Paired-box genes (PAX) encode a family of nine well-characterized paired-box transcription factors (PAX1-9), which are important for embryogenesis and disease (1). PAX proteins have been implicated as regulators of organogenesis and key factors in maintaining pluripotency of stem cell populations during development. Among these PAX genes, PAX8 has been hypothesized to be crucial in determining cell fate during the development of the thyroid, kidney, brain, eyes and Müllerian system and regulates expression of the Wilms’ tumor suppressor gene (WT1) (2–7). A number of previous studies have identified that PAX8 is not only expressed in the aforementioned organs but also found at high levels in specific types of tumor, including thyroid and renal carcinomas and pancreatic neuroendocrine tumors (8–11). In addition, PAX8 has been found to be expressed at high levels in ovarian carcinomas and serous effusions (3,12), indicating that PAX8 detection may prove useful in the clinic (Table I).

A number of studies have found that PAX8 is important for the development of various types of tumor (8–10). Together with thyroid transcription factor (TTF)-1 and TTF-2 (FoxE1), PAX8 is markedly associated with thyroid gland organogenesis. PAX8 expression has also been identified in thyroid carcinomas (10,13,14). Tacha et al found that PAX8 was expressed in 90% of thyroid cancer cases (15). In addition, follicular thyroid carcinoma (FTC) accounts for 10–20% of all thyroid cancers and up to 40% of cause-specific mortalities. Notably, the resulting fusion protein, PAX8/peroxisome proliferator-activated receptor (PPAR)-γ, has been found in ∼50% of FTC cases (13,16,17). Chromosomal translocations involving PAX5 and PAX8 genes in thyroid cancer indicate that PAX genes have an oncogenic capacity when constitutively expressed, either as part of a fusion gene or as a whole gene (10,18).

Previously, PAX8 was found to be markedly associated with renal tumors (19,20). Renal cell carcinomas (RCC) stained positive for PAX8 in 90% of the cases studied and 100% of normal kidney samples stained PAX8-positive (15). Knoepp et al reported that immunoreactivity for PAX8 and PAX2 was observed in 88 and 83% of 24 cytology specimens, respectively. The presence of either PAX8 or PAX2 immunostaining revealed a total sensitivity of 92%, indicating that PAX8 and PAX2 are useful adjuncts for confirmation of RCC diagnoses in cytology specimens (9). Collecting duct carcinoma (CDC) is a relatively rare but aggressive form of renal malignancy with variable morphological features and lacks a suitable marker for detection. A previous study found that all CDC cases were positive for PAX8. The immunoprofile of PAX8⁺/p63⁻ is consistent with the diagnosis of CDC with a sensitivity of 85.7% and specificity of 100%. By contrast, a PAX8⁻/p63⁺ profile indicates upper urinary tract transitional cell carcinoma (UUC) with a sensitivity of 88.2% and specificity of 100%. The nephric lineage restriction of PAX8 indicates a renal tubular rather than an urothelial differentiation in CDC according to the inverse PAX8/p63 expression observed in CDC and UUC (20).

Furthermore, PAX8 has been recognized as a potential immunohistochemical marker of pancreatic neuroendocrine tumors (8,21). It was reported that among well-differentiated neuroendocrine tumors, only tumors from the pancreas were PAX8-positive (14/25, 56%) whereas no cases of pulmonary, ileal, duodenal, rectal or ovarian well-differentiated neuroendocrine tumors were positive for PAX8 (8). The observation that pancreatic well-differentiated neuroendocrine tumors frequently express PAX8 may be useful for distinguishing pancreatic primary tumors from tumors of other anatomical sites. By contrast, PAX8 expression is not specific for pancreatic origin in poorly differentiated neuroendocrine carcinomas, whereas it is observed in extrapancreatic poorly differentiated neuroendocrine carcinomas, indicating that PAX8 expression is not markedly associated with poorly differentiated neuroendocrine carcinomas. Sangoi et al found that PAX8 was positive in 74% of primary pancreatic neuroendocrine tumors and PAX8 expression did not correlate with World Health Organization categorization, grade, size, functional status or the presence of liver or lymph node metastases (22). Among liver metastases, only pancreatic neuroendocrine tumors (20/31, 65%) were PAX8-positive, whereas no cases of ileal, pulmonary, duodenal and rectal neuroendocrine tumor metastases were PAX8-positive. Overall, PAX8 is expressed in primary and metastatic pancreatic well-differentiated neuroendocrine tumors, enabling reliable differentiation between pancreatic and ileal and pulmonary well-differentiated neuroendocrine tumors using immunostaining methods.

Ovarian cancer is one of the most lethal forms of cancer in females and currently lacks useful markers and efficient screening methods (23), due to the complexity of variable subtypes. At present, the most common marker used in monitoring therapy of this disease is CA-125; however, this marker is not specific and sensitive enough to be useful as a screening test, with serum values in the normal range in half of patients with stage I disease (24,25). Considerable efforts have been made to identify suitable markers for detection and differentiation between various forms of ovarian cancer. In 2003, analysis of the PAX8 gene by DNA microarray revealed high expression in ovarian cancer. Using the prediction analysis of microarrays (PAM) method, the expression of 61 genes was analyzed in 68 breast and 57 ovarian carcinoma samples and PAX8 expression was found at higher levels in ovarian compared with breast cancer (26). Consistent with these observations, microarray analysis performed by Bowen et al found that PAX8 was highly expressed in EOCs, whereas it was absent from the ovarian surface epithelia of healthy individuals. In addition, the authors observed that PAX8 was localized to the nucleus of non-ciliated epithelia in simple ovarian epithelial inclusion cysts and in 3 epithelial ovarian cancer subtypes (serous, endometrioid and clear cell). PAX8 was also found to be expressed in the non-ciliated secretory cells of healthy fallopian tube mucosal linings but not in the adjacent ciliated epithelia (27). Laury et al reported that PAX8 staining was present in 99% of high-grade serous ovarian carcinomas and 100% of low-grade ovarian carcinomas and serous borderline tumors (28). Tacha et al identified that 79% of ovarian cancers expressed PAX8 (15). These observations indicate that PAX8 may prove useful for the detection of ovarian cancers.

PAX8 is not only crucial for determining cell fate during the development of the thyroid, kidney and Müllerian system, but has also been found to be expressed at high levels in thyroid and renal carcinomas and pancreatic neuroendocrine tumors. Recently, PAX8 has been used in the detection and differential diagnosis of ovarian epithelial carcinomas. Consistencies in PAX8 staining between EOC and the fallopian tube indicate that EOC may originate from the fallopian tube. However, the molecular mechanism of PAX8 in the carcinogenesis of these tumors remains unclear and requires further analysis.