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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 86-91

Aberrant thyroid transcription factor-1 expression in ovarian and nasopharyngeal carcinoma: Case reports with review of literature

Department of Histopathology and Cytopathology, Rajiv Gandhi Cancer Institute & Research Centre, Delhi, India

Date of Submission11-Aug-2021
Date of Acceptance02-Dec-2021
Date of Web Publication23-Feb-2022

Correspondence Address:
Dr. Meenakshi Kamboj
Department of Histopathology and Cytopathology, Rajiv Gandhi Cancer Institute & Research Centre, Delhi 110085
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jco.jco_30_21

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Introduction: Thyroid transcription factor-1 (TTF-1) is the recommended and sensitive immunohistochemical (IHC) marker for diagnosing lung adenocarcinomas and thyroid neoplasms, at the primary as well as the metastatic site, and is useful to rule out these sites in cases with adenocarcinomas of unknown primary. However, aberrant nuclear TTF-1 expression has also been reported in malignancies arising from gastrointestinal tract (GIT), breast carcinoma, female genital tract (FGT), and colon. Here, we present our experience of aberrant expression of TTF-1 in ovarian and nasopharyngeal carcinoma (NPC). Materials and Methods: TTF-1 immunostain was performed on 16 cases of NPC using clones SP141 and 8G7G3/1. A case of ovarian serous carcinoma with aberrant TTF-1 expression has also been discussed. Results: Of 16 cases of NPC, 2 cases (12.5%) showed strong TTF-1 expression with clone SP141, while all were negative with 8G7G3/1. In one of the case initial diagnosis of metastatic lung adenocarcinoma was made on cervical node biopsy as the tumor was negative for p40 and showed strong nuclear positivity for TTF-1 (SP141 clone). However, on clinical suspicion of NPC Epstein-Barr virus-encoded small RNA (EBER) by in situ hybridization was performed which was positive, and repeat TTF-1 using clone 8G7G3/1 was negative, suggested a NPC. In the case of ovarian tumor, cells were strongly positive for CK7 and TTF-1 (SP141 clone) expression, and thus the tumor was erroneously diagnosed as metastatic adenocarcinoma from a primary lung. However, IHC in the resected specimen showed strong expression for PAX-8 and TTF-1 using SP141 clone, while negative with clone 8G7G3/1 clone (Ventana), leading to final diagnosis of high-grade serous carcinoma of ovary with aberrant TTF-1 expression. In this case, addition of PAX-8 in initial biopsy diagnosis would have saved from labeling it as primary from lung. Conclusion: The sensitivity and aberrant expression vary between the various antibody clones used, with increased expression seen by SP141 clone as compared to 8G7G3/1 in our cases. Our findings highlight the significance of using a panel of diagnostic IHC markers before final diagnosis and importance of clinical details.

Keywords: 8G7G3/1 clone, nasopharyngeal carcinoma, ovarian carcinoma, SP141 clone, TTF-1

How to cite this article:
Kamboj M, Pasricha S, Mehta A, Gupta G, Sharma A, Durga G, Bansal D. Aberrant thyroid transcription factor-1 expression in ovarian and nasopharyngeal carcinoma: Case reports with review of literature. J Curr Oncol 2021;4:86-91

How to cite this URL:
Kamboj M, Pasricha S, Mehta A, Gupta G, Sharma A, Durga G, Bansal D. Aberrant thyroid transcription factor-1 expression in ovarian and nasopharyngeal carcinoma: Case reports with review of literature. J Curr Oncol [serial online] 2021 [cited 2022 Sep 25];4:86-91. Available from: http://www.https://journalofcurrentoncology.org//text.asp?2021/4/2/86/338056

  Introduction Top

Thyroid transcription factor-1 (TTF-1) is identified as a sensitive and specific marker for lung and thyroid epithelial neoplasms. However, aberrant expression has been described in tumors of many other sites as well, showing varying expression using different clones, affecting the specificity of TTF-1. Here we discuss our experience of TTF-1 expression using two different clones: in nasopharyngeal carcinomas (NPC) and a case of ovarian carcinoma. The purpose of these comparisons is to underscore the variability of TTF-1 expression using different antibody clones especially in nonpulmonary tumors and to be mindful of aberrant expression while reporting such cases.

  Materials and Methods Top

Archival tumor tissue blocks of 16 diagnosed cases of NPC were retrieved, and TTF-1 immunostain was performed using SP141 and 8G7G3/1 clones. A case of ovarian serous carcinoma with aberrant TTF-1 expression has also been discussed.

