B-cell neoplasms that occur virtually only in patients with AIDS. Classic Hodgkin lymphoma also occurs more frequently in patients with AIDS.

In contrast, primary T-cell lymphomas are generally uncommon in such patients.1 We describe a case of primary anaplastic lymphoma kinase-negative (ALK-) anaplastic large cell lymphoma in the brain of a 46-year-old AIDS patient. Although rare cases of primary anaplastic large cell lymphoma have been noted in the CNS,3 we are not aware of any previous reports of primary anaplastic large cell lymphoma occurring in the CNS of patients with AIDS.

REPORT OF A CASE

A 46-year-old man presented to the hospital with a 3-week history of progressive ataxia and inability to ambulate. Prior to this episode, he had been in his usual state of health with HIV infection and Crohn disease. A 3.0 × 2.0 × 2.0-cm mass in the right occipital lobe of the cerebrum was detected by magnetic resonance imaging (Figure 1) and was totally resected during the subsequent craniotomy. Morphologic and immunohistochemical findings (see "Pathologic Findings") indicated a diagnosis of CD30^sup +^ ALK^sup -^ anaplastic large cell lymphoma. The staging workup included a detailed physical examination, a body computed tomographic scan, and a bilateral bone marrow examination but failed to detect evidence of lymphoma outside the brain. The patient received a fractionated whole-brain irradiation with a total of 4140 cGY for 3 weeks. he tolerated the therapy well. Although conformai proton therapy to the focus of abnormality was planned for boosting the therapeutic effect, the patient died 2 months after diagnosis from aspiration fungal pneumonia with infection of Aspergillus funiigatits. A postmortem examination was not performed.

PATHOLOGIC FINDINGS

The resected fragments of the right occipital lobe were tan-white to pink and soft, and they formed an aggregate that measured 2.0 × 1.4 × 0.5 cm. This material was fixed in 10% neutral-buffered formalin, embedded in paraffin, sectioned in 3- to 4-µm thicknesses, and stained with hematoxylin-eosin and/or hematoxylin counterstain for immunohistochemistry. Microscopic examination revealed cerebral tissue infiltrated by large sheets and nests of anaplastic large atypical cells that frequently showed perivascular infiltration and penetration into the vascular wall; however, no apparent necrosis of the vascular wall was seen. The large cells had irregular nuclei, occasional nucleoli, and moderate-to-abundant amounts of eosinophilic granular cytoplasm. Scattered among the large cells were occasional multinucleated "hallmark" tumor cells exhibiting horseshoe-shaped or reniform nuclei with perinuclear hofs (Figure 2). Immunohistochemistry showed that most of the tumor cells expressed CD45, CD2, bd-2, CD43 (Figure 3), CD30 (Figure 4), epithelial membrane antigen, and Ki-67 (-90% nuclear reactivity) antigens but not CDS, CDS, CD20, CD79a, [kappa] or [lambda] light chain, ALK-1, HMB-45, or cytokeratin (CAM 5.2) antigens. In addition, expression of HIV p24 protein was not detected in the tumor cells or brain parenchyma by immunohistochemistry using antihuman HIV p24 antibody (CHEMICON International Inc, Temecula, Calif). Genomic DNA was extracted from the paraffin block and analyzed by the polymerase chain reaction technique using primer sets that recognize the V [gamma] 1 to 8, 9, 10, and 11 genes under denaturing and nondenaturing conditions (amplifiable products for the [beta]-globin gene were used as a control for DNA integrity). T-cell receptor [gamma] chain gene rearrangements were detected (Figure 5, lane 7). Fluorescence in situ hybridization analysis for the t(2;5) ALK gene (2p23) translocation was performed with chromosome-specific probes (LSI ALK Dual Color break apart rearrangement probe, Vysis Inc, Downers Grove, 111) for the 5' to 3' region of the ALK gene of chromosome 2 (2p23) in 200 nuclei. Although the conventional t(2;5) translocation was not detected, approximately 33% of the tumor cell nuclei contained 3 to 4 copies of the ALK gene (Figure 6) in contrast to normal tissue having less than 4.0% of the nuclei with more than 2 copies of ALK signals, a finding that indicates more than 2 copies of chromosome 2 per nucleus or a structurally abnormal chromosome 2 that results in additional copies of the ALK locus. The diagnosis of CD30^sup +^ but ALK^sup -^ anaplastic large T-cell lymphoma of the brain was rendered.

