Clusterin Expression Distinguish Follicular Dentritic Cell Tumor From Other Dentritic Cell Neoplasm: Report of a Novel Follicular Dentritic Cell Marker and Clinicopathologic Data on 12 Additional Follicular Dentritic Cell Tumors and 6 Additional Interdigitating Dentritic Cell Tumors ~2004AJSP August

Background(1) Tumor of dendritic cell lineage, including follicular dendritic cell tumor(FDCTs), interdigitating dentritic cell tumor(IDCTs) and Langerhans cell histiocytoses(LCH), are rare Share IHC positive for fascin, CD68 and many morphologic features

Background(2) CD21, CD23, CD35,CD1a and S100 distinguish them D/D FDCTs and IDCTs is of clinical importance CAN.42, Ki-FDC1p, Ki-M4p, R4/23 and desmoplakin

Clusterin(1) Expression in benign follicular dendritic cell Clusterin glycoprotein expressed in parenchyma cells of liver, stomah and brain Complement fixation, membrane protection, cell aggregation, cell-matrix interaction, lipid transport, apoptosis, stress –induced secreted chaperone protein

Clusterin(2) Expression in anaplastic large cell lymphoma, diffuse large B cell lymphoma, peripheral T-cell lymphoma, nodular sclerosis Hodgkin lymphoma, ca of breast, colon, pancreas, and prostate Expression on dentritic cell tumor has not previously been reported Substantial number

Material and method(1) Mayo Clinic in-house and consutation file, 1995~2003 Follicular dendritic cell sa/tumor, interdigitating dendritic cell sa/tumor, dendritic cell,NOS FDCT: 20>>>> 12 IDCT: 9>>>> 6 DCT, NOS: 5>>>> 3>>>6 LCH: 3+11

Material and method(2) Paraffin embedded tissue: CD21, CD23, CD35, CD1a, S100, CD68, fascin and clusterin were applied Selected case: additional IHC marker were applied Positive of clusterin was scored both quantitatively(0~4) and qualitatively

Material and method(3) EM was performed on selected case( 3 FDCT, 2 IDCT, 6 spindle cell tumor, NOS) Clinical data and f/u information were obtained in FDCT and IDCT cases from Mayo Clinic patient redords or discussion with the referring physcians

Result histological feature(1) FDCT: variable number of multinucleated tumor cells, intermixed inflammatory cell, centered in the cortical region of LN, Myxoid change, pseudovascular space, dense fibrosis, angiofollicular hyperplasia, necrosis Mitoses: 0~34/10 hpf(M: 11.4)

Result histological feature(2) IDCT: greater degree of nulclear pleomorphism, more polygonal cell with more abundant eosinophilic cytoplasm Paracortical distribution 2 case: histiocyte like Intermixed lymphoplasmacytic population and multinucleated tumor giant cell Mitose: 0~19/10 hpf (M: 7.5) necrosis

IHC(1) Clusterin diffuse strong cytoplasmic staining in all FDCT Majority of FDCT showed positive for one or more of the tranditional FDC marker CD1a and S-100 were negative in all FDCT CD68 and fascin were positive in the majority

IHC(2) 2 case of FDCTs were negative of CD21,CD23 and CD35, were classified as FDCT by EM Negative for actin, desmin, ALK-1, CK, CAM5.2 Both show positive for EMA

IHC(3) IDCT: negative or showed only focal weak positive for clusterin All IDCT were strongly positive for S-100, fascin and negative for CD1a, CD21,CD35 Subset case shows CD23 and CD68 positive

IHC(4) 6/14 LCH complete negative for clusterin and 8 cases showed variable positive All LCH were positive for CD1a, fascin and CD68 S-100 showed variable intensity in 13 cases CD21,CD35 were negative in all cases CD23: equivocal in 9 cases

IHC(5) 6 spindle cell tumor, NOS: all showed some degree of fascin, 2 showed strong culsterin in the minor subset of cells Others: negative

EM(1) Were performed in selected case( 3 FDCTs and 2 IDCTs) FDCT: long interwining process connected by well-formed desmosome IDCT: complex interdigitating process without intercellular junction, variable number of lysosome and intermediate filament

EM(2) Unclassifiable spindle tumor: nonspecific features that lack membrane interdigitating process, intercellular junction, dense bodies and basal lamina

Clinical feature(1) Follow-up clinical information was available in 9 FDCT(M: 58.4 m) 4 achieved apparent cure meta was noted in 5 cases None of the patient with FDCT is known to have died

Clinical feature(2) IDCT occurred in older adult Four presented with solitary LN(+) Follow up clinical information was avaiable in 5 IDCT cass Three achieved apparent cure Two presented with disseminated dx and progressed rapidly to death from their dx

Clinicopathological Correlation No apparent correlation of behavior of FDCT or IDCT with mitotic activity, necrosis, degree of atypia or tumor location The two very aggressive IDCT had very similar histiocyte-like morphology and CD68(+) that was distinct from the other three cases

Discussion(1) The distinction of FDCT from other subtypes of dendritic cell tumor and other spindle cell tumor requires a panel of IHC stain(CD21, CD23, CD35, S-100, CD1a, CD68, actin, desmin and CK) we demonstrate the additional marker, clusterin, increases the diagnostic sensitivity

Discussion(2) Strong clusterin staining also distinguishes FDCTs from other dendritic cell neoplasm Robust clusterin staining is useful as supportive evidence for FDCT in cases with weak or focal expression of the extablished FDC markers

Discussion(3) CD21 is thought to be the most reliable FDC marker with a sensitivity of 96% Weak and focal staining is a particular problem in hepatosplenic FDCT cases with an inflammatory pseudotumor-like morphology Some have used CD21and CD35 cocktail or additional marker (Ki-FDC1p, Ki-M4p, CAN.42, R4/23)

Discussion(4) In addition to be a supplemental marker, clusterin staining can help classify FDCT that is completely devoid of staining for these traditional marker Strong clustrin expression shows specificity for FDCTs among dendritic cell tumor

Discussion(5) IHC finding on 6 spindle cell tumor, NOS suggest that clusterin may not be entirely specific for FDCTs among all spindle cell tumor The clinical finding in our cases supplement previous report, behave as low gr sarcoma, with tendency for local recurrence and late metastases, some with castleman dx

Discussion(6) Attempt to correlate clinicopathologic parameterw with clinical outcome have been limited by the rarity of the tumor One previous study of 17FDCTs found a statistically significant correlation between intraabdominal location, significant pleomorphism and a worse outcome

Discussion(7) IDCTs display a variable behavior from benign to rapidly fatal dx No apparent association between mitoses, necrosis, nuclear pleomorphism or extranodal location It’s interesting to speculate that IDCTs displaying more histiocytic differentiation may be associated with more aggressive behavior

Conclusion IHC for clussterin is of significant utility in diagnostic evaluation of dendritic cell tumor Strong clusterin stain appears to be a highly sensitive marker of FDCT Additional study is needed to delineate the specificity of clusterin expression among a broader spectrum of sarcoma and other spindle cell tumor