Clusterin, Apolipoprotein J (apo J), SGP-2, SP 40-40, CLI, pADHC-9, complement lysis inhibitor, gp80, glycoprotein III, T64
Clusterin was identified using gene array technology for the recognition of tumor-specific markers in lymphoid neoplasms6. The name derives from ability to induce clustering of Sertoli cells. It is a 75-80 kDa heterodimeric glycoprotein encoded by a gene localised on chromosome 8q21 and having a nearly ubiquitous tissue distribution, being produced by a wide array of tissues, on the surface of cells lining body cavities and is found in most biologic fluids. Truncated forms targeted to the nucleus have also been identified. A number of physiologic functions have been proposed for clusterin based on its distribution and its in vitro properties. These multiple functions include complement regulation, lipid transport, sperm maturation, the inhibition of complement-mediated cell lysis, endocrine secretion, membrane protection, and promotion of cell interactions. Overexpression or underexpression has been implicated in a range of disease including various cancers, glomerulonephritis, polycystic renal disease, renal tubular injury, mammary gland involution, infertility, neurodegenerative conditions including Alzheimer's disease, atherosclerosis, and myocardial infarction. Recent studies of knockout mice have implicated clusterin in exacerbating neuronal death in hypoxia-ischemia. The question of whether clusterin is a multifunctional protein, or has a single primary function influenced by cellular context, remains a central issue3. On the basis of its elevated expression in apoptotic tissues, it was originally proposed that the protein might be casually involved in apoptosis. However, more recent data has been interpreted to suggest that clusterin expression is not enhanced, but rather is down-regulated in the cells undergoing apoptosis and that its expression in the apoptotic tissue is restricted to the vital neighboring cells. This has led to the proposal that rather than being a cell death gene, clusterin is a cell survival gene, exerting a protective function on the surviving bystander cells. Clusterin has been shown to have potent chaperone-like activities and protects a wide variety of proteins from heat or mercaptoethanol-induced denaturation1,2,3,6,8.
Immunohistochemical expression
Reactivity seems to be better preserved in with B-5 fixative than with formalin8.
In reactive lymphoid tissues (tonsils, lymph node, and spleen), clusterin has been identified in follicular dendritic cells (FDC) and fibroblastic reticular cells. The FDCs showed strong cytoplasmic staining that extends into the cell processes. Fibroblastic reticular cells show a weaker but discernable marking of their cytoplasmic processes. None of the lymphoid elements display staining. Megakaryocytes show strong cytoplasmic immunoreactive8.
Clusterin seems to be positive in anaplastic large cell lymphoma irrespective of whether the tumour is positive or negative for ALK-1.
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T-cell lymphomas:
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Systemic anaplastic large cell lymphoma
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36/36(staining is cytoplasmic with dot-like Golgi enhancement; there may also be membrane staining. 23/36 cases were also positive for ALK-1, 13 cases were negative for ALK-1)6 ,
39/41(34/35 T-cell, 5/6 Null cell, 18/18 ALK-1+ve cases, 21/23 ALK-1-ve cases 22/24 pleomorphic, 14/14 monomorphic, 2/2 small cell, 1/1 lymphohistiocytic, 3/4 case with secondary cutaneous involvement. Staining was diffusely cytoplasmic with Golgi enhancement in most cases, membranous in a minority)9,
34/34(Golgi reactivity in 33 cases, accompanied by cytoplasmic staining in 24 cases, only cytoplasmic in one case: >75% of cells reactive in 15 cases, 25-75% of cells reactive in 7 cases, < 25% of cells reactive in 11 cases)8,
40/49(16/17 ALK-1 positive, 20/28 ALK-1 negative)7
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Primary cutaneous anaplastic large cell lymphoma
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0/96, 5/99, 7/78,
12/29(1/1 ALK-1 positive, 11/28 ALK-1 negative)7
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Peripheral T-cell lymphoma
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0/386,
1/5(cytoplasmic reactivity in about 50% of cells in one case)8, 1/147
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T/NK lymphoma
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0/76, 0/58
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Angioimmunoblastic
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0/28
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subcutaneous panniculitis-like
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0/28
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Precursor T-cell lymphoblastic
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0/28, 0/37
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Adult T-cell leukaemia/lymphoma
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0/18
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Hepatosplenic
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2/3(cytoplasmic reactivity in about 50% of cells in two cases)8
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Lymphomatoid papulosis
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1/77
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Mycosis fungoides
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0/28, 0/47 ,
1/1(a case in transformation, CD30+)7
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B-cell lymphomas:
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Diffuse large B-cell lymphoma
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1/31(one case showed moderate cytoplasmic staining without Golgi enhancement)6,
4/16(strong membranous staining in 4 cases)8,
5/43Four clusterin-positive diffuse large B-cell lymphomas had anaplastic cytologic features and four of five were diffusely positive for CD30.)7
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Follicle centre cell lymphoma
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0/116, 0/247
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T-cell rich B-cell lymphoma
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1/12(one case showed weak cytoplasmic staining)6
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Mantle-cell lymphoma
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0/56, 0/137
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Marginal-zone lymphoma
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0/96, 0/127
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CLL
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0/106, 0/77
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Lymphoplasmacytic lymphoma
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0/27
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Plasmacytoma
