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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e31823e472e
New Antibody/Techniques

Napsin A Expression in Lung and Kidney Neoplasia: A Review and Update

Ordóñez, Nelson G. MD

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University of Texas, M.D. Anderson Cancer Center, Houston, TX

The author has no funding or conflicts of interest to disclose.

Reprints: Nelson G. Ordóñez, MD, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 (e-mail: nordonez@mdanderson.org).

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Abstract

Napsin A is an aspartic protease present in the epithelial cells of the lung and kidney. Recent studies have shown that, in lung tumors, napsin A expression is restricted to lung adenocarcinomas, whereas among renal tumors, it is frequently expressed in renal cell carcinomas, especially the papillary and clear cell subtypes. Owing to its restricted expression, napsin A is a useful marker that can assist in the diagnosis of both lung adenocarcinomas and renal cell carcinomas.

Until recently, surfactant proteins, especially surfactant protein A (SP-A) and thyroid transcription factor-1 (TTF-1), were the only peripheral airway epithelial cell markers recognized as being useful in the diagnosis of lung adenocarcinomas. SP-A, although highly specific for lung adenocarcinoma, has a relatively low sensitivity when compared with TTF-1.1,2 It also has the drawback of its expression being directly related to histologic subtype and degree of differentiation.3–5 Although well-differentiated adenocarcinomas usually strongly express SP-A, poorly differentiated tumors, which are often the ones that pose the most diagnostic difficulty, are usually negative.6 As a result of this, over the past decade, TTF-1 became the lung-associated marker used more often by surgical pathologists to assist in the diagnosis and classification of lung tumors. Among lung carcinomas, TTF-1 is expressed in 75% to 85% of adenocarcinomas.7–12 It is not related to histologic subtype as acinar, tubular, bronchioloalveolar, mucinous (colloid), and signet-ring cell adenocarcinomas can express this antigen.13–15 Among neuroendocrine carcinomas of the lung, the vast majority of small cell carcinomas exhibit reactivity for TTF-1 (80% to 90%),16–18 whereas typical and atypical carcinoid tumors and poorly differentiated non-small cell neuroendocrine carcinomas exhibit a lower percentage of positivity. Only a minority of sarcomatoid carcinomas have been reported to be TTF-1 positive.19–21 Squamous cell carcinomas are commonly negative; however, a percentage of positive cases (1% to 37%) have been reported in some series.1,14,17,22–32 Despite its high specificity for tumors of thyroid and lung origin, TTF-1 is not absolutely specific as it can frequently be demonstrated in some extrapulmonary small cell carcinomas16,33–35 and, on rare occasions, in adenocarcinomas of the colon,12,30,36,37 stomach,7,30,38 ovary,17,39,40 endometrium,7,40–42 uterine cervix,41,43 and breast.44

With the introduction of newer biologically targeted chemotherapy, an accurate classification of lung tumors has become increasingly important. It has recently been reported that napsin A is both a more sensitive marker for lung adenocarcinomas than SP-A and a more specific marker than TTF-1, and that, because of this, immunostaining for napsin A could be very valuable in assisting in the differential diagnosis of these tumors.

Napsin A, also known as aspartyl protease 4, ASP4, napsin 1, TA01/TA02, Kdap, SNAPA, and EC3.4.23, is an aspartic proteinase that belongs to the peptidase A1 family, which also includes cathepsins D and E, renin, pepsin, gastricsin, and bovine chymosin. It is a single chain protein of 420 amino acids with a molecular weight of approximately 45 kDa that is encoded by the NSPSA gene located on chromosome 19q13.3.45,46 Napsin A is predominantly expressed in the lung and kidney.47–50 It has been demonstrated that the expression of napsin A is regulated by TTF-1, which also regulates the expression of surfactant protein B.51 In the lung, napsin A is expressed in alveolar type II pneumocytes, where by immunoelectron microscopy it has been demonstrated to be colocalized with prosurfactant B protein and surfactant B in the lamellar bodies, and it is believed to be involved in the N-terminal and C-terminal processing of prosurfactant B protein.52,53 Napsin A is also present in intra-alveolar macrophages, presumably as a result of phagocytosis (Fig. 1A). In the kidney, napsin A is expressed in the proximal tubules, where it is believed to function as a lysosomal protease involved in protein catabolism54 (Fig. 1B).

