Acta Clinica Belgica International Journal of Clinical and Laboratory Medicine

ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20

Large Cell Anaplastic Lymphoma (Ki-1 Lymphoma) D. Ebo & A. Van Hoof To cite this article: D. Ebo & A. Van Hoof (1992) Large Cell Anaplastic Lymphoma (Ki-1 Lymphoma), Acta Clinica Belgica, 47:3, 170-177, DOI: 10.1080/17843286.1992.11718227 To link to this article: http://dx.doi.org/10.1080/17843286.1992.11718227

Published online: 16 May 2016.

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LARGE CELL ANAPLASTIC LYMPHOMA (Ki-1 LYMPHOMA)

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0 . Ebo, A. Van Hoof*

SUMMARY The «large cell anaplastic lymphoma, Ki-I positi ve» is a recently described lymphoma subtype (about 1-8 % of all NHL). Distinction from Hodgk in' s disease and true histiocytic lymphoma/malignant hi tiocytosis is not always possible, even by experienced pathologists. It was recently incorporated in the updated Kiel Classification of lymphomas. Classical histologic appearance is a sinusoidal growth pattern in lymph nodes and presence of large bizarre anaplasti c cells. Use of cell markers LCA, EMA and Ki-Ior Ber-H2 is essential for diagnosis. The mean age of patients is 50 years. Approximately 50% of patients have an advanced stage (Ill-JV). Prognosis depends on age and tumor locali sations. Cutaneous involvement only is usually associated with a good prognosis. Median survival for patients with extra-cutaneous di sease is 13 months. Treatment with intensive chemotherapy is usually needed. Long term remissions are more frequently seen in children and adolescents.

Further studies have shown that the Ki-I (CD30) antigen is also expressed by a varying proportion of activated T and B cells, macrophages and the majority of the tumor cells of the so called Large Cell Anapl astic Lymphoma (LCAL). This new group ofnon Hodgkin' s Lymphomas (NHL) has characteristic cytomorphological and antigenic features. It was first published by H. Stein and coworkers in 1985 (2), and was subsequently incorporated in the updated Kiel Classification (3) (table I). This type of lymphoma is actually more often recognized. It is still not entirely clear whether LCAL is really a new entity or merely represents a subtype of some well known types of large cell lymphoma. Its relationship to Hodgki n's disease, malignant hi stocytosis, true histiocytic lymphoma and certain prelymphomas is still a matter of di scussion. We present a patient with a typical LCAL - Ki-I positive - and a review of the literature.

Acta Clin Belg. 47, 3: 170-7 INTRODUCTION Ber-H2 is a monoclonal antibody developed by H. Stein and coworkers that reacts with a membrane glycoprotein which was initially designated as Ki-I and later as CD30 at the Third International Workshop on Human Leucocyte Differenti ation Antigens (Oxford 1986). In 1982, the Ki-I antibody was reported to mark pecifically the neopl astic cells of Hodgkin 's di sease ( I).

* Hematology A.Z. St.-Jan, 8000 Brugge, Belgium. Reprints: A. Van Hoof. Acta Clinica Belgica 47.3 ( 1992)

CASE REPORT The patient was a caucasian female, 66 years old when she was referred. Two months before admission she started complaining of anorexia, fever, ni ght sweats and progressive weight loss. She noted the appearance of pink blue skin indurations which initially seemed to di sappear spontaneously. On physical examination some subcutaneous noduli were found on the left hemiabdomen and arms. Lymph nodes were not enlarged, there was no hepatospl enomegaly. There was slight proptosis of the right eye. Biopsy of an ulcerative skin lesion showed a

LARGE CELLANAPLASTIC LYMPHOMA (Ki- I LYMPHOMA)

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TABLE I: UPDATED KIEL CLASSIFICATION ( 1988)

B cell type

T cell type

Low Grade malignancy

Low Grade malignancy

- Lymphocytic : chronic lymphocytic, prolymphocytic, hairy cell leukaemia

- Lymphocytic : chronic lymphocytic, prolymphocytic - Small cerebriform cell (mycosis fungoides, Sezary syndrome)

- Lymphoplasmacytic/cytoid - Plasmacytic - Centroblastic-centrocytic follicular-diffuse, diffuse - Centrocytic

- Lymphoepitheloid (Lennert's) - Angioimmunoblastic - T-zone, pleiomorphic, small cell (HTL V+)

