Primary Ki-1-positive anaplastic large-cell lymphoma: A distinct clinicopathologic entity*

Annals of Oncology 5 (Suppl. 1): S25-S30, 1994. © 1994 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Primary Ki-1-positive anaplastic large-cell lymphoma: A distinct clinicopathologic entity* M. E. Kadin Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts, USA

Summary

Introduction

Key words: anaplastic, cutaneous, lymphoma, T-cell

Clinical features

The history of Ki-1 + ALCL began in 1982 with the Patients with Ki-1 + ALCL are generally younger than production of a monoclonal antibody, Ki-1 (CD 30), most other patients with NHL. Median or mean ages of specific for Hodgkin and Reed-Sternberg (RS) cells of under 45 years were reported in 3 recent studies of 30 HD and a subset of normal lymphoid cells located be- or more patients [4-7]; one study with a median age of tween, around, and sometimes within B-cell follicles 44 years did not include patients under 16 [7]. A bi[1]. Further evaluation of the Ki-1 antibody showed modal age distribution, similar to HD, has been obthat it also reacts with a subset of large-cell non-Hodg- served [4-6, 8]. However, the peak age incidence of Kikin's lymphomas (NHLs), which have subsequently 1 + ALCL is in the second decade [4-6], whereas the been termed ALCL and include cases previously desig- peak in HD is in the third decade [9]. A smaller second nated as malignant histiocytosis [2]. We found that Ki- peak after age 60 has been observed in both Ki-1 + 1 + ALCL frequently occurs in children with skin ALCL and HD [4-6, 8,9]. The male/female ratio was lesions and peripheral lymphadenopathy and suggested 1.65 :1 in one series of Ki-1 + ALCL cases [8], and was that early therapy might result in prolonged survival [3]. 1.9:1 in the latest series studied by Greet and colA number of studies carried out in the past decade leagues (personal communication). have further defined the characteristics of Ki-1 + The distinction of primary from secondary Ki-1 + ALCL. The results of these studies are summarized ALCL is important because primary Ki-1 + ALCL has below. a better prognosis (see below). Secondary Ki-1 + ALCL occurs in the progression of some low-grade lymphoproliferative disorders, including lymphomatoid papu• This work was supported by the Beth Israel Hospital Pathology Foundation, NIH grant CA54062, and the Council for Tobacco losis, mycosis fungoides, and angioimmunoblastic lymphadenopathy, derived from T-cells; follicular lymResearch grant 2630.

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The morphology of anaplastic large-cell lymphoma (ALCL) is associated with a clinical syndrome of peripheral lymphadenopathy (>80%) and frequent extranodal disease (>40%) in children and young adults (median age <40 yrs.). Skin lesions occur in more than 20% of patients; other extranodal sites are bone, soft tissue, gastro-intestinal tract, lung, and pleura. Marrow involvement is infrequent (<10%). Features that distinguish ALCL from Hodgkin's disease (HD) are noncontiguous nodal disease (>50%), infrequent mediastinal mass (<20%), and frequent inguinal lymphadenopathy (>40%). Most patients present with stage III/rV disease. Stage is highly predictive of achieving complete remission, disease-free survival, and overall survival. Localized skin lesions have an excellent prognosis and occasional spontaneous regressions are noted. Distinctive histopathologic features of ALCL are partial lymph node involvement with sinus infiltration, sparing of B-cell regions, and tumor cell pleomorphism. Other features are high mitotic rate, necrosis, fibrosis, and plasma cell infiltrates. Morphologic variants of

ALCL resemble carcinoma, syncytial variant of nodular sclerosing HD, true histiocytic lymphoma or interdigitating cell sarcoma, and mycosis fungoides. ALCL can be distinguished from these morphologically similar disorders by immunophenotype (CD30+, CD45 + , CD15", EMA + , BNH9+, keratin", lysozyme"). A recurrent cytogenetic translocation, t(2; 5) (p23; q35), has been observed among morphologic variants, including a small-cell-predominant variant and tumor cell line which contains a spectrum of small cerebriform and large anaplastic CD30 + cells. 70% of ALCL cases are of T-cell lineage, 15% B, 5% T/B, and 10% undefined. ALCL appears to be distinct from peripheral T-cell lymphomas such as HTLV-1+ adult T-cell leukemia, angioimmunoblastic lymphadenopathy, angiocentric T-cell lymphoma, and mycosis fungoides, which occur mainly in older patients. These combined clinical, pathologic, immunophenotypic, and cytogenetic observations support the concept that ALCL is a distinct clinicopathologic entity.

