|
|
Teaching Case 8Available Clinical HistoryA thirty-eight year old white Caucasian woman complained of a 3-week history of nasal obstruction and enlarging vague fullness in her left posterior neck, which eventually became a distinct mass. Clinical work-up included unsuccessful fine needle aspiration (mostly small lymphocytes). CT scan of the neck showed the mass to be mostly retropharyngeal. Biopsy was obtained via indirect laryngoscopy, showing the illustrated features in figures 1 and 2. H&E Images
Tissue examination clearly reveals a poorly-differentiated malignant neoplasm, intimately associated with dense lymphocytic and eosinophilic infiltrate. The tumor also appears to be in close approximation to the surface respiratory epithelium. Cytomorphologically, highly malignant 'epithelioid' cells with syncytial growth pattern are noted showing very high N/C ratio with markedly large nucleoli. At this point, a differential diagnosis could be rendered based only on the H&E findings. Results of Immunohistochemistry StudiesThe initial immunohistochemical work-up showed the following results: Broad-spectrum cytokeratin (OSCAR clone): Uniformly positive Obviously, other diagnostic entities such as melanoma, anaplastic large cell lymphoma, angiosarcoma, and granulocytic sarcoma are excluded by these results, leading to the generic diagnosis of poorly differentiated carcinoma. One could arguably stop at this point without performing additional studies, but the clinician requested additional markers to help determine the mode of treatment, as discussed below. Additional marker studies showed the following results: Cytokeratin 5 Uniformly positive
Final DiagnosisAt this point, a definitive diagnosis of nasopharyngeal carcinoma (NPC) could be reliably established, and the diagnoses of metastatic lung and ovarian serous carcinomas are excluded. DiscussionAt first glance, one might have questions about the manner in which the additional markers were selected. For instance, the panel does not include hormone receptors, which if positive, could point to breast as the site of origin. The reason for not pursuing this is that the tumor had a very high nuclear grade, which almost invariably is associated with a loss of steroid hormone receptors. Also, why were cytokeratins 7 and 20 not included in the work-up? Given the clinical setting, the differential diagnosis includes metastatic lung, breast and minor salivary gland carcinoma, all of which typically have the same coordinate expression of cytokeratins 7 and 20 (cytokeratin 7-positive, 20-negative). Finally, the diagnosis of primary squamous cell carcinoma or NPC (which is negative for the expression of cytokeratins 7 and 20), could be confirmed by adding two highly sensitive markers of squamous differentiation, namely cytokeratin 5 and p63. Let us discuss these two markers and then have final thoughts about the differential diagnosis of NPC. p63 is a member of the p53 gene family, and has been found to be a highly sensitive and specific marker of squamous and transitional cell epithelium and tumors derived from there (1). p63 is also highly sensitive and a specific nuclear marker of myoepithelial cells of the breast. In a very recent study, it was documented that in all benign lesions, p63-immunoreactive cells formed a continuous basal rim along the epithelial structures. Similar findings were reported around nests of in situ carcinoma (2). Given its relatively 'young age', it is possible that this transcription factor may also be expressed in other situations. Therefore, it is always prudent to perform p63 studies in conjunction with cytokeratin 5, until the former is screened on a sizable number of cases. Nevertheless, both the published literature, and our experience with it, suggest that it is a very powerful marker. Cytokeratin 5 is a member of the cytokeratin intermediate filament family. It was recently described as a marker for stratified epithelium such as squamous and transitional cell epithelium (3,4). It has also been described as a highly specific and sensitive positive marker of mesothelial cells and mesothelioma. In other words, cytokeratin 5 is one of these markers with 'contextual specificity', whose specificity is dependent on the clinical setting and differential diagnosis. Back to the case at hand... This poorly differentiated tumor is positive for co-expression of cytokeratin 5 (figure 3) and p63 (figure 4), and the tumor cells show expression of the Epstein-Barr virus, EBER-1 mRNA, by in situ hybridization studies [ISH] (figure 5), pointing directly to the diagnosis of NPC. As you may have noticed, this patient is a white Caucasian female and not from a high-incidence region of the world (China, central and northern Africa), where NPC constitutes up to 20% of human cancers, in contrast to 0.25% in the US. According to the World Health Organization, NPC is classified based on the level of squamous differentiated into 2 major categories: keratinizing (well differentiated squamous carcinoma) and non-keratinizing; the latter is in turn divided into two categories, differentiated (with a phenotype similar to transitional carcinoma), and undifferentiated carcinoma. The latter is the most common subtype (60%) with the first two being less common in decreasing order of frequency. NPC is believed to be associated with, if not caused by, viruses. Interestingly, the keratinizing type does not appear to be highly associated with EBV, which is most commonly expressed in the undifferentiated group (5), whereas HPV was detected only in a subset of the keratinizing type (6). From a clinical standpoint, even though the undifferentiated type is the most aggressive and usually accompanied by regional nodal metastasis, it is easier to cure by radiation therapy than the other two types, with the keratinizing type being the most refractory to radiation. This responsiveness to radiation is one more reason why these tumors should be recognized and separated from the sinonasal undifferentiated carcinomas (SNUC). This is exactly the reason the treating physician requested differentiation of this tumor from SNUC. Using IHC and ISH, one can reliably differentiate between SNUC and undifferentiated NPC. The former does not show strong high molecular weight cytokeratin expression, and is negative for EBV genomic expression by ISH. Also, a major subset of SNUC shows variable expression of neuroendocrine markers. The case at hand illustrates the characteristic and reproducible immunophenotype of nasopharyngeal carcinoma. References
|