High Grade malignancy

High Grade malignancy - Pleiomorphic, medium and large - lmmunoblastic - LCAL Ki-I+ - Lymphoblastic

-

Centroblastic Immunoblastic LCAL Ki-I+ Lymphoblastic

Rare type

Rare type

Fig I: Large mononuclear anap/astic cells, some showing mitotic activity (x 400) Acta Clinica Belgica 47.3 ( 1992)

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LARGE CELLANAPLASTIC LYMPHOMA (Ki- I LYMPHOMA )

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homogeneous popul ation of large malignant lymphoid cells wilh irregular nuclei containing prominent nucleoli (fig I). The cytoplasm was abundant, pale or sli ghtl y basophilic: The tumor ce ll s stai ned posi ti ve with LCA (leucocy te common antigen) and were . Ki -I positive. The diagnosis ofLCAL was made. No karyotyping or analysis of the T-cell receptor gene was done.

Inten sive combination chemotherapy (Cyc lophospham ide, Adriamycin, Vm-26, Bleomycin, Yincristin , Corticosteroids) induced an impressive but very short regression of the tumor. Multiorgan fa ilure developed and patient died three months after the start of the treatment.

intestinal tract. Cutaneous involvement with or withoutextracutaneous lesions has been described in children, adol escents and adults. These ski n lesions are often present as pai nful noduli or ulcerations with signs of inflammati on and can simulate a non-neoplastic process especially when they tend to or do di sappear spontaneously (810). A subset of patients showing on ly cutaneous involvement at diagnosis has pursued an indolent course or has shown a considerable improved prognosis after prompt recognition and early treatment with chemotherapy. About 50% of all patients are in stage III or IV at di agnos is. With regard to lymphoma, involvemen t of skin , lun g and bones and gastrointestinal tract seems unexpectedly frequent. In 3 1 children studied by Heitger et al. ( 11 ), 77 % had stage Ill -IV , 26 % had sk.in infiltrati on. Involvement of lungs, bone and bone marrow was seen in resp. 20 %, 6 % and 13 %. CNS invol;vement was rare (I patient). Of the 13 children studi ed by Yechi et al. , 38 % had stage III -IV. Skin invol vement was found in 3/1 3 (6). Whencomparingclinicaldatafrom 16 LCAL pati ents with 32 large cell NHL patients, Piris et al. (5) however could find no significant differences with regard to age at presentati on, sex or clinical signs. These authors doubt the value of differentiating LCAL from other hi gh-grade malignant lymphomas.

CLINICAL FEATURES AND BEHA YI OUR

HISTOPATHOLOGY

This di sea e is relatively rare. Among the first 1000 patients included in the French GELAtreatment protocol for aggressive lymphomas, 72 cases were classified as LCAL (4). From a series of 500 lymphomas, Piris et al. were able to diagnose 17 as typical LCAL (5). In a pediatric population, the incidence may be higher (16 %) (6). It shows a male predominance, with a male/ female ratio of about 2.2 : I. There is a striking bimodal age di stribution with a peak frequency at the 2nd and 8th decade (7). Most patients present with a solitary tumor or multiple tumor masses involving lymph nodes, ski n, bone and gastro-

The classical appearance of a LCAL is a si nu soidal pattern of growth wi thin lymph nodes and the presence of large bizarre anaplastic ce lls (fig. I and 2) ( 12, 17).

Laboratory data showed a moderate leucopenia (white cell count: 2.3. 109 /1) and thrombocytopeni a (93.109/ I), a low grade diffu se intravascular coagul ation (fibrinogen: I. I g/I ; FOP 40 µg/ml) and a very high LOH level ( 1300 TU/ml ). A syndrome of inappropriate ADH-secretion was also present (sodium 122 mEq/I , serum creatinine 0.9 mg/di , urine osmol ality 590 mOsm/kg). Bone marrow aspiration and bone biopsy were normal. A ma lignant pleural effusion was present. Tu moral infiltration of the right retroorbital region was con firmed with CT and NMR scan. CNS infiltration could not be shown (normal CT scan, normal cerebrospinal fluid ).

Acra Clinica Belgica 47.3 ( 1992)

Smears stained with a May-Griinwald-Giemsa stain show a cytomorphologic spectrum that vari es from immuno-blastlike cell s to bizarre anaplastic variants. Some authors have tried to delineate two distinct morphological types (7). This distinction is actually however not widely accepted, but could have some prognostic importance.