Ethics approval was not required as only archival data from records were used and patients’ individual information was not used. The data have been tabulated in the text ahead. General informed consent was taken from the patient regarding sharing of clinical data for research purposes.

  Results Top

Scenario 1. A 61-year-old postmenopausal woman was evaluated for complaints of breathlessness of 1-month duration. Positron emission tomography-computed tomography (PET-CT) scan showed a large complex solid-cystic left ovarian mass along with a metabolically active umbilical lesion, suspicious of metastasis, and ascites. Bilateral pleural effusion (left>right) was also seen with underlying left lung collapse. No definite lesion was identified in the lung parenchyma. The serum CA-125 level was 799 U/mL (reference range 5–35 U/mL).

Biopsy from the left adnexal mass showed an adenocarcinoma in glandular and papillary pattern lined by flattened to cuboidal epithelium with stratified hyperchromatic nuclei [Figure 1]A. On immunohistochemistry (IHC), the tumor cells were strongly positive for CK7, Napsin-A, and TTF-1 (SP141 clone) [Figure 1]B and C, and negative for CK20. With these features, a diagnosis of metastatic adenocarcinoma from a primary from lung was offered.
Figure 1: Biopsy from adnexal mass showing an adenocarcinoma in glandular and papillary pattern (A). Immunohistochemistry stains show diffuse strong expression for TTF-1 (B, using SP141 clone) and Napsin-A (C). Section from the ovarian tumor show cysts, glands and papillae lined by flattened to cuboidal epithelium with stratified hyperchromatic nuclei (D). Immunohistochemical stains show diffuse PAX-8 positivity (inset). TTF-1 is strongly positive in tumor cells using clone SP141 (E) and negative using clone 8G7G3/1 (F)

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Considering a diagnosis of lung adenocarcinoma, molecular profiling was done, and no pathogenic mutation was detected in EGFR, ALK, ROS, or MET gene. In view of metastatic lung disease, the patient was given chemotherapy with palliative intent, which comprised paclitaxel, carboplatin, and bevacizumab. After six cycles of chemotherapy, significant response was reported in the adnexal mass and pleural effusion was completely resolved; however, the size of ovarian cystic component increased. Later, the patient underwent radical hysterectomy with pelvic lymphadenectomy and omentectomy.

On gross examination, the left adnexal mass measured 24 cm in maximum dimension, and the cut surface showed solid-cystic areas filled with hemorrhagic fluid. Right ovary measured 2 cm × 1 cm × 1 cm and was grossly unremarkable.

On microscopic examination, sections from left ovarian tumor showed large cystic spaces and glands lined by stratified tall columnar epithelium, along with papillary in-growths within cysts [Figure 1D]. Adjacent areas showed stromal reaction along with small infiltrative glands, and areas of calcification. Tumor involved the left ovarian surface and fallopian tube, while the other ovary was normal. On IHC [Figure 1D–F], the tumor cells showed strong expression for PAX-8, TTF-1 (by SP141 clone), CA-125, ER and p16, WT-1 expression was focal; IHC for CDX2, SATB-2, and thyroglobulin was negative. P53 showed abnormal mutational expression (null phenotype). A repeat TTF-1 IHC using 8G7G3/1 clone (Ventana) was negative.

In view of PAX-8 and CA125 positivity, a final diagnosis of high-grade serous carcinoma of ovary with aberrant TTF-1 expression was reported. Omentum, pelvic lymph-nodes, and peritoneal staging biopsies were free of tumor.

Scenario 2. We received a cervical node biopsy, clinically metastasis of unknown origin (MUO), with radiology showing multiple lymphadenopathy, bilateral lung nodules, nasopharyngeal mass, and liver nodules [Figure 2]A. The biopsy showed a diffusely infiltrative tumor, which on IHC [Figure 2]B and C showed strong nuclear positivity for TTF-1 (SP141 clone), faint CK expression, and was negative for P40 and PAX-8. With this immunoprofile, a diagnosis of primary lung adenocarcinoma was favored. However, in view of strong clinical suggestion of primary nasopharyngeal tumor with a large nasopharyngeal mass on radiology, Epstein–Barr virus-encoded small RNA (EBER) by in situ hybridization (ISH) was performed, which was strongly positive, suggesting an NPC. Thus, TTF-1 expression seemed to show aberrant expression here. Repeat TTF-1 stain using clone 8G7G3/1 (Ventana) turned out to be negative. This raised a possibility of variability in specificity of the two clones.
Figure 2: Tissue core from cervical node with a solid sheet of tumor cells with peripheral lymphocytes (A). Tumor cells show positive expression for TTF-1 using clone SP141 (B) and negative expression for TTF-1 using clone 8G7G3/1 (C). EBER-ISH is positive in tumor cells (inset). Tissue core from nasopharyngeal tumor with a solid and syncytial sheet of tumor cells with peripheral lymphocytic reaction with fibrosis (D). Tumor cells show positive expression for TTF-1 using clone SP141 (E) and negative expression for TTF-1 using clone 8G7G3/1(F)