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0/27
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Burkitt lymphoma
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0/38, 0/77
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Precursor B-cell leukaemia/lymphoma
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0/77
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Post transplantation lymphoproliferative disease
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0/18
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Nodular lymphocyte predominant Hodgkin disease
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0/56, 0/37
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Classical Hodgkin lymphoma
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Nodular sclerosing
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0/166,
1/32(dendritic cells around the RS cells may mimic membranous staining)7
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Mixed cellularity
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0/36, 0/87
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Lymphocyte depleted
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0/46
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Interfollicular
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0/26
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Classical Hodgkin, not otherwise specified
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8/16(8 nodular sclerosis, 5 mixed cellularity, 3 nodular lymphocyte-rich classical . 1 case showed Golgi pattern staining of rare Reed-Sternberg cells. 1 case showed dot-like staining but not in paranuclear Golgi distribution. 6 cases showed delicate membrane staining.)8
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Carcinoma
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14/30( breast (7), lung (5), colon (7), bladder (4), kidney (1), prostate (5), thyroid(1). Most of the neoplastic cells showed Golgi positivity in one invasive lobular carcinoma of breast and in one poorly differentiated colonic carcinoma. There was granular cytoplasmic staining in 4 transitional cell carcinoma of the bladder, one renal cell carcinoma , three prostatic carcinomas and 4 breast carcinomas)8
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Breast
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normal epithelium
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negative5
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benign lesion
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5/39(2 of 18 fibroadenomas, 1 of 6 fibrocystic diseases, 1 of 4 nodular adenoses, 1 of 2 papillomas, and 3 of 12 ductal hyperplasias lacking atypia: I know, this does not summate)5
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atypical hyperplasia
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7/15(staining is granular cytoplasmic)5
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in situ carcinoma
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17/35(staining is granular cytoplasmic)5
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invasive carcinoma
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60/114(staining is granular cytoplasmic)5
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metastatic carcinoma
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32/40(staining is granular cytoplasmic)5
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Prostate
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normal epithelium
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negative10
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chronic pancreatitis
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13/2610
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mucinous cystadenoma
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4/610
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adenocarcinoma
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16/3310
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Malignant melanoma
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0/48
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Pulmonary carcinoid
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1/5(membranous and cytoplasmic staining in one case)8
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Mesothelioma
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0/28
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Thymoma
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0/18
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Seminoma
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0/18
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The intensity of staining of prostatic carcinoma correlates with high Gleason grade4. There is upregulation of clusterin levels following androgen ablation therapy11.
Diagnostic utility
Identification of anaplastic large cell lymphoma (used in conjunction with CD30), including ALK-1-negative cases, and its differentiation from Hodgkin lymphoma, Diffuse large B-cell lymphoma . It is probably NOT informative in the differentiation of systemic anaplastic large cell lymphoma from primary cutaneous anaplastic large cell lymphoma.
References
1 Rosenberg ME,Silkensen J. Clusterin: physiologic and pathophysiologic considerations. Int J Biochem Cell Biol 1995; 27:633-45
2 Koch-Brandt C,Morgans C. Clusterin: a role in cell survival in the face of apoptosis? Prog Mol Subcell Biol 1996; 16:130-49
3 Jones SE,Jomary C. Clusterin. Int J Biochem Cell Biol 2002; 34:427-31
4 Steinberg J, Oyasu R, Lang S, et al. Intracellular levels of SGP-2 (Clusterin) correlate with tumor grade in prostate cancer. Clin Cancer Res 1997; 3:1707-11
5 Redondo M, Villar E, Torres-Munoz J, et al. Overexpression of clusterin in human breast carcinoma. Am J Pathol 2000; 157:393-9 FULL TEXT
6 Wellmann A, Thieblemont C, Pittaluga S, et al. Detection of differentially expressed genes in lymphomas using cDNA arrays: identification of clusterin as a new diagnostic marker for anaplastic large-cell lymphomas. Blood 2000; 96:398-404 FULL TEXT
7 Saffer H, Wahed A, Rassidakis GZ, et al. Clusterin expression in malignant lymphomas: a survey of 266 cases. Mod Pathol 2002; 15:1221-6 FULL TEXT
8 Nascimento AF, Pinkus JL,Pinkus GS. Clusterin, a marker for anaplastic large cell lymphoma immunohistochemical profile in hematopoietic and nonhematopoietic malignant neoplasms. Am J Clin Pathol 2004; 121:709-17
9 Lae ME, Ahmed I,Macon WR. Clusterin is widely expressed in systemic anaplastic large cell lymphoma but fails to differentiate primary from secondary cutaneous anaplastic large cell lymphoma. Am J Clin Pathol 2002; 118:773-9
10 Xie MJ, Motoo Y, Su SB, et al. Expression of clusterin in human pancreatic cancer. Pancreas 2002; 25:234-8
11 July LV, Akbari M, Zellweger T, et al. Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy. Prostate 2002; 50:179-88
This page last revised 27.10.2006.
©SMUHT/PW Bishop