26 Histopathology

A distinctive histopathology has been described for ALCL (Fig. 1). Stein and colleagues emphasized the preferential paracortical involvement of lymph nodes, foci of necrosis, and intrasinusoidal dissemination of tumor cells [2]. They described a cytological spectrum ranging from large cells with pleomorphic nuclei, clumped heterochromatin, one or more nucleoli, and abundant, often vacuolated cytoplasm, to cells with more regular, rounded vesicular nuclei with basophilic cytoplasm. Additional morphologic features of ALCL are high mitotic rate, variable fibrosis, infiltrates of plasma cells, or histiocytes [19, 20]. Eosinophils and neutrophils are present in varying amounts, being most frequent in cutaneous ALCL. Several morphologic variants of ALCL have been described, including pleomorphic and monomorphic [13], pale cell and basophilic cell [21], sarcomatoid [22], and ALCL with high content of reactive histiocytes [20]. Kinney and colleagues recently described a smallcell variant of primary Ki-1 + T-cell lymphoma with a minor content of large anaplastic cells [23]. Histologic progression to ALCL suggests that the small-cell variant is part of the spectrum of Ki-1 + ALCL. This concept is supported by the presence of a spectrum of small lymphocytes with irregular nuclei and large anaplastic cells in a clonal T-cell line developed in our laboratory from a child with ALCL (Fig. 2) [24]. The morphologic variability within the spectrum of Ki-1+ ALCL can pose a difficult diagnostic problem. Among the disorders commonly confused with ALCL pathologically are poorly differentiated carcinoma; melanoma; HD, especially the syncytial variant of nodular sclerosis; and true histiocytic lymphoma, or sarcoma of interdigitating reticulum cells. I mmu nophenotype

The differentia] diagnosis of ALCL from morphologically similar disorders usually can be resolved by

Fig. 1. Distinctive cytopathology of Ki-1+ ALCL.

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phoma derived from B-cells; and HD [8, 10]. Because secondary Ki-1 + ALCL follows a prior lymphoma, it has a later peak age incidence than primary Ki-1 + ALCL in the fifth decade [8]. Peripheral lymphadenopathy is the most common presenting site of Ki-1 + ALCL at clinical presentation, occurring in 80% of patients [5]. Mediastinal lymphadenopathy is much less frequent (<20%) [5, 6], compared with 60% in HD [11]. Nodal disease was found to be non-contiguous in more than 50% of patients with Ki-1 + ALCL [5], whereas contiguous nodal disease is highly characteristic of HD [11]. In contrast to HD, in which inguinal lymph nodes are involved in about 5% of patients [11], inguinal lymph nodes were involved in more than 40% of children with disseminated Ki-1 + ALCL [12]. Enlarged lymph nodes are often tender, and spontaneous regression, or waxing and waning of nodes, is sometimes observed [5,6]. Extranodal disease is common in Ki-1 + ALCL, occurring in 25% [13], 30% [6], 42% [5], and 65% [7] of patients. Skin lesions, often showing inflammation, occur in more than 20% of patients [2-4]. Other extranodal sites are bone, soft tissue, gastrointestinal tract, liver, lung, and pleura [5-7, 12, 14]. Bone marrow involvement is infrequent (<10%) [5-7]. In one study, bone marrow involvement was more often seen in patients with relatively monomorphic as opposed to anaplastic Ki-1 + large-cell lymphomas [13]. Most patients with Ki-1 + ALCL present with stage III or stage IV disease [5, 7]. Systemic B symptoms were observed in 39-42% of patients [5, 8]. Clinical stage at presentation was found to be highly predictive of achieving a complete remission, freedom from progression, and overall survival [5,7]. Nakamura and colleagues found that 29 Japanese ALCL patients had a five-year survival rate of 52% which was significantly better than that for other high-grade node-based T-cell lymphomas, but not significantly different than that for node-based low-grade T-cell lymphomas or HD [6]. Localized skin lesions of Ki-1 + ALCL have an excellent prognosis. Kaudewitz and colleagues found that the favorable prognosis was associated only with primary cutaneous ALCL [10]. Belgaards and colleagues found expression of the Ki-1 (CD30) antigen was more significant than the specific histologic type in predicting the favorable prognosis of primary cutaneous large-cell lymphomas [15]. Some patients with Ki-1 + ALCL have unusually long survivals with spontaneous or treatment-induced regression and several recurrences [16]. Greer and colleagues noted that few patients with Ki-1 + ALCL, particularly those with localized skin lesions, have an indolent course while others, especially those with stage IV disease, have a fulminant course which is difficult to recognize pathologically [17]. Bone marrow transplantation has been effective salvage therapy for chemotherapy resistant Ki-1 + ALCL, achieving complete remissions in about one-half of pediatric [18] and adult patients [5,7].