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We retrospectively collected previously diagnosed cases of NPC and performed TTF-1 using both the clones. A total of 16 cases were evaluated including the case discussed above. Strong TTF-1 expression was seen in two cases with clone SP141, whereas all were negative with 8G7G3/1 [Figure 2D–F]. Of these 16 cases, 11 were men and 5 were women. Age range varied from 7 to 75 years. EBER expression by ISH was positive in all 11 cases where performed and was not done in 5 cases (diagnosed on classical morphology and radiologic details).

  Discussion Top

TTF-1 is a 38-kDa homeodomain-containing DNA-binding protein belonging to the NKX2 gene family.[1] It was originally identified in thyroid follicular cells and regulates the transcription of genes specific to thyroid, lung, and diencephalon.[2],[3]

TTF-1 is the most sensitive and specific recommended marker for diagnosing lung adenocarcinomas and thyroid neoplasms, both at primary and metastatic sites, and is thus included in the panel for adenocarcinomas of unknown primary.[1],[4]

Sensitivity and specificity of TTF-1 for diagnosing primary lung adenocarcinomas have been reported to be 80.72% and 90.48%, respectively, and sensitivity for metastatic lung carcinoma to vary from 69% to 82%.[5],[6],[7] Combination IHC with Napsin-A proves beneficial, which has a specificity of 95.02% and sensitivity of 87.25% for lung adenocarcinoma.[5] A meta-analysis on the role of TTF-1 in the diagnosis of metastatic pulmonary adenocarcinomas in effusions estimated sensitivity of 74% and specificity of 99%.[8] TTF-1 expression in thyroid tumors decreases with the decreased degree of differentiation, with 100% expression in differentiated carcinomas (papillary and follicular), 86% in poorly differentiated carcinomas, and are usually negative in anaplastic carcinoma.[6],[9]

TTF-1 expression is also seen in pulmonary as well as extrapulmonary small-cell carcinomas and large-cell neuroendocrine carcinomas, including gastrointestinal tract (GIT), prostate, bladder, breast, and female genital tract (FGT). TTF-1 expression has also been reported in <10% of squamous cell carcinoma.[4],[6] However, aberrant nuclear TTF-1 expression has been reported in epithelial malignancies arising from breast, FGT and colon, and occasionally in ependymomas.[1],[4]

Many anti-TTF-1 antibodies are available for use to identify this protein, which include mouse MAb 8G7G3/1 (Dako), and the two recent rabbit MAb SP141 (Ventana) and SPT24 (Novocastra), which are more sensitive but less specific than the clone 8G7G3/1 for lung tumors.[1],[10],[11] This reduced specificity of SP141 and SPT24 has led to higher expression in many other tumors as compared to the 8G7G3/1 antibody.[1]

Using different detection systems has also shown varied expression with same clones. Cameselle-Teijeiro et al.[12] suggested using polymer detection system, instead of the avidin-biotin peroxidase complex methods, to avoid false-positive staining.

Among ovarian malignancies, 70% are carcinomas, majority being of serous subtype, which can be diagnosed successfully with the morphology and routine IHC diagnostic panels, even at the metastatic sites.[1] In cases with lung nodules along with simultaneous presence of ovarian tumor, aberrant expression of TTF-1 makes the differential diagnosis difficult. Addition of Müllerian markers (PAX-8) is useful in establishing the origin of the tumor in such cases.[4] In our case, addition of PAX-8 in initial biopsy diagnosis would have saved from labeling it as primary from lung.

As TTF-1 is not known to play any role in the embryologic development of Müllerian tissue and FGT; it is described as an aberrant expression.[1] It is also suggested that aberrant expression of more sensitive clones could be the real detection of TTF-1 protein in many tumors not known before.[5] Saito et al.[13] reported that TTF-1 inhibits the epithelial-to-mesenchymal transition in response to transforming growth factor-β in lung adenocarcinoma cells, and possibly the same process is seen neoplastic ovarian cells.[1]

