Faculty Bibliography

Understanding of cAMP signaling has greatly improved over the past decade. The advent of live cell imaging techniques and more specific pharmacologic modulators has led to an improved understanding of the intricacies by which cAMP is able to modulate such a wide variety of cellular pathways. It is now appreciated that cAMP is able to activate multiple effector proteins at distinct areas in the cell leading to the activation of very different downstream targets. The investigation of signaling proteins in cancer is a common route to the development of diagnostic tools, prognostic tools, and/or therapeutic targets, and in this review we highlight how investigation of cAMP signaling microdomains driven by the soluble adenylyl cyclase in different cancers has led to the development of a novel cancer biomarker. Antibodies directed against the soluble adenylyl cyclase (sAC) are highly specific markers for melanoma especially for lentigo maligna melanoma and are being described as "second generation" cancer diagnostics, which are diagnostics that determine the 'state' of a cell and not just identify the cell type. Due to the wide presence of cAMP signaling pathways in cancer, we predict that further investigation of both sAC and other cAMP microdomains will lead to additional cancer biomarkers. This article is part of a Special Issue entitled: The role of soluble adenylyl cyclase in health and disease.

Transplant-associated thrombotic microangiopathy (TA-TMA) refers to inflammatory and thrombotic diseases of the microvasculature characterized by hemolytic anemia, thrombocytopenia, and evidence of organ damage, particularly acute renal failure. This syndrome occurs in 10% to 20% of patients with allogeneic hematopoietic stem cell transplants (HSCTs). It is much less frequent in the autologous setting. TA-TMAs present diagnostic challenges because they may not clearly fall into one of the categories of the 2 major TMAs: atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP). In addition, complications of the transplant itself, including infection, graft-versus-host disease, and disseminated intravascular coagulation, as well as the side effects of immunosuppressive drugs, can mimic a TMA. Because the pathophysiology of TA-TMA is poorly understood, current treatment options are suboptimal, and the condition carries a very high mortality rate. In 3 recent case summaries, the median acute response rate to plasma exchange was as high as 55%, but this therapy failed to alter underlying disease pathology and had little impact on overall mortality, which was approximately 80%. Indeed, the vast majority of TA-TMA patients lack suppression of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity to less than 5% to 10% of normal and do not have a complete response to plasma exchange, characteristics indicating that a TTP-like disorder is not involved. Recent advances in the treatment of aHUS may offer a therapeutic option in the aHUS-like TMAs associated with HSCTs. These issues are discussed in the context of a patient recently evaluated and treated at our institution; the case serves to illustrate the difficulties associated with the diagnosis and treatment of TA-TMA.

Epithelioid sarcoma (ES) represents an aggressive soft tissue tumor with varied morphologic and histopathologic presentations that typically elicits a broad differential diagnosis, including granuloma annulare, necrobiotic granuloma, fibrous histiocytoma, synovial sarcoma, amelanotic melanoma and poorly differentiated primary cutaneous and metastatic adenocarcinoma. ES is characterized microscopically by a nodular arrangement of abundant, deeply eosinophilic, polygonal tumor cells with frequent central necrosis and hemorrhage, rare mitotic figures and minimal pleomorphism. At the periphery, tumor cells are spindle shaped and may exhibit frequent local infiltration along tendons, fascial planes and neurovascular bundles. Immunohistochemistry typically reveals expression of both epithelial and mesenchymal antigens, such as cytokeratin and vimentin, respectively. The absence of a connection between tumor cells and the overlying epidermis, with or without an in situ carcinoma component, typically rules out a primary cutaneous squamous cell carcinoma. We report a case of stage IV proximal-type ES that mimicked molluscum contagiosum clinically and was histopathologically reminiscent of invasive squamous cell carcinoma because of attachment and colonization of the overlying epidermis. The case represents an unusual pathologic presentation of ES and highlights potential pitfalls in establishing the diagnosis.

Due to the proximity of the skin, subcutis, and axilla to the breast, the possibility of a "breast mass" actually representing a dermatologic lesion should be considered, particularly if the proliferation does not look characteristically "mammary" in appearance. Even more underappreciated is the scenario of a dermatologic proliferation morphologically masquerading as a breast tumor. The pathologist can fall prey to this pitfall if he/she is led to believe that the location of the tumor is the breast proper. The aim of this review is to provide an overview of dermatologic mimickers of breast lesions and helpful ways to discern between them when possible.