Home > Antigens > Thyroid transcription factor-1 > Cytoplasmic TTF-1
Cytoplasmic TTF-1 in hepatocellular carcinoma
Cytoplasmic staining with TTF-1 has been little studied. This cytoplasmic staining is due to a cross-reacting antigen of 160 kd, which is not an alternative splicing product of TTF-115. The binding of both thyroid transcription factor-1 and HepPar1 is to mitochondrial proteins in hepatocytes14. The staining is usually granular. Staining is seen with a biotin-free protocol8, although several authors used a biotin-based system in combination with HIER: false perinuclear positivity due to endogenous biotin may sometimes appear. The diffuse cytoplasmic staining of hepatocytes (and hepatocellular carcinoma) is seen only with clone 8G7G3/1 (DakoCytomation and others)9, not with clone SPT24 (NovoCastra)8.
Immunohistochemical expression
In a large series of consecutive cases, about 6% (23/361) of all tumours from a variety of sites showed cytoplasmic staining9.
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a minority of pulmonary adenocarcinomas show coarse granular cytoplasmic staining2,9 (& personal observation).
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occasionally in squamous carcinomas of the lung, head, neck and cervix5,6.
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occasional positivity in oncocytic thyroid tumours3.
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perinuclear staining in small and large intestine4.
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perinuclear staining in pancreatic ductal and acinar cells4.
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some gastrointestinal and pancreatic carcinoids4
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Colonic adenocarcinoma9.
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Rather commonly in decalcified bone9.
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Cytoplasmic immunoreactivity appears to be much more common in hepatocellular carcinomas than in other adenocarcinomas. The table below gives results in hepatocellular carcinoma and its mimics, with Hep Par 1 for comparison.
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cytoplasmic TTF-1
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Hep Par 1
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Benign liver tissue
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27/279
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hepatocellular carcinoma
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54/76(2/2 grade 1, 28/38 grade 2, 20/28 grade 3, 3/7 grade 4 and 1/1 fibrolamellar.)1, 9/97,
23/30(using cell blocks from FNA specimens)12,
41/44(37/40 primary and 4/4 metastatic)13
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50/761,
26/30(using cell blocks from FNA specimens)12
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cholangiocarcinoma
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2/2013
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adenocarcinoma (not hepatocellular)
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3/851,
6/47(pulmonary, cytological preparations)2,
1/49(non-pulmonary, cytological preparations)2, 0/137, 1/2013
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1/831
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renal cell carcinoma
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0/721
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0/741
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adrenal cortical carcinoma
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0/221
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0/211
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|
|
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1Threshold for positivity 5% of tumour cells.
There appears to be considerable variation in cytoplasmic staining between commercial antibodies and with different buffers11:
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Dako
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Zymed
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Santa Cruz
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Novocastra
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Hepar-1
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buffer:
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EDTA
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DTRS
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EDTA
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DTRS
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EDTA*
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DTRS
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EDTA
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DTRS
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Hepatocellular carcinoma
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54/77
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45/77
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31/77
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11/77
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53/77
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5/77
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0/77
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0/77
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64/77
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pulmonary adenocarcinoma
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12/12, nuclear positivity only
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renal cell carcinoma (n=41)
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negative
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adrenocortical carcinoma (n=20
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negative
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urothelial carcinoma (n=19)
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negative
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oral and oesophageal squamous cell carcinoma (n=11)
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negative
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salivary gland tumours (n=37)
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negative
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gastric (n=16)adenocarcinoma
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negative
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colorectal adenocarcinoma (n=17)
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negative
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pancreatic adenocarcinoma (n=11)
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2/11
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negative
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prostatic adenocarcinoma (n=25)
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negative
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gynaecological carcinoma (n=31)
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2/6 mucinous ovarian tumours
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negative
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breast carcinoma (n=35)
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negative
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thyroid carcinoma (n=20)
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20/20, nuclear positivity only
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mesothelioma (n=11)
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negative
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* Santa Cruz antibody with EDTA produced non-specific cytoplasmic staining in 28 different tumours
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The lack of cytoplasmic staining with the Novocastra antibody may make interpretation of nuclear staining easier.