In a study on 62 cases of ovarian carcinoma using two clones, positive TTF-1 with SPT24 and 8G7G3/1 was detected in 17.7% and 3.2% of ovarian carcinomas, respectively, and this difference in expression was highly significant (P = 0.004). The expression by SPT24 included 22.2% of serous carcinomas and 21.7% of endometrioid adenocarcinomas.[1] Another study on 2 of 168 (1.2%) primary ovarian carcinomas showed positive TTF-1 (clone 8G7G3 ⁄ 1), which was confined to solid poorly differentiated areas, with no clinical evidence of a pulmonary lesion.[14]

Kubba et al.[4] showed TTF-1 positivity in 37% serous, 20% endometrioid, and 33% clear cell carcinomas. They also reported a higher expression of 26% in whole tissue using SPT24 vs. 0.7% in tissue microarray (TMA) using 8G7G3/1 clone. The detection method used was a polymer detection system.[4]

Zhang et al.[2] evaluated TTF-1 expression with three different primary antibodies (8G7G3/1, SPT24, and BGX-397A) and two secondary automated detection systems (Envisionþ/Dako autostainer vs. Refine/Bond Max) in 104 ovarian and endometrial tumors on routine surgical specimens (RSS) and 108 ovarian tumors on TMA specimens.[2] They detected TTF-1 expression in 15% of ovarian carcinomas using the clone SPT24 and in only 7.5% using the clone 8G7G3/1. They found TTF-1 in most subtypes of ovarian (11% serous, 11% clear cell, and 7% ovarian), and also in ovarian mucinous tumors (8.6% adenocarcinoma and 16% of cystadenoma).[2] Their study proved SPT24 and Refine/Bond Max autostainer detection method as the most sensitive system. Also, the reactivity for SPT24 was higher in RSS specimens than in TMA, seen in up to 26% of RSS and 6.4% on TMA, whereas with 8G7G1/3 it was 5.7% of RSS vs. 1% of TMA.[2]

TTF-1 positivity has also been reported in <10% of endometrial adenocarcinoma.[15] A case of a C5 vertebral soft tissue mass in a female with a known history of breast carcinoma and endometrioid endometrial carcinoma showed aberrant TTF-1 expression (by both 8G7G3 and SPT24) (other markers for lung and breast were negative). In retrospect the poorly differentiated areas of endometrial carcinoma also expressed TTF-1, proving it to be a metastatic endometrial carcinoma with aberrant TTF-1 expression.[15]

Kubba et al.[4] also reported TTF-1 immunoreactivity in 4% of endocervical adenocarcinomas, 16% of endometrial endometrioid adenocarcinomas, and 23% of endometrial serous carcinomas using 8G7G3/1. Zhang et al.[2] showed TTF-1 in uterine tumors more than ovarian tumors (22% vs 7.4 to 10.7%), by both SPT24 and BGX- 397A antibodies, with slightly overall stronger intensity by SPT24. It was detected in 82% of uterine malignant mixed Müllerian tumor.

Presence of TTF-1 positive circulating tumor cells has been associated with a higher rate of vascular infiltration, lymphatic metastasis, decreased progression-free survival, and median survival time in endometrial carcinoma.[15]

Normal ovarian tissue (epithelial and stromal tissue) shows a negative expression of TTF-1 with both clones.[1] However, TTF-1 expression has been found in benign proliferative and secretory endometrium in 75% and 55% of cases, respectively.[15] TTF-1 reactivity has also been seen in benign fallopian tubal epithelia, and in a benign polypoid endometrium adjacent to MMMT. The significance of this finding is unclear.[2]

In our analysis, we found 12.5% of NPCs with strong aberrant TTF-1 using SP141 clone. Our findings indicate a difference in positivity with the two antibodies of TTF-1, and a misclassification of NPC as primary adenocarcinomas of lung. We did not find any literature with aberrant TTF-1 in NPC, although it is seen in low-grade papillary adenocarcinoma of nasopharynx.[16]

In a study comparing use of TTF-1 clones in lung tumors, aberrant expression was reported by clone SP141 in 46.2% of squamous carcinoma and 42.1% of sarcomatoid mesothelioma, whereas both these tumors were negative using TTF-1 8G7G3/1 antibody. Among sarcomatoid carcinomas of lung in this study, 33.3% were positive for TTF-1 using SP141, whereas 16.7% were positive using 8G7G3/1.[10]

  Conclusion Top

Although TTF-1 is considered a relatively sensitive and specific marker for lung and thyroid neoplasms, its expression in other tumors is also known, where clone SPT24 is more sensitive than clone 8G7G3/1.

