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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.

• a minority of pulmonary adenocarcinomas show coarse granular cytoplasmic staining2,9 (& personal observation).

• occasionally in squamous carcinomas of the lung, head, neck and cervix5,6.

• occasional positivity in oncocytic thyroid tumours3.

• perinuclear staining in small and large intestine4.

• perinuclear staining in pancreatic ductal and acinar cells4.

• some gastrointestinal and pancreatic carcinoids4

• Colonic adenocarcinoma9.

• Rather commonly in decalcified bone9.

• 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.

1Threshold for positivity 5% of tumour cells.

There appears to be considerable variation in cytoplasmic staining between commercial antibodies and with different buffers11:

The lack of cytoplasmic staining with the Novocastra antibody may make interpretation of nuclear staining easier.

Diagnostic utility

• Diagnosis of hepatocellular carcinoma and differentiation from renal cell carcinoma, adrenocortical carcinoma and adenocarcinoma NOS.

• 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.

©SMUHT/PW Bishop