Diagnostic utility
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Diagnosis of hepatocellular carcinoma and differentiation from renal cell carcinoma, adrenocortical carcinoma and adenocarcinoma NOS.
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FNA approaches to the kidney and adrenal may transverse the liver. Positivity for Hep par 1 and cytoplasmic TTF-1 may help to identify adventitious hepatocytes. Positive reactive hepatocytes should not be mistaken for hepatocellular adenocarcinoma.
References
1 Wieczorek, T. J., J. L. Pinkus, et al. (2002). "Comparison of thyroid transcription factor-1 and hepatocyte antigen immunohistochemical analysis in the differential diagnosis of hepatocellular carcinoma, metastatic adenocarcinoma, renal cell carcinoma, and adrenal cortical carcinoma." Am J Clin Pathol 118(6): 911-21.
2 Hecht, J. L., Pinkus, J. L., Weinstein, L. J., Pinkus, G. S. The value of thyroid transcription factor-1 in cytologic preparations as a marker for metastatic adenocarcinoma of lung origin Am J Clin Pathol 2001;116:483-488.
3 Bejarano, P. A., Y. E. Nikiforov, et al. (2000). "Thyroid transcription factor-1, thyroglobulin, cytokeratin 7, and cytokeratin 20 in thyroid neoplasms." Appl Immunohistochem Mol Morphol 8(3): 189-94.
4 Agoff, S. N., L. W. Lamps, et al. (2000). "Thyroid transcription factor-1 is expressed in extrapulmonary small cell carcinomas but not in other extrapulmonary neuroendocrine tumors." Mod Pathol 13(3): 238-42.
5 Kaufmann, O. and M. Dietel (2000). "Expression of thyroid transcription factor-1 in pulmonary and extrapulmonary small cell carcinomas and other neuroendocrine carcinomas of various primary sites." Histopathology 36(5): 415-20.
6 Kaufmann, O. and M. Dietel (2000). "Thyroid transcription factor-1 is the superior immunohistochemical marker for pulmonary adenocarcinomas and large cell carcinomas compared to surfactant proteins A and B." Histopathology 36(1): 8-16.
7 Chen S et al. Value of thyroid transcription vactor (TTF-1) and anti-hepatocyte monoclonal antibodies in differentiating hepatocellular carcinoma (HHC) from metastatic adenocarcinoma (MA) in liver [abstract]. Mod Pathol 2001;14:193A.
8 Communication from Aalborg Sygehus, NordiQC.
9 Bejarano, P. A. and F. Mousavi (2003). "Incidence and significance of cytoplasmic thyroid transcription factor-1 immunoreactivity." Arch Pathol Lab Med 127(2): 193-5. FULL TEXT
10 Giordano, T. J., K. A. Shedden, et al. (2001). "Organ-specific molecular classification of primary lung, colon, and ovarian adenocarcinomas using gene expression profiles." Am J Pathol 159(4): 1231-8.
11 Pan, C. C., P. C. Chen, et al. (2004). "Cytoplasmic immunoreactivity for thyroid transcription factor-1 in hepatocellular carcinoma: a comparative immunohistochemical analysis of four commercial antibodies using a tissue array technique." Am J Clin Pathol 121(3): 343-9.
12 Gokden M,Shinde A. Recent immunohistochemical markers in the differential diagnosis of primary and metastatic carcinomas of the liver. Diagn Cytopathol 2005; 33:166-72
13 Lei JY, Bourne PA, diSant'Agnese PA, et al. Cytoplasmic staining of TTF-1 in the differential diagnosis of hepatocellular carcinoma vs cholangiocarcinoma and metastatic carcinoma of the liver. Am J Clin Pathol 2006; 125:519-25
14 Pang Y, von Turkovich M, Wu H, et al. The binding of thyroid transcription factor-1 and hepatocyte paraffin 1 to mitochondrial proteins in hepatocytes: a molecular and immunoelectron microscopic study. Am J Clin Pathol 2006; 125:722-6
15 Gu K, Shah V, Ma C, et al. Cytoplasmic immunoreactivity of thyroid transcription factor-1 (clone 8G7G3/1) in hepatocytes: true positivity or cross-reaction? Am J Clin Pathol 2007; 128:382-8 FULL TEXT
This page last revised 27.11.2008.
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