Thus, a prudent inclusion of a panel of diagnostic IHC markers and clinical as well as radiological input is mandatory before labeling any tumor based alone on TTF-1 expression.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Hakim SA, Youssef NS Diagnostic utility of thyroid transcription factor-1 in ovarian carcinoma and its relationship with clinicopathologic prognostic parameters. Appl Immunohistochem Mol Morphol2017;25:237-43.  Back to cited text no. 1
Zhang PJ, Gao HG, Pasha TL, Litzky L, Livolsi VA TTF-1 expression in ovarian and uterine epithelial neoplasia and its potential significance: An immunohistochemical assessment with multiple monoclonal antibodies and different secondary detection systems. Int J Gynecol Pathol 2009;28:10-8.  Back to cited text no. 2
Copper WA, Bubendorf L, Kadota K, Ladanyi M, MacMohan H, Matsubara D, et al. Invasive non-mucinous adenocarcinoma of the lung. In: Alain CB, Wendy AC, Sanja D, Francoise GS, Deepali J, Keith MK, et al., editors. WHO Classification of Tumours Editorial Board. WHO Classification of Thoracic Tumours. 5th ed. Lyon: International Agency for Research on Cancer; 2021. pp.64-74.  Back to cited text no. 3
Kubba LA, McCluggage WG, Liu J, Malpica A, Euscher ED, Silva EG, et al. Thyroid transcription factor-1 expression in ovarian epithelial neoplasms. Mod Pathol 2008;21:485-90.  Back to cited text no. 4
Jin L, Liu Y, Wang X, Qi X Immunohistochemical analysis and comparison of Napsin A, TTF1, SPA and CK7 expression in primary lung adenocarcinoma. Biotech Histochem 2018;93:364-72.  Back to cited text no. 5
Bhargava R, Dabbs DJ Immunohistology of carcinoma of unknown primary site. In: Dabbs DJ, editor. Diagnostic Immunohistochemistry: Theranostic and Genomic Applications. 5th ed. Philadelphia, PA: Elsevier;2019. pp. 219-60.  Back to cited text no. 6
Mukhopadhyay S, Katzenstein AL Comparison of monoclonal Napsin A, polyclonal Napsin A, and TTF-1 for determining lung origin in metastatic adenocarcinomas. Am J Clin Pathol 2012;138:703-11.  Back to cited text no. 7
Shen Y, Pang C, Shen K, Wu Y, Li D, Wan C, et al. Diagnostic value of thyroid transcription factor-1 for pleural or other serous metastases of pulmonary adenocarcinoma: A meta-analysis. Sci Rep 2016;6:19785.  Back to cited text no. 8
Benedict M, Costa J Metastatic papillary thyroid carcinoma with multifocal synchronous transformation to anaplastic thyroid carcinoma. Case Rep Pathol 2016;2016:4863405.  Back to cited text no. 9
Klebe S, Swalling A, Jonavicius L, Henderson DW An immunohistochemical comparison of two TTF-1 monoclonal antibodies in atypical squamous lesions and sarcomatoid carcinoma of the lung, and pleural malignant mesothelioma. J Clin Pathol 2016;69:136-41.  Back to cited text no. 10
Compérat E, Zhang F, Perrotin C, Molina T, Magdeleinat P, Marmey B, et al. Variable sensitivity and specificity of TTF-1 antibodies in lung metastatic adenocarcinoma of colorectal origin. Mod Pathol 2005;18:1371-6.  Back to cited text no. 11
Cameselle-Teijeiro J, Abdulkader I, Piso-Neira M, Reyes-Santías R, Alfonsin-Barreiro N Thyroid transcription factor-1 expression in endometrioid tumors: A note of caution. Hum Pathol 2011;42:1053-5; author reply 1055-6.  Back to cited text no. 12
Saito RA, Watabe T, Horiguchi K, Kohyama T, Saitoh M, Nagase T, et al. Thyroid transcription factor-1 inhibits transforming growth factor-beta-mediated epithelial-to-mesenchymal transition in lung adenocarcinoma cells. Cancer Res 2009;69:2783-91.  Back to cited text no. 13
Graham AD, Williams AR, Salter DM TTF-1 expression in primary ovarian epithelial neoplasia. Histopathology 2006;48:764-5.  Back to cited text no. 14
Casteillo F, Fournel P, Da Cruz V, Karpathiou G, Boutet C, Jacquin JP, et al. TTF-1-positive metastatic endometrioid carcinoma: A case report and review of literature of a potential diagnostic pitfall. Appl Immunohistochem Mol Morphol 2020;28:e6-e9.  Back to cited text no. 15
Stelow EB, Bell D, Wenig BM Nasopharyngeal papillary adenocarcinoma. In: El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ, editors. WHO Classification of Head and Neck Tumours. 4th ed. Lyon:International Agency for Research on Cancer. 2017. pp. 70.  Back to cited text no. 16


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