Figure 1
Figure 1
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LUNG TUMORS

Immunohistochemical studies have shown that the napsin A staining pattern in lung adenocarcinomas is granular and cytoplasmic (Fig. 1C). The first investigation into the expression of this marker in lung carcinomas was by Hirano et al49 in 2000. Using the 4B2 anti-napsin A mouse monoclonal antibody, these authors reported napsin A positivity in 47 (81%) of 58 adenocarcinomas, but in none of the squamous cell carcinomas, small cell carcinomas, or carcinoid tumors included in the study. In a subsequent study by the same group of investigators published in 2003 in which the TMU-Ad02 mouse monoclonal antibody was used napsin A positivity was demonstrated in 39 (91%) of 43 lung adenocarcinomas, whereas all of the squamous cell carcinomas, small cell carcinomas, and carcinoid tumors were negative for this marker.55 Subsequent studies by other groups of investigators using the TMU-Ad02, IP64, or KCG1.1 monoclonal antibodies have reported comparable results with those obtained by Hirano et al55 (Table 1). The percentage of napsin A positivity in adenocarcinomas in different published studies has ranged from 58% up to 91% of the cases.1,2,6,49,55–58 It should be pointed out that the lower percentages reported were in studies using either tissue microarray,59 biopsy specimens,62 or cytology material31 (Table 1). Several comparative studies on napsin A and TTF-1 expression have been published, some of which have indicated that napsin A is a more sensitive marker for lung adenocarcinomas than TTF-1,37,56,58,61 whereas others have shown the opposite2,31,59,60,62 (Table 2). In a combined review of 11 such studies, 627 (75%) of 836 lung adenocarcinomas were reported to be napsin A positive, whereas 623 (74.4%) of 837 exhibited TTF-1 positivity.1,2,31,32,37,56,58–62 These results indicate that the sensitivity of napsin A for lung adenocarcinomas is comparable with that of TTF-1. Only 1 investigation has been published on the expression of napsin A in bronchioloalveolar adenocarcinomas.31 The results of that study indicate that, similar to TTF-1, napsin A is expressed in the majority of cases of both mucinous and nonmucinous tumors, but its sensitivity is higher than that of TTF-1. All 7 of the adenocarcinomas with enteric differentiation investigated for napsin A expression by Inamura et al2 were negative for this marker, whereas 3 (43%) of the 7 were positive for TTF-1.

Table 1
Table 1
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Table 2
Table 2
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None of the small cell carcinomas or carcinoid tumors of the lung that have been investigated for napsin A expression have been shown to express this marker.6,31,53,58 This is in contrast to TTF-1, which has been reported to be expressed in the large majority of small cell carcinomas (80% to 100%)16,33,65–68 and in a large percentage (35% to 70%) of carcinoid tumors of the lung.65,69–71 It should be emphasized, however, that the number of cases of neuroendocrine carcinomas of the lung that have been investigated for napsin A expression is too low to draw any definitive conclusion regarding the expression of this marker in these tumors (Table 1).

The majority of published studies have indicated that napsin A is not expressed in squamous carcinomas of the lung1,6,31,58,60,62; however, 2 of the most recent publications on napsin A expression in these tumors have reported positivity in 12.5% and 26% of the cases, respectively.32,64 In a recent study by this investigator, none of the 70 pulmonary or 32 extrapulmonary squamous cell carcinomas investigated exhibited napsin A expression.72 As intra-alveolar macrophages and hyperplastic type II pneumocytes show strong napsin A positivity (Fig. 1D), it was suggested that these cells were the most likely cause of the napsin A positivity reported in the 2 previously mentioned investigations, particularly when it is considered that one of the studies was done on sections of cell blocks prepared from fine needle aspiration biopsies and the other on tissue microarrays in which it can sometimes be difficult to determine whether the reactive cells are tumors cells or, in actuality, represent non-neoplastic entrapped cells within the tumor.

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KIDNEY TUMORS

In 2003, using in situ hybridization, Ueno et al1 were the first to report napsin A expression in a renal cell carcinoma. Subsequent immunohistochemical studies have demonstrated napsin A positivity in the majority of papillary renal cell carcinomas (75% to 83%),31,37,58,73 in a smaller percentage (10% to 43%) of clear cell renal cell carcinomas,31,37,58,73 and rarely (3%) in chromophobe renal cell carcinomas58 (Table 3). In a combined review of 4 published series, 54 (79%) of 68 papillary and 21 (28%) of 76 clear cell carcinomas exhibited expression for this marker.31,37,58,73 Although none of the Xp11 translocation renal cell carcinomas or renal oncocytomas that have been investigated has shown napsin A positivity, relatively few such cases have been included in published series; therefore, no definitive conclusions regarding the expression of this marker in these types of tumors can be drawn. Examples of papillary and clear cell renal cell carcinomas exhibiting napsin A positivity are shown in Figures 1E and F

Table 3
Table 3
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DIAGNOSTIC APPLICATIONS OF NAPSIN A IMMUNOSTAINING