27

rant T-cell phenotype, which is characteristic of T-ceU malignancies [31]. In our experience, CD2 and CD4 are commonly preserved in ALCL, whereas T-cellreceptor (TCR-) associated antigens CD3 and Bfl are frequently not detected [19]. Molecular genotype and cytogenetics

Table I. Markers in differential diagnosis of ALCL.

ALCL HD Carcinoma Histiocytosis

CD15

+ +

-/+ +/© - / +

© -

—

+/—

+

-

-

CD45

Antigens EMA BNH.9 Lysozyme

CD30

— -

-

©

-

-/+ -

—

—

©

©

-

-

-

Keratin

© = Distinguishing marker.

immunophenotypic studies (Table 1) [4, 19]. Most types of ALCL express EMA, CD25, CD71, HLADR, CD45, and blood group H & Y determinants recognized by antibody BNH9 [25], and do not express CD15. Expression of EMA, BNH9, and CD45, and lack of CD 15 facilitates the distinction of ALCL from HD [4, 19]. Expression of CD 30 and usual absence of cytokeratin enables the distinction of ALCL from most carcinomas, although embryonal carcinomas [26] and some pancreatic carcinomas [27] express CD30 + , and cytokeratin expression has been detected in ALCL [28]. Expression of CD30 and absence of lysozyme favors a diagnosis of ALCL over true histiocytic neoplasm. It should be noted that up to one-third of cases of ALCL lack CD45 in paraffin tissues [29], and CD15 may be detected in some ALCLs [30]. Correlation with T- and B-cell markers, histopathology, and clinical features should always be done to avoid mistaken diagnoses of ALCL. Whenever possible, frozen sections should be used to detect antigens that may not be preserved in fixed paraffin-embedded tissues. Antibody Ber-H2 detects a formalin-resistant epitope of CD30 which can be detected in paraffin sections [27]. This epitope usually does not survive fixation in B5, which is widely used by American hematopathologists. Most cases of ALCL have a T-cell phenotype [2,3, 5-8, 13, 19]. However, one or more common T-cell antigens usually are not expressed, resulting in an aber-

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F/g. 2. Clonal T-cell line (JB6) from 12-year-old child with ALCL. Note spectrum of small and large anaplastic cells.

In a molecular analysis of DNA from 30 large-cell lymphomas which express the CD30 antigen, O'Connor and colleagues found clonal rearrangements of TCR genes in 16, of immunoglobulin (Ig) genes in 6, and no rearrangements in 8 cases [32]. Herbst and colleagues found that 15 of 22 Ki-1 + ALCL exhibited rearrangement of Ig and/or TCR genes [33]. A recurrent reciprocal translocation, t(2; 5) (p23; q35), has been noted in permanent cell lines [34, 35] and fresh tumor cell suspensions [36, 37] of ALCL and so-called malignant histiocytosis [38]. However, not all cases have shown the same translocation. In some cases, translocations between 5q35 and chromosomes 3 [35] or 6 [38] have been observed. Sainati and colleagues demonstrated a novel translocation t(2; 13) (p23; q34) in a Ki-1 + ALCL [39]. Ohno and colleagues found a t(9; 14) (pl3; q32) in a diffuse ALCL which expressed CD30 and had an immunoglobulin gene rearrangement [40]. Morgan and colleagues showed lack of involvement of c-fms at 5q35, and no involvement of N-myc at 2p23 in three malignancies with features of so-called malignant histiocytosis [41]. Lack of the t(2; 5) or other translocations involving 5q35 has been found in Ki-1 + LCLs which do not have clinical features and morphology of ALCL. Bitter and colleagues showed that the translocation t(2; 5) (p23; q35) is characteristic of young patients with Ki-1 + ALCL who have peripheral lymphadenopathy, skin disease, and a favorable prognosis [42]. Patients with Ki-1 + lymphomas which lacked this translocation had non-ALCL, heterogeneous clinical findings, and a poor response to systemic chemotherapy. Offit and colleagues showed that non-B-cell lymphomas which had CD30 expression and translocations involving 5q35 were associated with young age, skin involvement, and a favorable clinical outcome [43]. Gordon and colleagues indicated the presence of the t(2; 5) in three pediatric Ki-1 + peripheral T-cell lymphomas without the typical pathology of ALCL [44]. Kinney and colleagues demonstrated the t(2; 5) in each of four Ki-1 + T-cell lymphomas which had a majority of small irregular lymphocytes and a minor population of CD30+ large anaplastic cells [23]. In two cases of this small-cell variant, there was histologic progression to a monomorphic ALCL. These cases raise the question whether the t(2; 5) is specific for ALCL or is associated with peripheral T-cell lymphomas, which commonly have this pathology.

