Aggressive locally recurrent vulvar cancer: review of cases presented to Massachusetts General Hospital 1990 to present.

Isolated recurrences of squamous cell vulvar carcinoma treated by surgical re-excision have excellent outcomes. There is a subset of these patients who develop multiple local recurrences that are difficult to manage and have a high risk of dying from their cancers. We reviewed women presenting with vulvar cancer (200 patients) to Massachusetts General Hospital from 1990 to present and identified 12 women with aggressive, locally recurrent squamous cell carcinomas of the vulva. The identified women all had successful primary radical vulvectomy and groin node dissections with negative surgical margins (except patient 2) and lymph nodes with no lympho-vascular space invasion. Seven women had underlying lichen sclerosis. Eight had a history of vulvar intraepithelial neoplasia or persistent carcinoma in situ. Ten patients had greater than three recurrences after primary surgical therapy. One died of recurrent vulvar cancer 10 months after her initial diagnosis. Two patients died after three recurrences. The only unifying clinicopathologic factor among these women was persistent lichen sclerosis and persistent carcinoma in situ. Understanding the underlying mechanisms that predisposed these premalignant lesions to transform into carcinomas will help predict in which women these are likely to re-occur and may help determine which women require more aggressive initial treatment.

Myelin protein zero and membrane adhesion.

Protein zero (P0) is a member of the immunoglobulin gene superfamily (IgCAM) that is expressed at high levels in myelinated vertebrates in central (fish and amphibia) and peripheral (all species) myelin. This glycoprotein is the major adhesive component of peripheral myelin, where it mediates self-adhesion of the Schwann cell plasma membrane. Although the expression of P0 is naturally limited to Schwann cells, the molecular mechanisms of P0-mediated adhesion can be considered general and "obligatory" because, when expressed in a variety of cell lines, P0 induces strong intercellular adhesion. Modeling studies, X-ray crystallographic analysis, and experimental site-directed mutagenesis have provided excellent working models for understanding how P0 mediates adhesion at the atomic level. These models remain to be experimentally tested. However, in humans, certain mutations in P0 produce dysmyelinating disease, possibly due to disruptions in the predicted P0 lattice.

Protein zero, a myelin IgCAM, induces physiologically operative tight junctions in nonadhesive carcinoma cells.

In the peripheral nervous system, protein zero (P0), a homophilic immunoglubulin cell adhesion molecule, mediates adhesion of Schwann cell membranes as they enwrap axons and generate compact myelin. Although P0 is naturally only expressed in peripheral myelin, it can behave as a vigorous adhesion molecule in a variety of cell types (Filbin et al. [1990] Nature 344:871-872; Schneider-Schaulies et al. [1990] J Neurosci Res 27:286-297; Doyle et al. [1995] J Cell Biol 131:465-482) and can thus be characterized as an obligatory adhesion molecule. Previously, we showed that when HeLa, a cervical carcinoma cell line devoid of epithelial junctions, is forced to express P0, strong cell-cell adhesion is induced, proteins associated with junctional elements are upregulated, and ultrastructurally tight junctions, adherens junctions, and desmosomes become apparent (Doyle et al., 1995). In this report, we assessed whether the tight junctions were physiologically operative in P0 HeLa expressors. Consistent with the presence of operative tight junctions, we found that P0 expressors in monolayers maintained endogenous proteins in their apical and basolateral plasma membrane subdomains. Furthermore, these cells generated a higher transepithelial resistance than did control HeLa cells, which is indicative of the formation of an effective intercellular permeability barrier.

Suppression of tumorigenicity in an aggressive cervical carcinoma induced by protein zero, a nervous system IgCAM.

In mammals, protein zero (P0), a neural IgCAM, is expressed solely in the peripheral nervous system where it mediates self-adhesion of Schwann cell membranes as compact myelin is generated. We show that when P0 is expressed in HeLa, a cervical carcinoma cell line, cells regain adhesion-mediated growth control, including the acquisition of contact inhibition and loss of anchorage-independent growth. Additionally, P0-expressing HeLa cells lose the ability to invade an artificial matrix, which correlates with decreased secretion of matrix-degrading enzymes. Lastly, and of great interest, unlike the aggressively metastatic cell line from which they were derived, P0-HeLa cells are neither tumorigenic nor metastatic when injected into athymic nude mice. By all these criteria, P0 expression appears to efficiently suppress in the long term, the transformed state of this carcinoma cell line. N-cadherin and its intracellular partners plakoglobin, alpha- and beta-catenin were significantly upregulated in the P0-HeLa cells. It appears therefore that P0 induces epithelialization and suppression of tumorigenicity in HeLa through the activation of the cadherin/catenin signaling systems. We conclude that the forced expression of bona fide adhesion molecules, such as P0, may serve as 'upstream' inducers of an essentially dormant but undamaged adhesion program in carcinoma cells that ultimately triggers the re-acquisition of normal epithelial characteristics, thereby suppressing tumorigenicity. Therapeutically, it may be that intercellular adhesion, no matter how it is induced, may serve as a single master event that is able to induce reversion of the carcinomatous state.