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

Resulthistological 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)

Resulthistological 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 mu

ltinucleated 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