Napsin A

Making a diagnosis of ovarian clear cell carcinoma has the following implications. Gynecologic oncologists will expect a chemotherapy-resistant disease and therefore opt for a primary surgical approach instead of starting with neoadjuvant chemotherapy, which is the primary treatment for high-grade serous carcinomas in some countries.1 Due to the poor response to chemotherapy, they will consider including the patient in clinical trials tailored toward clear cell carcinoma in the adjuvant setting.2,3 For the genetic risk, they will investigate the family history for evidence of Lynch syndrome. The risk of Lynch syndrome among women with ovarian clear cell carcinoma is increased and appears equal to the elevated risk among women with ovarian endometrioid carcinoma.4 In contrast, the possibility of BRCA1/2 germline mutation will be highly unlikely.5 Clear cell carcinoma is an uncommon histologic type, accounting for approximately 10% of ovarian carcinomas in North America. The terminology refers to the characteristic glycogen-rich, cytoplasmic clearing of the carcinoma cells rather than reflecting the cell of origin, which currently is considered to be from the glandular component of endometriosis. Ovarian clear cell carcinoma mostly presents as an early stage pelvic mass and is associated with a relatively favorable prognosis. Later-stage cancers follow a very aggressive course without effective treatment options. The most common molecular alterations are mutations in ARID1A, PIK3CA, and the TERT promoter, findings that have not yet been translated into a specific molecular therapy.1 The reproducibility of a morphologic diagnosis of clear cell carcinoma among pathologists and its distinction from the four other major types of ovarian carcinoma (high-grade serous, endometrioid, low-grade serous, and mucinous) are very good.6,7 Yet diagnostic pitfalls remain. These include clear cell carcinomas that lack the characteristic tubulocystic architecture or stromal hyalinization. Also problematic are solid tumors that show morphologic overlap with high-grade endometrioid carcinoma with extensive secretory changes or high-grade serous carcinoma with clear cell changes.8 Furthermore, without architectural context, accurate cytologic typing of clear cell carcinoma on ascitic fluid is extremely challenging. Immunohistochemistry (IHC) employing a panel of biomarkers, including Wilms tumor 1 (WT1), tumor protein p53, progesterone receptor, hepatocyte nuclear factor 1 homeobox B (HNF1B), cyclin-dependent kinase inhibitor 2A, and AT-rich interactive domain 1A, can assist in the histologic typing of ovarian carcinoma.7 In this issue of the Journal, Kandalaft et al9 add another diagnostic biomarker to the IHC panel. The investigators propose napsin A (HUGO gene name: NAPSA) as a sensitive and specific biomarker for ovarian clear cell carcinoma. Napsin A is an aspartyl protease, which is normally expressed in type II alveolar pneumocytes and the proximal tubules of the kidney.10 It can be seen in intra-alveolar macrophages probably due to phagocytosis of napsin A–containing surfactant. Napsin A has been recently established as a lung adenocarcinoma marker.11 In that context, it has approximately the same sensitivity as TTF1 (transcription termination factor, RNA polymerase I) but a higher specificity in the distinction of pulmonary adenocarcinoma from squamous cell carcinoma.12 In the current study of ovarian carcinomas, the investigators found that all 36 clear cell carcinomas expressed napsin A.9 Expression in at least 1% of cells occurred in 35 cases and in less than 1% of cells in one case. This contrasted with no expression in 37 high-grade serous carcinomas, 21 serous borderline tumors, and focal expression in three (10%) of 29 endometrioid carcinomas. The sensitivity for clear cell carcinoma was 100%, and the specificity against endometrioid and high-grade serous carcinoma was 90% and 100%, respectively. In a very recent and somewhat similar study available online, Yamashita et al13 reported napsin A expression, which they defined as staining in 10% or more of cells in 71 (83%) of 86 ovarian clear cell carcinomas. Napsin A expression was not detected in other types, including serous, endometrioid, and mucinous carcinomas, corresponding to a specificity of 100%. Based on these two studies, the combined sensitivity of napsin A for ovarian clear cell carcinoma is 88% (n = 107/122). Both studies used whole tissue sections and similar IHC platforms but differed with respect to the staining cutoff: any staining vs 10% or more, which likely explains the differences in their sensitivities and specificities. A low cutoff with high sensitivity for clear cell carcinoma performs well in the distinction from high-grade serous carcinoma. However, some cautious interpretation is needed when being used to rule out a diagnosis of endometrioid carcinoma. This is because Kandalaft et al9 reported that 10% of endometrioid