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LARGE CELLANAPLAST/C LYMPHOMA (Ki- I LYMPHOMA)

Fig. 2: Lymph node showing sinusoidal infiltration by large blastic cells (x JOO)

The type I (pale) cell measures approxim ately 10-30 um in diameter, and is polygonal. It has a di stin ct pink-s tainin g ce ll membran e we ll demarcated from the hi ghtly amphophilic or pale cytopl asm. Mostly the nucl ei are round to oval, so me however show irregul ar folding s. The nucleo li are multiple and prominent. Th e chromatin is coarse with marked clearing. Type II (basophilic) cell meas ures approximately 15-50/ in di ameter, is quite round Lo ova l. The cell membrane is less well demarcated from an abundant deeply arnphophilic cytoplasm which freq uentl y present a paranucleair pale zone. Usually the nuclei are more irreg ul ar and lobul ated. The nucleoli are prominent and multi ple, occasionally solitary and inclusion-like. Hi stopathologic features include usually incomplete lymphnode invol vement by the neoplastic proces resulting in partial or subtotal effacement of the node architecture. Preferentially para-cortical involvement with frequently intrasinusoidal di ssemination is seen. Foci of necrosis can be observed. The residual small follicles remain intact while they are surrounded by

scattered tumor cells that can infiltrate thei r mantles. Fibrosis in the form of capsular thickening, parenchymal fibrou s bands and delicate reticulin fibers is less striking but nevertheless frequent. A more rare presentation consists of a more diffu se involvement of the lymphoreticul ar system appearing as a reactive haemophagocytic syndrome. In some cases, a high content of reactive hi stiocytes was described ( 13). IMMUNOHISTOCHEMISTRY Immunohi stochemical analysis of thi s type of anap lastic tumors by means of monoclon al antibod ies is esse nti al for diagnosis (14). Typically tumor cells should stain positively for the Ki -I (C D30) antigen when using the Ki -I or the Ber-H2 antibody. On fro zen sections the Kil antibody strongly labels Hodgkin 's and ReedStemberg cell s, most large cell anaplastic lymphomas and all cases oflymphomatoid papulosis, a self healing non malignant cutaneous eruption. Other types of lymphomas are not labeled except for some peripheral T cell lymphomas (both HTLVl -positive and negative), including those Acta C/inica Belgica 47.3 ( 1992)

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LARGE CELL ANA PLASTIC LYMPHOMA (Ki- I LYMPHOMA)

of angioimmunoblastic type and Lennert' s type. B-immunoblastic lymphomas are only rarely positive. In a study by Offit et al. 12 out of 20 diffuse large cell non-B cell lymphomas were positive for Ki-I (15). OveraJ J, ~he CD30 antigen is normally found in about 15 % or Jess of unselected non-Hodgkin's lymphoma cases. In normal lymphoid tissue, it labels a small population oflarge cells, preferentially localized arround B cell follicles and in some instances at the rim of germinaJ centers.No consistent data are avai !able about the normal function of this CD30-positive lymphocyte subset in normal lymph nodes. Outside the lymphoid tissue it stains only acinar cells of the pancreas and occasionally carcinomas derived from these cells. The Ber-H2 antibody against the Ki-I (CD30) antigen can be used in routinely processed paraffin sections. It labels the CD30 antigen in a similar pattern. The staining is most intense on the cell surface membrane, but in addition dotlike labelling in the Golgi region is often seen, reflecting the processing pathway oftheCD30 glycoprotein. In contrast to frozen sections Ber-H2 also stains a proportion of plasmacells. Most studies of LCAL emphasized the tendency of these tumors to express a variety of «activation» markers including HLA DR, CD25 (Il-2 receptor) and CD71 (transferrin receptor). The tumor cells not infrequently (+40%)alsostain positive forEMA (epitheloid membrane antigen) and should be positive for LCA. To complicate things however not all LCAL are LCA positive. Lack of LCA expression is frequently associated with extreme Joss of differentiation antigens. CD30 expression can also occur in embryonal carcinoma and mycosis fungoides. Moreover, some lymphomas in which nearly all of the neoplastic cells are Ki l positive have morphologic features that can differ from LCAL (16). The LCAL are heterogeneous in their cell lineage and include T, B or nuJI ceJl lymphomas. Approximately 55-70% of these lymphomas show clearly or incomplete T eel characteristics. The Acta Clinica Belgica 47.3 ( 1992)

remaining 30-45% can equally be devided in B cell or nu JI cell malignancy (7, 17). Coexpression of both Band T cell markers is rarely seen (4, 6). Some cases express histiocyte-associated markers (CD68, alpha-1-antitrypsin); this shows that LCAL has considerable immunophenotypic heterogeneity ( 18). DIAGNOSIS DIAGNOSIS

