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CD13-Positive Anaplastic Large Cell Lymphoma of T-Cell Origin--A Diagnostic and Histogenetic Problem: A Case Report and Review of the Literature.

A Case Report and Review of the Literature

Anaplastic large cell lymphomas (ALCLs) are characterized by a pleomorphic appearance, sinus growth pattern, and CD30 positivity. These neoplasms are heterogeneous in their cell lineage. Most ALCLs express T-cell antigens, although a few have a B or a non-T/non-B phenotype. The chromosomal abnormality t(2;5)(p23;q35) and the resulting nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) fusion protein and ALK gene dysregulation have been associated with a subgroup of ALCLs. This latter group may show a wide spectrum of morphological patterns, occur more often in younger patient, and have better prognosis than NPM/ALK-negative ALCLs.[1]

The expression of myelomonocytic antigens (CD11c, CD11b, CDw12, CD13, CD14, CD15, CD68, lysozyme, [[Alpha].sub.1]-antitrypsin) in ALCL has been previously reported.[1-8] Approximately 15% to 20% of classic ALCLs express CD15 and often share morphological similarities with Hodgkin disease, which has led to the introduction of the provisional entity called Hodgkin-like or Hodgkin-related ALCL.[1] The expression of myelomonocytic antigens in ALCL often has been associated with diagnostic difficulties. Most of these tumors do not show T- or B-cell-specific markers, raising the question of a possible histiocytic or myeloid origin. Differentiating extramedullary myeloid cell tumors (EMCT; granulocytic sarcoma, chloroma) from ALCLs is of clinical significance. In a series of 90 patients with isolated EMCTs, Imrie et al[9] reported a median survival of 22 months compared with a 5-year survival rate of 65% to 85% for ALCL treated by multiagent chemotherapy.[1] Similarly, differentiating true histiocytic lymphoma from ALCL could be as difficult. In fact, a previous study of 5 cases of true histiocytic lymphoma has shown that 2 cases expressed CD30, with one showing genotypic clonality for both B and T lineages.[10] It is clear that unsettled issues in the nosology, histogenesis, and diagnosis of ALCL, true histiocytic lymphoma, and EMCTs will continue to surface.[11,12] This report documents the diagnostic difficulties that are associated with the expression of CD13 in ALCL of T-cell origin.


A 12-year-old boy presented in March 1999 with a painful lump in the left occipital area, which was initially treated with antibiotics. During the following 2 weeks, additional scalp lesions and a tender swelling over the right jaw appeared. The patient complained of difficulty opening his mouth and developed blisters on the oral mucosa, a 6-lb weight loss, and a 100 [degrees] F temperature. A computed tomographic (CT) scan of the head revealed multiple soft tissue masses with adjacent lytic lesions in the right frontal, left parietal, and bilateral occipital areas. A bone scan revealed increased uptake in these areas of the skull and in the right mandible and left posterior eighth rib. No lymphadenopathy or hepatosplenomegaly was present. Excisional biopsy of a scalp lesion was performed 2 months after the initial presentation, and the specimen showed poorly differentiated loosely cohesive cells, which with initial workup by flow cytometry were thought to represent an EMCT. Further workup proved the tumor to be ALCL. The results of a CT scan of the chest, abdomen, and pelvis were negative. Bone marrow aspirate, biopsy, and cerebrospinal fluid cytologic examinations were negative for malignancy. A complete blood cell count and peripheral blood smear examination were unremarkable. The patient was treated initially with prednisone, vincristine, adriamycin, and intrathecal methotrexate. At the end of induction therapy, a CT scan of the head showed persistence of the right frontal skull and soft tissue lesion, whereas all other lesions were nearly completely resolved. A bone scan revealed again increased uptake in the right frontal, left parietal, and bilateral occipital areas, and a biopsy of the right frontal lesion was negative for malignancy. Maintenance therapy was given, which included 5 cycles with adriamycin, vincristine, prednisone, and 6-mercaptopurine and 10 cycles with methotrexate, vincristine, prednisone, 6-mercaptopurine, and intrathecal methotrexate. After the first 3 cycles of the maintenance therapy, results of a CT scan of the head were normal, and bone scan results were negative. The patient had a complete resolution of all signs and symptoms and was considered to be in a complete remission for 10 months at the time of submission of this manuscript.


