Recent advancements in the understanding of the histogenesis and molecular genetics of neoplasias have improved diagnostic accuracy and refined tumor classification by pathologists, including ophthalmic pathologists. For example, we now know that many historically eminent pathologists were often wrong regarding the diagnosis and classification of soft tissue sarcomas and mimickers thereof.
This increased molecular understanding also has therapeutic implications in some settings and may explain why, for example, uveal melanoma behaves so differently than cutaneous melanoma regarding treatment success: the two are histogenically and molecularly different.
The former is derived from spindled, dendritic stromal melanocytes and is driven by mutations in G–protein-coupled receptors and often BRCA1-associated protein 1 (BAP-1). The latter is derived from intraepithelial melanocytes and driven by BRAF mutations and/or ultraviolent induced damage.
Despite this progress, pathologists still occasionally struggle to distinguish or appropriately classify certain tumors. The histopathologic diagnosis of some ocular tumors, such as routine retinoblastoma and uveal melanoma, is usually straightforward, especially if the globe is enucleated, allowing the pathologist to examine the entire tumor and its relation to normal anatomic structures. However, contemporary pathologists surprisingly often face clinically ambiguous tumors. The ambiguity can be due to a combination of factors, such as an unusual location, a history of prior malignancy, or an unusual age for the suspected tumor type. The ambiguity is exacerbated if the submitted biopsy is small, and the candidate diagnoses have overlapping immunohistochemical characteristics.
In this issue, Mudhar et al (see page 765) report an advance in distinguishing among certain intraocular tumors using immunohistochemistry for PAX8. PAX8 is a paired-box transcription factor typically expressed during fetal development. It is most frequently used in diagnostic surgical pathology to demonstrate that a malignancy is of renal, thyroid, or Müllerian origin.
During a routine workup for metastatic renal cell carcinoma to the globe, Mudhar et al noted PAX8 staining of some normal intraocular structures. PAX8 was already known to be a transcription factor important in the embryologic development of the eye, but its expression profile had not previously been well documented in the adult eye.The strong nuclear PAX8 staining of, for example, the ciliary body epithelium, and the absence of PAX8 staining of uveal melanocytes and the retinal pigment epithelium led the authors to hypothesize that PAX8 expression could help distinguish intraocular tumors with otherwise overlapping structural features and immunoreactivity patterns.
This newly identified pattern of PAX8 staining in normal human eyes and intraocular tumors may help to remove the diagnostic ambiguity in the following situations.
- Heavily pigmented ciliary body tumors. Not all pigmented intraocular tumors are melanoma. Melanocytomas, melanomas, pigmented adenomas, and pigmented adenocarcinomas all express melanocytic markers and may express some keratins, while the first two are PAX8 negative and the latter two are PAX8 positive.
- Rosette-forming, small round blue cell tumors in the peripheral retina or ciliary body. Medulloepitheliomas are diffusely PAX8 positive while retinoblastomas show only rare PAX8-positive cells.
- Primary adenocarcinomas and metastatic adenocarcinomas to the eye. Metastatic adenocarcinomas are common in the uveal tract and can histologically mimic primary adenomas or adenocarcinomas of the nonpigmented ciliary epithelium. In this situation, one must be aware that PAX8 positivity does not indicate origin of a tumor outside the eye. PAX8–positive tumors (such as metastatic papillary thyroid carcinoma, ciliary body adenoma and ciliary body adenocarcinoma) have overlapping tubular and trabecular morphologies and also share characteristics with oncocytic renal neoplasms, which are also PAX8 positive.
Although each of the diagnostically difficult scenarios listed above is uncommon or rare (as are some of the tumors), in aggregate they are not infrequently encountered in a moderately busy ophthalmic pathology practice. The correct diagnosis is critical for treatment, staging, and prognosis. Mudhar et al convincingly demonstrate that PAX8 belongs in the immunohistochemical panel required in the work-up of a puzzling intraocular tumor. The new knowledge of both the normal and tumoral expression of PAX8 in the eye will greatly benefit the practicing ophthalmic pathologist and the referring surgeon, providing crucial diagnostic discrimination between neoplasms of uveal melanocytes, ciliary/iris epithelium, and neuroepithelium. This knowledge will also help pathologists and surgeons in the diagnosis of metastatic disease.