AND

DIFFERENTIAL

I

LCAL has to be differentiated from some nonhematological neoplasms such as anaplastic carcinoma and malignant melanoma. In addition, some types of Hodgkin 's di sease can cause confusion especially the syncitial variant of the nodular sclerosing type and the lymphocyte depleted type with bizarre Reed-Sternberg cells. Infiltration in the subcapsular lymph node sinuses and appearance of monomorphous sheets of tumor cells - often with a histiocyte-like appearance are usuaJly not found in Hodgkin' s di sease. Additional staining for LCA, Ki-I, Vimentin, Cytokeratin and SI 00 may be helpful in difficult cases. It should be emphasized that both anaplastic carcinoma and lymphoma may stain positive for EMA. Even by extensive immunochemistry however, LCAL can not always be distinguished from true histiocytic lymphoma, malignanthi stiocytosis ( 19) and certain variants of Hodgki n' s di sease (20). Jn addition, the mere presence of CD 30 antigen is not suffi cient for classifying a case of Iymphoma as LCAL. It should have both the typical histological and cytological features already di scussed. Some NHL in which nearly all the neoplastic ceJls are Ki-I positive, do have morphologic features that differ from LCAL. These cases should not be regarded as typical LCAL since the clinical picture, karyotype and outcome are different ( 16). LCAL: A CHARACTERISTIC KARYOTYPE? An abnormality involving the long arm of chromosome 5 or 6 can be associated with the LCAL lymphoma (16, 21, 22).

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LARGE CELLANAPLASTIC LYMPHOMA (Ki-I LYMPHOMA)

Abnonnalities of the long arm of chromosome 6 are more often associated with a B-phenotype, while chromosome 5 abnonnalities are apparently more often associated with a T cell phenotype. In a series of 12 Ki-I positive non-B-cell NH Ls, five (42 %) had a reciprocal translocation involving chromosomes 2 and 5 (23). The region involved in the chromosome 5 translocation is at band q35 and is close to position of the c-fms gene which encodes a receptor for macrophage growth factor (M-CSF). An abnormality affecting thi s gene might possibly play a causate role in LCAL. However, recent studies concerning DNA-restriction fragment analysis in one case showed no evidence that the breakpoint involves the fm sgene or its immediate vicinity (22). The same abnormalities of chromosome 6 and 5 have been described for Hodgki n' s disease and true histiocytic lymphoma. Thi s suggests that certain variants of these diseases might in fact be identical to LCAL or might belong to a spectrum of closely related di sorders.

Ki- I (CD30) : A TUMORMARKER ? Recently e nzyme-linked immunoso rbe nt assays (ELISA) has been developed that allows the quantitative detennination of the Ki -I (CD 30) antigen in soluble form. Preliminary results suggest that the Ki-I antigen may be used as a serum tumor marker (24) .. Pizzolo et al. (25) found detectable level s in 24 out of 50 patients (48%) with active Hodgkin' s disease, whereas it was absent in control sera and in cases in complete remi ssion. A possible role for serum CD 30 as a tumor marker in Hodgki n' s disease is therefore suggested .

THERAPY, RESPONSE AND PROGNOSIS There is still a debate goi ng in the literature on whether or not this LCAL always carries a bad prognosis . A short-term follow up study of adult patients

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(5) revealed that fort he first 2 years after diagnosis there were no differences in patient survival between LCAL patients and patiens with large cell NHL. For patients with non cutaneous presentation, the prognosis is relatively good for young (< 40 years) patients treated with intensive chemotherapy(l I, 12). 74 %ofchildrenremained in first complete remi ssion with a median observation time of 2.8 years after treatment with various types of intensive chemo-therapy ( 11) . The overall median survival of adult patients refe ring to different studies is about 13 months. Age (

Large cell anaplastic lymphoma (Ki-1 lymphoma).

The "large cell anaplastic lymphoma, Ki-1 positive" is a recently described lymphoma subtype (about 1-8% of all NHL). Distinction from Hodgkin's disea...
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