The excisional biopsy specimen was fixed in 10% neutral-buffered formalin, embedded in paraffin, cut at 5 [micro]m, and stained with hematoxylin-eosin. The following immunoperoxidase stains were performed using an automatic immunostainer (Dako Corporation, Carpinteria, Calif) and a streptavidin-biotin-peroxidase complex technique (LSAB2 system, Dako): CD15, CD45, CD43, CD45RO (Signet Laboratories Inc, Dedham, Mass), CD20, CD30, CD45R, CD68, epithelial membrane antigen, ALK1, desmin, vimentin, lyzozyme, S100, and myeloperoxidase (Dako). Heat-induced epitope retrieval was performed in a Handy Steamer Plus (Black and Decker) in citrate buffer, pH 6.0 (Dako), for 20 minutes. The tissue sections for lysozyme immunostaining were pretreated with protease (Ventana Medical Systems, Tucson, Ariz), whereas no pretreatment was required for myeloperoxidase immunostain.

Flow cytometric studies were performed on fresh tissue using a FACScan flow cytometer (Becton Dickinson, San Jose, Calif) and the staining procedure recommended by the manufacturer. The following monoclonal antibodies were used: CD3, CD4, CD5, CD7, CD8, CD10, CD13, CD14, CD19, CD22, CD33, CD34, CD45, anti-[Kappa], anti-[Lambda], HLA-DR (Becton Dickinson), terminal deoxynucleotidyl transferase (Dako), and intracytoplasmic CD3 and myeloperoxidase (Caltag, Burlingame, Calif).

Tissue for transmission electron microscopy was fixed in 2% glutaraldehyde and embedded in epoxy resin. Ultrathin sections were stained with lead citrate and uranyl acetate and examined with a Philips CM100 transmission electron microscope.

Genomic DNA was extracted from frozen tissue using a tissue extraction kit (Qiagen, Chatsworth, Calif) according to the manufacturer's directions. Joining region of the heavy chain of immunoglobulin H ([J.sub.H]) and gamma T-cell receptor ([Gamma]-TCR) gene rearrangements were identified by polymerase chain reaction (PCR) assay using a clonality assay kit (IVS Technologies, Carlsbad, Calif) according to the manufacturer's protocol.


Flow Cytometry

This was the first study to be performed. Wright stain of cell suspension showed large loosely cohesive cells, with abundant basophilic cytoplasm, occasional cytoplasmic vacuoles, and mostly round or oval nuclei with occasional prominent single nucleolus. The bright CD45-positive mononuclear cells were gated. Most were HLADR and brightly CD13 positive (Figure 1), suggestive of acute myeloid leukemia. The tumor cells were negative for membrane CD3, CD4, CD5, CD7, CD10, CD8, CD14, CD19, CD22, CD33, CD34, [Kappa] and [Lambda] light chains, and terminal deoxynucleotidyl transferase. Fortunately, our panel included a cytoplasmic CD3-myeloperoxidase cocktail. Tumor cells were cytoplasmic CD3 positive and myeloperoxidase negative. A small number of membrane CD3-positive T cells and CD33-positive myeloid cells were also noted. The ratio between CD4 and CD8 positive cells was 4:1.


Light Microscopy

The hematoxylin-eosin-stained sections showed loosely cohesive large cells with abundant slightly eosinophilic and often vacuolated cytoplasm and ovoid or reniform nuclei with a few small distinct nucleoli (Figure 2, A). There were scattered mitotic figures and areas of necrosis and degeneration. Admixed with the large cells were scattered eosinophils, lymphocytes, neutrophils, and macrophages. The inflammatory cells were more prominent in the zones of necrosis. Histiocytic malignancy, ALCL, and EMCTs were considered.


Electron Microscopy

A population of large cells with slightly irregular, ovoid, or indented nuclei with scant peripheral heterochromatin was identified. Moderate-sized nucleoli were seen in some sections. Those cells had abundant simple cytoplasm, which included a few mitochondria, a small Golgi apparatus, and multiple free polyribosomes. No cytoplasmic granules and no cell processes were found. Scattered lymphocytes and macrophages were also recognized.