COMMENT

HIV-related lymphomas are divided into 3 major categories: (1) lymphomas also occurring in immunocompetent hosts (including Burkitt lymphoma, diffuse large Bcell lymphoma, extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type, rare peripheral T-cell lymphoma, and classic Hodgkin lymphoma); (2) lymphomas occurring more specifically in HIVpositive patients (including primary effusion lymphoma and plasmablastic lymphoma of the oral cavity); and (3) lymphomas also occurring in other immunodeficiency states (polymorphic B-cell lymphoma similar to posttransplantational lymhoproliferative disorders seen in organ transplant recipients).1 As seen in the immunocompetent population, HIV-associated lymphomas are consistently monoclonal, and they frequently show common cytogenetic abnormalities involving oncogenes, such as myc and bcl-6, as well as certain tumor suppressor genes.1 EpsteinBarr virus infection has been found in almost all cases of primary CNS lymphoma4 and primary effusion lymphoma, in 80% of diffuse large B-cell lymphomas with immunoblastic morphology, in 30% to 60% of Burkitt lymphomas,5 and in nearly all cases of Hodgkin lymphomas1,6 in HIV-positive patients. Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 is particularly associated with primary effusion lymphoma.7 HIV-associated lymphomas are most likely to involve extranodal sites (including the CNS) as well as the lymph node in about one third of the patients at the time of presentation.1,2

Anaplastic large cell lymphoma is a T-cell lymphoma characterized by lymphoid cells that are usually large with abundant cytoplasm and pleomorphic, often horseshoe-shaped nuclei. There are 2 different forms of anaplastic large cell lymphoma-primary systemic anaplastic large cell lymphoma and primary cutaneous anaplastic large cell lymphoma. Primary systemic anaplastic large cell lymphoma accounts for approximately 3% of adult and 10% to 30% of childhood non-Hodgkin lymphomas" and occurs more often in males during the first 3 decades of life1; about 70% of patients present with advanced stage III or IV disease and B symptoms at diagnosis.8 The neoplastic cells express CD30 antigen and ALK protein in most cases, whereas ALKr primary systemic anaplastic large cell lymphoma is more common in older individuals, with a male-female ratio of 6.5:1.' ALK^sup +^ primary systemic anaplastic large cell lymphoma frequently involves both lymph nodes and extranodal sites, such as the skin, bone, soft tissues, lung, and liver,8 but rarely the gut and CNS,3 whereas ALK^sup -^ primary systemic anaplastic large cell lymphoma shows similar features but with less frequent extranodal involvement.1 In contrast, primary cutaneous anaplastic large cell lymphoma does not express ALK and is common in older individuals, with a lower male-female ratio of 1.2 to 2:1. 1

Morphologically, anaplastic large cell lymphoma includes the common variant (70%), the lymphohistiocytic variant (10%), the small cell variant (5%-10%), and a combination of at least 2 of the preceding morphologic variants (about 10%). All cases contain a variable proportion of the "hallmark cells." The neoplastic cells frequently show sinusoidal and/or paracortical infiltration and often grow in a cohesive pattern in the involved lymph node. Vascular wall invasion by tumor cells is also frequently seen in extranodal cases. The tumor cells express CD30 antigen by immunohistochemistry with a characteristic membranous and Golgi staining pattern and, in most cases of anaplastic large cell lymphoma, express one or more T-cell markers. Some cases may lack several pan T-cell antigens or may have a "null" cell phenotype but have genetic evidence of T-lineage differentiation. The tumor cells also variably express CD45, CD45RO, and CD43 as well as the epithelial membrane antigen and the cytotoxic-related markers T-cell intracytoplasmic antigen-1, granzyme B, and/or perform. T-cell receptor gene rearrangement can be detected in approximately 90% of all anaplastic large cell lymphomas whether they express T-cell markers or not. Approximately 60% to 85% of cases have detectable ALK expression14 because of a genetic alteration of the ALK locus on chromosome 2. The most frequent alteration is the translocation t(2;5)(p23;q35) between the ALK gene on chromosome 2 and the nucleophosmin gene on chromosome 5,'" but other variant translocations involving the ALK gene have been reported.1 ALK expression by the tumor cells appears to be the most important prognostic indicator and has been associated with a favorable prognosis.1·9 A more recent study by George et aP of 4 new cases of primary CNS anaplastic large cell lymphoma, which also incorporated additional data from 5 previously reported cases, further indicated that a better prognosis is associated with ALK-I expression and young age at the time of diagnosis. They found that only 5 of 9 patients were ALK-I immunoreactive. Of these 5 ALK^sup +^ anaplastic large cell lymphoma patients, 3 (mean age, 13 years; range, 4-18 years) were alive between 4.8 and 6.1 years after diagnosis. The other 2 ALK^sup +^ patients included a 10year-old girl who was in remission at the time of her death from sepsis and a 13-year-old boy who died shortly after diagnosis. In contrast, the 4 ALK" patients and the ALK^sup +^ 13-year-old boy mentioned above (mean age, 43; range, 13-66 years) all died from the tumor between 4 days and 11 weeks after diagnosis.3

CNS anaplastic large cell lymphoma is an aggressive lymphoma3 and must be differentiated from Hodgkin lymphoma, other T-cell lymphomas with CD30 positivity, and metastatic tumors. Immunophenotyping for pan T-cell and pan B-cell markers, CDl 5, ALK protein, and epithelial markers and molecular analysis of antigen receptor gene rearrangements are helpful in narrowing the differential diagnosis. Other types of primary or secondary CNS lymphomas," primary or secondary CNS germinoma, metastatic carcinoma or melanoma, anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, primitive neuroectodermal tumor, and atypical teratoid/rhabdoid tumor also need to be excluded, particularly if the biopsy sample is small and bloody. Correlation of the clinical history, neuroimaging studies, histology, immunohistochemistry, and/or molecular genetic studies is essential in the differential diagnosis of these entities.