carcinoma showed focal napsin A expression, and not all clear cell carcinomas showed diffuse napsin A expression. Expression was focal in 16% of clear cell carcinomas. Given that focal expression may not be sampled on a limited core biopsy specimen, some clear cell carcinomas could potentially demonstrate a false-negative napsin A result. How does napsin A compare with the previously proposed clear cell marker HNF1B? HNF1B is a hepatic transcription factor involved in glucose homeostasis.14 A tissue microarray study directly compared napsin A with HNF1B and found a higher sensitivity for HNF1B (92% vs 82%) but a higher specificity for napsin A (99% vs 78%) and concluded that napsin A was the single best marker for ovarian clear cell carcinoma by optimally combining sensitivity and specificity.15 Since HNF1B shows a higher sensitivity, it may serve as a secondary marker to confirm the occasional clear cell carcinoma that lacks napsin A expression. While the specificity of HNF1B against high-grade serous carcinoma is 93%, the lower specificity toward mucinous and endometrioid carcinomas limits its ability to rule out the latter two types.15 Beside diagnostic test accuracy, there are other factors to consider when judging the better biomarker. The available polyclonal antibodies for HNF1B have been notoriously problematic with respect to consistent staining results. The monoclonal napsin A antibody produces a distinct granular immunoreactivity that appears easily interpretable, although a formal reproducibility study for the interpretation of the IHC has not yet been performed. In the endometrium, napsin A has been shown to be a marker for endometrial clear cell carcinomas with similar accuracy as seen in the ovary.16 The growing list of uncommon tumor types at various organ sites that express napsin A, however, limits the use of napsin A as a marker for the primary site of origin. In addition to the lung, ovary, and endometrium, napsin A is expressed in most papillary renal cell carcinomas, a minority of renal clear cell carcinomas,17 and the occasional adenocarcinoma arising in the thyroid,18 adrenal cortex, salivary gland,19 esophagus,20 and gallbladder.21 Kandalaft et al9 also investigated the accuracy of panels of other biomarkers such as paired box 8 (PAX8), WT1, estrogen receptor, and TTF1 in the diagnosis of ovarian clear cell carcinoma. It appears a diagnosis of ovarian clear cell carcinoma can be considered if the tumor expresses PAX8 but does not express WT1. However, since endometrial clear cell carcinoma has a similar expression profile with these two biomarkers, the panel cannot distinguish between ovarian and endometrial origin of the carcinoma.16 IHC detection of PAX8 expression is helpful in ruling out the possibility of metastatic pulmonary adenocarcinoma to the ovary, since most pulmonary adenocarcinomas do not express it. When there is occasional TTF1 positivity of an ovarian clear cell carcinoma and the issue is whether it represents a pulmonary metastasis, the presence of PAX8 expression is particularly helpful in establishing the ovarian origin of the carcinoma. However, PAX8 would not help in the distinction from metastatic renal cell carcinoma, and a renal biomarker such as renal cell carcinoma maker would be more helpful in this circumstance. The role of napsin A in ovarian clear cell carcinoma is not yet understood. However, it appears that the aberrant expression, which is perhaps due to chromatin remodeling or changes in the methylation pattern, shows robust discrimination against other types of carcinoma and therefore provides a useful cell lineage marker. Correct assessment of cell lineage is of critical importance because the significance of molecular alterations highly depends on the cellular context. The establishment of napsin A as a clear cell carcinoma biomarker is therefore another milestone in the subclassification of ovarian carcinomas, and in Figure 1, we propose its inclusion as an update to our recently published IHC algorithm for ovarian carcinoma typing.7 A combination of PAX8 and napsin A expression with absent WT1 expression is a characteristic immunoprofile of gynecologic clear cell carcinoma and could be used to identify patients for inclusion in clinical trials for clear cell carcinomas. Immunohistochemical biomarker expression to assist in typing of ovarian carcinomas. CCC, clear cell carcinomas; EC, endometrioid carcinomas; HGSC, high-grade serous carcinoma; LGSC, low-grade serous carcinoma; MC, mucinous carcinoma. aPaired box 8 (PAX8) is absent in 15% of ECs and 50% of MCs. bWilms tumor 1 (WT1) is absent is 3% of HGSCs. cWT1 is expressed in up to 10% of ECs. These low-grade ECs lack concomitant aberrant p53 expression. dNapsin A is expressed in 10% of ECs. ep53 wild-type pattern is seen in 5% of HGSCs. fHormone receptors are expressed in 5% of MCs. gHormone receptors are absent in 15% to 30% of ECs.

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