Immunohistochemical studies showed strong membrane positivity for CD30 in almost all large cells (Figure 2, B) and strong cytoplasmic and nuclear staining for ALK1 (Figure 2, C). The cells also showed moderate CD45 positivity and strong membrane staining for CD43 and CD45RO. Single tumor cells were epithelial membrane antigen positive. The immunostains for CD15, CD20, CD68, lysozyme, vimentin, S100, and myeloperoxidase were negative. Scattered macrophages were CD68 and lysozyme positive. A small number of CD15- and myeloperoxidase-positive granulocytes and rare CD20-positive small B cells were also seen.

Molecular Studies

In the tissue studied, a polyclonal pattern (ladder or smear) was observed after [J.sub.H] PCR amplification. A clonal pattern, consisting of one band migrating at 250 base pairs (bp), was observed for [Gamma]-TCR PCR. The positive controls provided by the manufacturer showed a single band of 104 bp for the [J.sub.H] PCR and 252 bp for the [Gamma]-TCR.


We describe herein an extranodal ALCL with a T-cell genotype, which strongly expresses CD13 with no T-cell-associated surface markers with the flow cytometry. Similarly, Carbone et al[6] reported a CD13/CD68/lysozyme-positive ALCL in a 44-year-old woman with lymphadenopathy and a CD13/CD68-positive ALCL in a 7-year-old boy with lymphadenopathy and splenomegaly (Table). Those 2 tumors weakly expressed the [Beta] chain of the TCR and were classified as T-cell neoplasms. Weiss et al[13] reported variable CD13 expression in 4 CD30-positive non-Hodgkin lymphomas with histiocytic or immunoblastic appearance. The tumors showed variable expression of T-cell, B-cell, and monocyte/macrophage markers. T- and B-cell--specific antigens were coexpressed in 3 tumors. The molecular studies revealed clonal [Beta]-TCR and/or [Gamma]-TCR gene rearrangements. One of the tumors had an additional monoclonal [Lambda] light chain gene rearrangement.

A Summary of Previous Reports of CD13 Expression in Anaplastic Large Cell Lymphomas of T-Cell Origin(*)
 Age, y/
Source, y Sex Site Diagnosis

Weiss et al,[13] 12/M LN LC-NHL-UL
 1988 15/M ST LC-NHL-UL

Carbone et al,[6] 44/F LN ALCL
 1993 7/M LN ALCL
Simonitsch et al,[8] 12/NR NR MH

Age, y/
Sex Site Immunophenotype

12/M LN CD45, CD3, CD5, CD8, CD9,
 [Beta]F1, CD13, CD25, CD30,
 CD35, CD71, CD74, HLA-DR,
15/M ST CD45, CD1, CD4, CD2, CD7, CD22,
 CD37, [Kappa], [Lambda], CD11b,
 CD11c, CD13, CD14, CD30, CD62L,
 CD74, 41H
18/M LN CD45, CD7, CD20, [Kappa],
 [Lambda], CD13, CD30, CD25,
 CD71, CD74, HLA-DR,
43/M LN CD45, CD4, [Kappa], [Lambda],
 CD13, CD30, CD25, CD71, HLA-DR
44/F LN CD45, CD45RO, [Beta]F1, CD13,
 CD30, CD68, lysozyme, CD74, CDw75,
 CD43, HLA-DR, vimentin, EMA
 7/M LN CD45, CD45RO, [Beta]F1, CD13,
 CD30, CD68, CD74, CD43, HLA-DR,
 vimentin, EMA
12/NR NR CD30, CD11c, CDw12, CD13,
 CD14, CD68, CD68R

Age, y/
Sex Site Genotype Survival

12/M LN [Beta]-TCR NR
15/M ST [Lambda] Light chain NR
 [Beta]- and [Gamma]-TCR
18/M LN [Beta]-TCR NR
43/M LN [Beta]- and [Gamma]-TCR NR
44/F LN ND Alive at 7
 7/M LN ND Alive at 44
12/NR NR [Delta]-TCR NR

(*) NR indicates not reported; LN, lymph node; ST, soft tissue; LC-NHL-UL: large cell non-Hodgkin lymphoma of uncertain lineage; ALCL, anaplastic large cell lymphoma; MH, malignant histiocytosis; [Beta]F1, antibody against T-cell receptor (TCR) [Beta] chain; EMA, epithelial membrane antigen; and ND, not determined.

