TTF-1 protein expression in pleural malignant mesotheliomas and adenocarcinomas of the lung

doi:10.1016/S0304-3835(97)00466-7

Cancer Letters

Volume 124, Issue 1, 13 February 1998, Pages 73-78

https://doi.org/10.1016/S0304-3835(97)00466-7 Get rights and content

Abstract

TTF-1 is a tissue-specific transcription factor expressed in the epithelial cells of thyroid and lung. This study investigates the immunohistochemical expression of TTF-1 in pleural malignant mesotheliomas (MM) and adenocarcinomas (AC) of the lung, respectively. For this purpose, 33 biopsy specimens of pulmonary AC and 24 specimens of MM were studied. TTF-1 immunoreactivity was identified in 19 of 33 cases of AC (57.5%) and in none of the 24 cases of MM. Positivity for TTF-1 was 100% specific and 57.5% sensitive for lung AC. Alternatively, negativity for TTF-1 was 57.5% specific and 100% sensitive for MM. These results suggest that TTF-1 can be favourably added to the immunohistochemical diagnostic panel for distinction between AC of the lung involving the pleura and pleural MM.

Introduction

A recurrent problem in diagnostic pathology is the inability to reliably distinguish pleural malignant mesothelioma (MM) from pleural involvement by metastatic carcinoma, particularly pulmonary adenocarcinoma (AC) 1, 2. This may be a very difficult task on the basis of routine histology alone and the problem is often compounded by incomplete clinical evaluation and limited sampling inherent to closed biopsy techniques. Electron microscopy [3]and histochemical studies 4, 5are helpful adjunct methods, but they do not always provide a definitive solution for this diagnostic dilemma 1, 2, 4.

A number of previous studies assessed the value of immunohistochemistry in distinguishing pleural MM from pulmonary AC 1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15. Overall, the results of these studies indicated the need to use a `panel' of selected antibodies because no single immunohistochemical marker is both entirely specific and sensitive for MM and AC. In addition, no specific marker for MM has yet been identified and the immunodiagnosis of MM is still mainly based on exclusion. Recently, novel promising antimesothelioma antibodies such as thrombomodulin [16]and calretinin [17]have been proposed, but they need further evaluation before being introduced into routine practice.

The thyroid transcription factor-1 (TTF-1) is a 38-kDa nuclear protein, initially identified as a mediator of thyroid-specific gene transcription, encoded by a single gene locus and consisting of three exons separated by two introns [18]. TTF-1 is expressed in cell types which originate from neuroectoderm (developing brain) and endoderm [19]. In addition to its presence in thyroid epithelial cells, where it activates the transcription of thyreoglobulin and thyreoperoxidase genes, the TTF-1 protein is detected in human fetal lung, being localized in the nuclei of epithelial cells of the developing airways. After birth, it is selectively expressed in type II epithelial cells of alveoli and in a subset of bronchiolar cells, where it acts as a promoter factor for transcription of the surfactant proteins A, B and C 19, 20, 21. TTF-1 is never expressed in cells originating from mesoderm [19]. In turn, the mesothelial origin of MM is now widely accepted [22]and the presence of mesothelium with embryonal mesoderm has also been described [23].

In previous studies, we showed that neoplasms arising from cells that produce TTF-1 still retain the capability to express this transcription factor 24, 25. In particular, adenocarcinomas of lung showed a TTF-1 immunoreactivity ranging from 25 to 75% 24, 26, 27.

On the basis of the aforementioned observations we hypothesized that TTF-1 could be favourably used as an immunohistochemical marker to distinguish MM from pleural involvement of pulmonary AC.

Section snippets

Materials and methods

Twenty-four cases of pleural MM were obtained from the files of the Institute of Anatomic Pathology of the University of Udine. A diagnosis of MM was performed on the basis of at least two of the following criteria: (1) open biopsy or pleurectomy specimen or thoracotomy with typical involvement of the pleural cavity and staging at the time of thoracotomy to exclude bronchogenic carcinoma; (2) diagnosis based on traditional histological criteria; (3) the presence of vimentin and cytokeratins and

Results

The histologic patterns of 24 MM included epithelial type (15 cases), sarcomatous type (three cases), biphasic (five cases) and poorly differentiated (one case).

The AC were diagnosed according to World Health Organization criteria [28]. Twenty-seven cases were not otherwise specified (NOS) and six cases were bronchiolo-alveolar adenocarcinomas (BAC). Staining results for TTF-1 are summarized in Table 1.

Anti-TTF-1 antibody stained 19 of 33 AC (57.5%) and none of the 24 pleural MM (P<0.0001) (

Discussion

The differential diagnosis between pleural malignant mesothelioma and pleural metastatic carcinoma is often difficult on morphological grounds alone, especially when the former is of the epithelial type, which is the most common histological variant of MM 1, 2. Pleural metastatic carcinomas can arise from different organs, i.e. lung, breast, ovary, prostate and colon, with the lung as the main primary site of origin [22]. Among pulmonary cancers, AC is the most common type involving the pleura

Acknowledgements

We wish to thank Dr Sabrina Guerra for her significant help in reviewing this article.