This case, to our knowledge, represents the first welldocumented primary ALK anaplastic large cell lymphoma in the brain of an AIDS patient. Although extremely rare, anaplastic large cell lymphoma and its "uncommon" variants should be included in the differential diagnosis of a lesion from the CNS of a patient with AIDS. It is essential to use all possible tools to establish the diagnosis. These include immunohistochemistry (particularly CD30 staining), molecular genetic analysis, and cytogenetic analysis.3 The lack of HIV p24 protein in the tumor cells of the case in our study might be due to the effect of highly active antiretroviral therapy. In addition, the unusual molecular cytogenetic anomaly of multiple copies (3-4 signals) of ALK genes per nucleus (Figure 6) suggests the presence of more than 2 copies of chromosome 2 or a structurally abnormal chromosome 2 resulting in additional copies of the ALK locus. The possibility that this anomaly of the ALK gene represents a new variant of ALK gene abnormalities of anaplastic large cell lymphoma and its role in the pathogenesis of anaplastic large cell lymphoma, especially in immunocompromised individuals, deserves further investigation.

The authors thank Syed Jalal, PhD, Mayo Medical Laboratories, Rochester, Minn, for assistance in performing the fluorescence in situ hybridization analysis for the ALK-I gene and Marcia E. Cornford, MD, PhD, Department of Pathology, Harbor-UCLA Medical Center, Torrance, Calif, for assistance in performing immunohistochemical staining for HIV p24.

References

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2. Beral V, Peterman T, Berkclman R, Jäffe H. AIDS-associated non-Hodgkin lymphoma. Lancet. 1991,-337:005-809.

3. George DH, Scheithauer BW, Aker FV, et al. Primary anaplastic large cell lymphoma of the central nervous system. Prognostic effect of ALK-1 expression. Am I Surg Pathol. 2003:27:487^193.

4. Camilleri-Broet S, Davi F, Feuillard I, et al. AIDS-related primary brain lymphomas: histopathologic and immunohistochemical study of 51 cases. The French Study Group for HIV-Associated Tumors. Hum Pathol. 1997;28:367-374.

5. Hamilton-Dutoit SJ, Raphael M, Audouin I, et al. In situ demonstration of Epstein-Barr virus small RNAs (EBER 11 in AIDS-related lymphomas: correlation with tumor morphology and primary site. Blood. 1993;82:619-624.

6. Spina M, Vaccher E, Nasti G, Tirelli U. HIV-associated Hodgkin's disease. Semin Oncol. 2000:27:480^188.

7. Cesarman E, Chang Y, Moore PS, et al. Kaposi's sarcoma-associated herpesvirus-likc DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl / Med. 1995:332:1186-1191.

8. Stein H, Manson DY, Gerders J, et al. The expression of the Hodgkin's dis ease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidencethat Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood. 1985:66:848-858.

9. Cascoyne RD, Aoun P, Wu D, et al. Prognostic significance of anaplastic iymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood. 1999:93:3913-3921.

10. Lamant L, Meggetto F, al Saati T, et al. High incidence of the t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin's disease. Comparison of cytogenetic analysis, reverse transcriptase-polymerase chain reaction, and p-80 immunostaining. Blood. 1996;87: 284-291.

11. Anders KH, Latta H, Chang BS, et al. Lymphomatoid granulomatosis and malignant lymphoma of the central nervous system in the acquired immunodeficiency syndrome. Hum Pathol. 1989:20:326-334.

Edward H. Rowsell, MD, PhD; Nazila Zekry, MD; Boleslaw H. Liwnicz, MD, PhD; Jeffrey D. Cao, MD; Qin Huang, MD, PhD; Jun Wang, MD

Accepted for publication October 20, 2003.

From the Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, Loma Linda, Calif (Drs Rowsell, Zekry, Liwnicz, Cao, and Wang), and the Department of Anatomic Pathology, City of Hope National Medical Center, Duarte, Calif (Dr Huang).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: )un Wang, MD, Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, 11234 Anderson St, Room 2151, Loma Linda, CA 92354 (e-mail: jwang@ahs.llumc.edu).

Copyright College of American Pathologists Mar 2004
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