In this report, ALCL showed strong nuclear and cytoplasmic staining with ALK1 antibody, which recognizes the normal ALK protein and the fusion NPM/ALK protein. This antibody can be used to identify ALK dysregulation, since ALK is not expressed in the normal lymphoid tissue and a good correlation has been reported between the detection of t(2;5) by fluorescent in situ hybridization and the immunostaining with ALK1 antibody.[14,15] The ALK/NPM reciprocal transcripts have been found in several childhood ALCLs, previously diagnosed as malignant histiocytosis, which expressed multiple myelomonocytic markers, including CD13.[8] Most of those tumors were of null type, and only one showed simultaneously CD13 expression and a clonal [Delta]-TCR gene rearrangement. This underscores the diagnostic problems with the subgroup of ALCL expressing myelomonocytic surface markers. Although several cell lines derived from patients with disseminated CD30-positive lymphomas with histiocytic morphologic structure also show expression of multiple myelomonocytic markers, clonal TCR-[Beta] gene rearrangement, and t(2;5) translocation, no clear correlation between ALK abnormalities and expression of myelomonocytic antigens has been established.[12,16,17] The adult ALCLs with myelomonocytic differentiation reported by Simonitsch et al[8] did not show presence of the ALK/NPM reciprocal transcripts.

CD13 (aminopeptidase N) is expressed on myelomonocytic cells during most of the stages of differentiation.[18] CD13 expression can be found during the early stages of B- and T-cell development.[19,20] CD13-positive nonneoplastic T cells have been found in synovial fluid of patients with arthritis, in pericardial fluid of patients undergoing heart valve replacement, among the infiltrating lymphocytes in some cancers, and in benign cutaneous lymphocytic infiltrates.[21,22] Under experimental conditions, induction of CD13 expression in cultured lymphocytes has been achieved by providing a direct contact with CD13-positive cells such as fibroblast-like synoviocytes, epithelial cells, and monocytes or macrophages.[21] This finding is also supported by the study of Saito et al,[23] which showed that CD13 expression in lymphoid leukemia cells depends on their interaction with bone marrow stromal cells. Based on these hypotheses, CD13 expression in ALCL may indicate an origin from a pluripotent stem cell, a misprogramming during malignant transformation, or a microenvironmental effect on antigen expression.

Currently, the clinical significance of CD13 expression in ALCL is unknown. The patient described herein showed very good response to chemotherapy. The 2 patients with CD13/CD68-positive ALCL in the study of Carbone et al[6] also responded well to the conventional therapy and were alive 7 and 44 months after the establishment of the diagnosis.

In summary, we present a case of ALK-positive ALCL of T-cell origin expressing CD13. This case and the review of the literature show that ALCL can demonstrate a variable degree of expression of myelomonocytic antigens. Further studies are necessary to determine the relation between ALK dysregulation and myelomonocytic antigen expression in ALCL.


[1.] Kinney MC, Kadin ME. The pathologic and clinical spectrum of anaplastic large cell lymphoma and correlation with ALK gene dysregulation. Am J Clin Pathol. 1999;111 (suppl 1):S56-S67.

[2.] Jones DB, Gerdes J, Stein H, Wright DH. An investigation of Ki-1 positive large cell lymphoma with antibodies reactive with tissue macrophages. Hematol Oncol. 1986;4:315-322.

[3.] Burns BF, Cripps C, Dardick I. A case of a Ki-1 large cell anaplastic lymphoma with ultrastructural features. Hum Pathol. 1989;20:393-396.

[4.] Oka K, Mori N, Kojima M, Iijima T, Hanada T, Tsuchida M. Childhood Ki-1 lymphoma: a report of two cases. Arch Pathol Lab Med. 1989;113:998-1002.

[5.] Banks PM, Metter J, Allred DC. Anaplastic large cell (Ki-1) lymphoma with histiocytic phenotype simulating carcinoma. Am J Clin Pathol. 1990;94:445-452.

[6.] Carbone A, Glodhini A, Volpe R, Pinto A. KP1 (CD68)-positive large cell lymphomas: a histopathologic and immunophenotypic characterization of 12 cases. Hum Pathol. 1993;24:886-896.