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With regard to NETs, we found a strong and diffuse TTF-1 expression mainly in SCLC. This finding is in accordance with that previously reported in several studies, with TTF-1 expression ranged from 88 to 100% of cases (Byrd-Gloster et al., 2000; Di Loreto et al., 1998; Fabbro et al., 1996; Lau et al., 2002a; Ordonez, 2012). These results support the use of TTF-1 as a helpful and sensitive marker for SCLC.
The expression pattern of thyroid transcription factor 1 (TTF-1) and neuroendocrine markers, neuron cell adhesion molecule (NCAM; CD56), chromogranin A (CgA) and synaptophysin (Syp), of different lung cell lineages was histologically analyzed in 15 normal human fetal lungs and 12 neuroendocrine tumors (NETs) using immunohistochemical methods. During pseudoglandular phase strong nuclear TTF-1 staining was detected in the columnar nonciliated epithelial cells, while NCAM, CgA and Syp had a moderate expression in the proximal airways and mild expression in the distal airways. Neuroendocrine cells (NECs) in proximal lung airway were co-localizing TTF-1 and other neuroendocrine markers while neuroendocrine bodies (NEBs) exhibit only staining with NCAM and Syp. In the canalicular phase TTF-1 nuclear staining was expressed only in several epithelial cells in proximal airways, while budding airways epithelium showed strong TTF-1 expression. Expression of NCAM, CgA and Syp in this phase equals the one in pseudoglandular phase. NEBs cells were co-localizing TTF-1 and NCAM in proximal airways and few NECs in distal airway were co-localizing TTF-1 and Syp. TTF-1 staining in the saccular phase was limited to subsets of epithelial cells in the proximal airways with stronger positivity in the distal airways. NCAM expression is moderate only in proximal airways, while Syp and CgA show mild expression in proximal and distal airways. NECs were co-localizing TTF-1 and NCAM in proximal lung airway. With regard to NECs, all small cell lung cancer (SCLC) cells had strong TTF-1, NCAM, Syp and CgA positivity and TTF-1 co-localized with other neuroendocrine markers. All pulmonary typical carcinoids were TTF-1 negative, while pulmonary atypical carcinoids were focal positive for TTF-1 and some neoplastic cells co-localized TTF-1 with neuroendocrine markers.
Our results indicate that TTF-1 expression in NECs suggests a possible role in their normal development and differentiation. Our results also indicate that possible cell of origin for poorly differentiated SCLC and some atypical carcinoid could be a progenitor cell in neuroendocrine lineage while in typical carcinoids possible cell of origin is localized in terminally differentiated NECs.
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A total of 155 consecutive cytology specimens procured outside of the lung were analyzed, in which SPA immunohistochemistry was reported. Cases were reviewed to document final diagnoses, immunostain results (including TTF-1), and histopathology follow-up when available.
Cytoplasmic SPA immunoreactivity was identified primarily in metastatic lung adenocarcinomas (ADC). SPA was also positive in 3 carcinomas of gynecologic/breast origin. SPA and TTF-1 specificity and positive predictive value were high (>90%) with relatively low sensitivity and negative predictive value for identifying metastatic ADC of lung origin. A panel of SPA and TTF-1 correctly identified most (79.7%) lung metastatic adenocarcinomas.
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However, the utility of TTF-1 has rarely been investigated in cytology [12]. As reported in the literature, TTF-1 immunostaining has a sensitivity ranging from 58% to 76% in the detection of pulmonary adenocarcinoma in tissue biopsy specimens [17]. In cell block cytology material, the sensitivity reaches 90%.
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This is a retrospective study including 40 cases of primary lung lesions who underwent image guided FNAC from pulmonary nodules. The final histopathologic diagnosis was the gold standard. Cell blocks were stained with anti-TTF-1, and P63. Nuclear immunoreactivity for both markers was considered specific. Sensitivity, specificity, positive and negative predictive values, of the cytologic diagnosis and of the two markers, as well as the accuracy of the combined markers were calculated.
Cytomorphology achieved a sensitivity of 83.3%, specificity of 91%, PPV of 91%, and NPV of 83.3%, for the diagnosis of AC, and 91% sensitivity, 83.3% specificity, 83.3% PPV, and 91% NPV, for the diagnosis of SCC. The concordance between cytologic and histopathologic diagnoses of AC and SCC was 87%. TTF-1 achieved 87.5% sensitivity, 94.7% specificity, 95.5% PPV, and 85.7% NPV for AC, while P63 achieved 94.7% sensitivity, 95.8% specificity, 94.7% PPV, and 95.8% NPV for SCC. TTF-1 enhanced the sensitivity of cytomorphology for AC from 83.3% to 87.5%, and specificity from 91% to 94.7%. Similarly P63 enhanced the sensitivity for SCC from 91% to 94.7%, and specificity from 83.3% to 95.8%.
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TTF-1 protein expression in pleural malignant mesotheliomas and adenocarcinomas of the lung

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Hum. Pathol.

Hum. Pathol.

Hum. Pathol.

J. Biol. Chem.

Eur. J. Cancer

Pathology of malignant mesothelioma

Histopathology

Ultrastructural diagnosis of epithelial malignant mesothelioma

Cancer

Malignant mesothelioma: cytologic diagnosis with histologic, immunohistochemical, and ultrastructural correlation

Semin. Diagn. Pathol.

Pathology of human mesothelioma. Aetiology and diagnostic considerations

Pathol. Annu.

Distinction of mesothelioma from adenocarcinoma. An immunohistochemical approach

Cancer

The diagnostic distinction between malignant mesothelioma of the pleura and adenocarcinoma of the lung as defined by a monoclonal antibody (B72.3)

Am. J. Pathol.

Antigenic phenotype of malignant mesotheliomas and pulmonary adenocarcinomas. An immunohistologic analysis demonstrating the value of Leu-M1 antigen

Am. J. Pathol.

Immunohistochemical evaluation of pleural mesothelioma and pulmonary adenocarcinoma. A bi-institutional study of 47 cases

Am. J. Surg. Pathol.

The immunohistochemical diagnosis of mesothelioma

Am. J. Surg. Pathol.

Immunohistochemical evaluation of seven monoclonal antibodies for differentiation of pleural mesothelioma from lung adenocarcinoma

Cancer

The differential diagnosis of epithelial-type mesothelioma from adenocarcinoma and reactive mesothelial proliferation

J. Pathol.