2012/08/31 12:30

Case study 7 (choice of markers)

A 62-year-old woman with a history of breast cancer was noted to have a lung nodule detected on a computed tomography scan of the chest. A core biopsy of the nodule is illustrated in the Figure.

The neoplastic cells are positive for thyroid transcription factor-1 (TTF-1) and napsin A. What is your diagnosis?

    •    Reactive type II pneumocyte hyperplasia
    •    Adenocarcinoma with lepidic pattern
    •    Adenocarcinoma in situ/bronchioloalveolar carcinoma (BAC)
    •    Metastatic breast cancer
    •    Sclerosing hemangioma

The positivity for TTF-1 and napsin A indicates that this is a primary pulmonary adenocarcinoma and definitely excludes a metastatic breast carcinoma.1

The Figure shows an adenocarcinoma with a lepidic pattern of growth. This pattern of growth is characteristic of the so-called BAC, which has now been designated adenocarcinoma in situ by the new World Health Organization classification of lung tumors. The diagnosis of adenocarcinoma in situ should not be made in a biopsy specimen and should only be rendered in completely excised tumors.
Although sclerosing hemangioma can mimic an adenocarcinoma, and the tumor cells are positive for TTF-1 and napsin A, these tumors show a papillary, solid, and sclerosing pattern of grown, but not lepidic pattern.

    1.    Stoll LM, Johnson MW, Gabrielson E, et al. The utility of napsin-A in the identification of primary and metastatic lung adenocarcinoma among cytologically poorly differentiated carcinomas. Cancer Cytopathol. 2010;118:441-449.

When considering molecular tests for EGFR (epidermal growth factor receptor) mutation on lung adenocarcinoma, which histologic subtype should have priority for testing?
    •    Lepidic pattern
    •    Solid pattern
    •    Papillary and micropapillary patterns
    •    Acinar pattern
    •    All of the above


Although there are indications in the literature that the majority of adenocarcinomas harboring mutation in the EGFR gene occur in never smokers and are well-differentiated with a predominance of lepidic and papillary types,1,2 in reality, mutations can be found in any histologic type of adenocarcinoma, including poorly differentiated adenocarcinomas, in smokers, and in non-Asian patients.3 Therefore, it is recommended that all adenocarcinomas should be tested for activating EGFR mutations. There is no clear association between histologic pattern of adenocarcinoma and EGFR mutations.

    1.    Zakowski MF, Hussain S, Pao W, et al. Morphologic features of adenocarcinoma of the lung predictive of response to the epidermal growth factor receptor kinase inhibitors erlotinib and gefitinib. Arch Pathol Lab Med. 2009;133:470-477.
    2.    Motoi N, Szoke J, Riely GJ, et al. Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis. Am J Surg Pathol. 2008;32:810-827.
    3.    D'Angelo SP, Pietanza MC, Johnson ML, et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol. 2011;29:2066-2070.

A biopsy of a lung tumor showing a poorly differentiated non–small-cell carcinoma is obtained. The tumor cells are positive for napsin A, negative for thyroid transcription factor-1 (TTF-1), while a p63 stain shows nuclear labeling of rare scattered tumor cells. What is your diagnosis?
    •    Adenocarcinoma
    •    Squamous cell carcinoma
    •    Adenosquamous carcinoma
    •    Large-cell carcinoma
    •    Pleomorphic carcinoma

Napsin A is an aspartic proteinase, which is involved in the maturation of the surfactant protein B and is expressed in the cytoplasm of lung and kidney cells.1 The staining is cytoplasmic and strongly positive in up to 80% of primary lung adenocarcinomas. In the study by Stoll et al,2 the sensitivity and specificity of TTF-1 were each 81%. Napsin A exceeded the specificity of TTF-1 at 96% with a lower sensitivity of 65%. In the study, the only carcinoma of non-lung origin in which napsin A was detected was renal cell carcinoma, suggesting that napsin A can be used as a surrogate marker in the workup of poorly differentiated lung adenocarcinoma or an unknown primary tumor. In an excised tumor, most of the tumors that are positive for napsin A are also positive for TTF-1. One possible explanation is the fact that expression of TTF-1 can be focal in adenocarcinomas, whereas the expression of napsin A is diffuse; therefore, this marker is very useful in a biopsy setting in which focal positivity for TTF-1 can be overlooked.

Focal or non-diffuse p63 staining can be seen in adenocarcinomas and is considered nonspecific. This can be a pitfall in cases where the tumor is negative for adenocarcinoma markers (TTF-1, napsin A, and mucin). Such nonspecific staining also can be seen in other neoplasms like large B-cell lymphomas. In a recent publication3 using an antibody targeting the ∆N domain of p63 (called p40) this nonspecific staining was almost completely absent making the interpretation much easier.

In the case of adenosquamous carcinoma, the same described profile can be seen; however, it tends to be positive in different cell populations. Napsin A stains the adenocarcinoma component, whereas p63 stains the squamous cell carcinoma component.
    1.    Dejmek A, Naucler P, Smedjeback A, et al. Napsin A (TA02) is a useful alternative to thyroid transcription factor-1 (TTF-1) for the identification of pulmonary adenocarcinoma cells in pleural effusions. Diagn Cytopathol. 2007;35:493-497.
    2.    Stoll LM, Johnson MW, Gabrielson E, et al. The utility of napsin-A in the identification of primary and metastatic lung adenocarcinoma among cytologically poorly differentiated carcinomas. Cancer Cytopathol. 2010;118:441-449.
    3.    Bishop JA, Teruya-Feldstein J, Westra WH, Pelosi G, Travis WD, Rekhtman N. p40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol. 2011 Nov 4. [Epub ahead of print.


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