[7.] Sakurai S, Nakajima T, Oyama T, Sano T, Hosomura Y. Anaplastic large cell lymphoma with histiocytic phenotype. Acta Pathol Jpn. 1993;43:142-145.

[8.] Simonitsch I, Panzer-Gruemayer ER, Chali DW, et al. NPM/ALK gene fusion transcripts identify a distinct subgroup of null type Ki-1 positive anaplastic large cell lymphomas. Br J Hematol. 1996;92:886-871.

[9.] Imrie KR, Kovacs MJ, Selby D, et al. Isolated chloroma: the effect of early antileukemic therapy. Ann Intern Med. 1995;123:351-353.

[10.] Hansen CA, Jaszcz W, Kersey JH, et al. True histiocytic lymphoma: histopathologic, immunophenotypic and genotypic analysis. Br J Haematol. 1989;73: 187-198.

[11.] Elghetany MT. True histiocytic lymphoma: is it an entity? Leukemia. 1997; 11:762-764.

[12.] Gogusev J, Nezelof C. Malignant histiocytosis: histologic, cytochemical, chromosomal, and molecular data with a nosologic discussion. Hematol Oncol Clin North Am. 1998;2:445-463.

[13.] Weiss LM, Picker LJ, Copenhaver CM, Warnke RA, Sklar J. Large-cell hematolymphoid neoplasms of uncertain lineage. Hum Pathol. 1988;19:967-973.

[14.] Cataldo KA, Jalal SM, Law ME, et al. Detection of t(2;5) in anaplastic large cell lymphoma: comparison of immunohistochemical studies, FISH, and RT-PCR in paraffin-embedded tissue. Am J Surg Pathol. 1999;23:1386-1392.

[15.] Pilfold K, Lamant L, Morris SW, et at. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood. 1997;89: 1394-1404.

[16.] Fischer P, Nacheva E, Mason D, et al. A Ki-1 (CD30)-positive human cell line (Karpas 299) established from high-grade non-Hodgkin's lymphoma, showing a 2;5 translocation and rearrangement of the T-cell receptor [Beta]-chain gene. Blood. 1988;72:234-240.

[17.] Hsu SM, Hsu PL. Aberrant expression of T cell and B cell markers in myelocyte/monocyte/histiocyte derived lymphoma and leukemia cells: is the infrequent expression of T/B cell markers sufficient to establish a lymphoid origin for non-Hodgkin's Reed-Sternberg cells? Am J Pathol. 1989;134:203-212.

[18.] Drexler HG. Classification of acute myeloid leukemias: a comparison of FAB and immunophenotyping. Leukemia. 1987;1:697-705.

[19.] Syrjala M, Ruutu T, Jansson SE. A flow cytometric assay of CD34-positive cell populations in the bone marrow. Br J Haematol. 1994;88:697-684.

[20.] Spit H, Lanier L, Phillips JH. Development of human T and natural killer cells. Blood. 1995;10:2654-2670.

[21.] Riemann D, Kehlen A, Langner J. CD13-not just a marker in leukemia typing. Immunol Today 1999;20:83-88.

[22.] Dreno B, Bureau B, Stalder JF, Litoux P. MY7 monoclonal antibody for diagnosis of cutaneous T-cell lymphoma. Arch Dermatol. 1990;126:1454-1456.

[23.] Saito M, Kumagai M, Okazaki T, et al. Stromal cell-mediated transcriptional regulation of the CD13/aminopeptidase N gene in leukemic cells. Leukemia. 1995;9:1508-1516.

Accepted for publication May 8, 2000.

From the Departments of Pathology (Drs Popnikolov, Payne, Hudnall, Hawkins, Mr Norris, and Dr Elghetany) and Pediatrics (Dr Kumar), The University of Texas Medical Branch, Galveston, Tex.

Reprints: M. Tarek Elghetany, MD, Department of Pathology, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-0743.
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Author:Popnikolov, Nikolay K.; Payne, Deborah A.; Hudnall, S. David; Hawkins, Hal K.; Kumar, Manjusha; Norr
Publication:Archives of Pathology & Laboratory Medicine
Date:Dec 1, 2000
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