It has become increasingly important to distinguish between adenocarcinomas and squamous cell carcinomas of the lung because of the development of targeted therapies, as these new therapies may have different therapeutic or adverse effects, depending on the histologic type of the tumor. Although the differential diagnosis between adenocarcinomas and squamous cell carcinomas is relatively easy on hematoxylin-and-eosin-stained sections when the tumors are rather well differentiated, when they are poorly differentiated, their distinction can be difficult, especially in small biopsy specimens. The differential diagnosis, however, can be greatly facilitated by the use of napsin A immunostaining, combined with other markers, such as TTF-1, keratin 5/6, p63, and keratin 7. TTF-1 is a marker that, in my experience,74 and that of other investigators,8,33,58,60,62,68 is not expressed in squamous cell carcinomas of the lung and it has been reported to react in some of the lung adenocarcinomas that do not express napsin A. Keratin 5/6 is a highly specific squamous cell carcinoma marker that is usually absent in lung adenocarcinomas. p63 and keratin 7 are highly sensitive markers for squamous cell carcinomas and lung adenocarcinomas, respectively, although p63 has been reported in 15% up to 65% of lung adenocarcinomas75–78 and keratin 7 in 20% to 60% of squamous cell carcinomas.28,74,78–82 These findings indicate that the specificity of these 2 markers is lower than that of TTF-1, napsin A, and keratin 5/6.

Epithelioid mesotheliomas can potentially be confused with a lung adenocarcinoma involving the pleura. Several immunohistochemical studies, however, have shown that because napsin A is frequently expressed in lung adenocarcinomas, but absent in mesotheliomas, immunostaining for this marker can assist in discriminating between these 2 malignancies.55–58 Therefore, napsin A should be included in the panel of immunohistochemical markers used to assess pleural-based malignancies.11,83

Renal cell carcinomas, particularly papillary and clear cell renal cell carcinomas, have been shown to express napsin A31,37,58,73; therefore, immunostaining for this marker may have some utility in assisting in the diagnosis of these tumors. Compared with Pax-8, which is also a novel marker for renal cell carcinomas, napsin A seems to be less sensitive, but more specific.84 In contrast to Pax-8, which has been reported to be frequently expressed in other tumors, especially in thyroid carcinomas,84–87 ovarian, endometrial, and cervical adenocarcinomas,84,88,89 thymic epithelial tumors,84 and neuroendocrine carcinomas of the pancreas and gastrointestinal tract,90,91 napsin A is largely restricted to lung adenocarcinomas and renal cell carcinomas.

As the histologic features of adenocarcinomas of different sites overlap, the diagnosis of these tumors, when they present as a metastasis of unknown origin, can be difficult. Primary lung adenocarcinomas can be difficult to distinguish from metastatic adenocarcinomas arising from various sites, particularly when they present as a solitary lung lesion in a patient who has no known history of a malignant condition. Current information indicates that napsin A is almost exclusively expressed in lung adenocarcinomas and papillary and clear cell renal cell carcinomas. Only 2 of 53 thyroid carcinomas in 1 study were reported to be napsin A positive.58 None of the 329 carcinomas of other sites, including the breast, colon, stomach, pancreas, liver, ovary, or endometrium, that were investigated for napsin A expression in several studies were positive for this marker.2,6,31,37,55,56,58,60,61 These findings indicate that napsin A could be a very useful marker in the study of metastatic adenocarcinomas of unknown primary site, especially when it is used in conjunction with other organ-related markers.

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ANTI-NAPSIN A ANTIBODIES

At present, 3 anti-napsin A mouse monoclonal antibodies (clones TMU-Ad02, IP64, and KCG1.1) and a few rabbit polyclonal antibodies that can be used on formalin-fixed, paraffin-embedded tissue specimens are commercially available. As the TMU-Ad02 clone was the first to become available, it is also the one that has been the most frequently used in published studies.2,6,55–57,60,62 This antibody, also known as 6A1, was developed by Hirano et al49 in 2000 using a 33 amino acid N-terminal sequence as immunogen. The IP64 antibody was generated using a recombinant protein corresponding to a 126 amino acid region of napsin A and the KCG1.1 antibody was, according to the commercial source, produced using a synthetic peptide corresponding to the N-terminal of the napsin A protein. Both of the latter antibodies have been used in more recent published studies.31,32,37,58,61 Although no comparative studies using the 3 previously mentioned anti-napsin A mouse monoclonal antibodies have been published, current information indicates that they have a comparable sensitivity and specificity for lung adenocarcinomas (Table 1). There are no publications utilizing the commercially available polyclonal antibodies.

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Keywords:

napsin A; lung adenocarcinoma; renal cell carcinoma; immunohistochemistry

© 2012 Lippincott Williams & Wilkins, Inc.

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