28 Table 2. Comparison of ALCL and other PTCL. Clinical

Pathology

Genetics

ALCL

Bimodal peak in

Lymphadenopathy in >80% Extranodal lesions in >40%

Large anaplastic cells; sinus and paracortical infiltration of lymph nodes; Nonepidermotropic skin lesions

t(2; 5)

ATL

Adults only; peak in 5th decade

Leukemia; hypercalcemia; lytic bone lesions; lymphadenopathy; skin lesions

Diffuse infiltration of LN, sinuses spared; epidermotropism in 50%; multilobated nuclei of tumor cells

14q+ (14q32)

AILD

80% of patients over age 50

Hypergamaglobulinemia; immune hemolytic anemia; generalized lymphadenopathy; skin rash

Arborizing postcapillary venules; regressive germinal centers; polymorphic cytology

Trisomies 3, 5, and 7

AIL

Median age 50 years; rare in patients under age 20

Destructive lesions of lungs, upper respiratory tract, CNS, and skin; absence of nodal disease

Angiocentric/angiodestructive infiltrate, necrosis; mid and deep dermal skin infiltrates; spectrum of lymphoid cells

Not defined

CTCL

Rare in children; peak in 6th to 7th decade

Primary skin lesions consist of multiple patches or plaques; skin tumors in advanced disease

Epidermotropic lymphocytes with cerebriform nuclei; paracortical infiltration of lymph nodes in advanced disease

No consistent abnormality

ALCL = Anaplastic large-cell lymphoma. ATL = Adult T-cell leukemia/lymphoma. AILD = Angioimmunoblastic lymphadenopathy.

AIL = Angiocentric immunoproliferative lesions/lymphoma. CTCL = Cutaneous T-cell lymphoma (mycosis fungoides). PTCL = Peripheral T-cell lymphoma.

mosomes 3 and 5 are the most common genetic abnormalities found in AILD [51]. Distinction of ALCL from other peripheral T-cell lymAngiocentric lymphomas are associated with an phomas angiodestructive histology and a clinical syndrome of lesions in the lung and upper respiratory tract which Some have argued that Ki-1 + ALCL is simply a peri- are not characteristic of ALCL [52]. In ALCL, CD30 + pheral T-cell lymphoma [44]. However, ALCL appears cells can have a perivascular and/or intravascular disto have clinical and pathologic characteristics which tribution, but destruction of blood vessels is not seen distinguish it from other peripheral T-cell lymphomas [23,53]. (Table 2). Survival of Japanese patients with ALCL was Because of the frequent skin involvement, there are significantly better than that of patients with other overlapping clinical features of ALCL and mycosis funhigh-grade node-based peripheral T-cell lymphomas in goides. However, the lesions of mycosis fungoides are the study by Nakamura and colleagues [6]. usually epidermotropic and comprise small- to mediumALCL differs from adult T-cell leukemia (ATL), sized cells with highly convoluted or cerebriform nuclei which has a more restricted age and geographic distri- and few or no large CD30+ cells, whereas skin lesions bution, leukemic tumor cells with lobulated nuclei, of ALCL usually are nonepidermotropic and contain hypercalcemia, short survival, and consistent associa- mostly large CD30+ cells. Skin tumors, typical of primation with HTLV-1 [45, 46]. In contrast, ALCL has a ry ALCL, are uncommon in mycosis fungoides and worldwide distribution, is rarely leukemic, is not asso- usually indicative of advanced disease or progression to ciated with hypercalcemia, and HTLV-1 has been de- secondary Ki-1 + ALCL [10]. The t(2; 5) characteristic tected only in a few cutaneous lesions [47]. The t(2; 5) of ALCL has not been reported in ATL, AILD, angiohas not been reported in ATL in which translocations centric T-cell lymphomas, or mycosis fungoides [54]. involving 14q32 are commonly found [48]. In summary, these combined clinical, pathologic, imALCL lacks the characteristic histopathology and munophenotypic, and cytogenetic observations supclinical features of angioimmunoblastic lymphadeno- port the concept that ALCL is a distinct clinicopathopathy (AILD) [49, 50]. AILD has a prominent vascula- logic entity. ture (abundance of postcapillary venules) and usually absent or regressive 'burned out' germinal centers, features lacking in ALCL. AILD lacks the sinus distribu- Acknowledgements tion and pleomorphism of tumor cells in ALCL. Patients with AILD generally are older and have hyper- I would like to thank Andreas Chott, M.D., and John gammaglobulinemia and an autoimmune hemolytic Greer, M.D., for their thoughtful review of the manuanemia, which are absent in ALCL. Trisomies of chro- script. Discussion

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Age incidence

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25. 26. 27. 28.

29.

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34.

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Correspondence to: Marshall E. Kadin, M.D. Department of Clinical Pathology, YA-309 Beth Israel Hospital 330 Brookline Avenue Boston, Massachusetts 02215 USA

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