Jennifer L. Herrmann

Liver Kinase B1 (LKB1) in the pathogenesis of epithelial cancers

LKB1 acts as a master kinase, with its major protein targets being the family of AMPKs. Through activation of multiple signaling pathways, LKB1s main physiologic functions involve regulating cellular growth, metabolism, and polarity. Germline mutations in LKB1 result in Peutz-Jeghers Syndrome, a rare cancer susceptibility syndrome. In addition, multiple LKB1 mutations have been identified in sporadic cancers, especially those of the lung. Recent studies from a variety of murine models have helped characterize LKB1s role in the pathogenesis of epithelial cancers. In some tumor types, LKB1 might function chiefly to suppress cell growth or invasion, while in other cases, it may serve to prevent metastasis. Moreover, molecular signatures of individual tumors likely influence LKB1s operational role, as multiple studies have shown that LKB1 can synergize with other tumor suppressors and/or oncogenes to accelerate tumorigenesis. To date, LKB1 has been considered mainly a tumor suppressor; however, some studies have suggested its potential oncogenic role, mainly through the suppression of apoptosis. In short, LKB1 is a tissue and context-specific kinase. This review aims to summarize our current understanding of its role in the pathogenesis of epithelial cancers.

Mini-reviewLiver Kinase B1 (LKB1) in the pathogenesis of epithelial cancers

LKB1 acts as a master kinase, with its major protein targets being the family of AMPKs. Through activation of multiple signaling pathways, LKB1s main physiologic functions involve regulating cellular growth, metabolism, and polarity. Germline mutations in LKB1 result in Peutz-Jeghers Syndrome, a rare cancer susceptibility syndrome. In addition, multiple LKB1 mutations have been identified in sporadic cancers, especially those of the lung. Recent studies from a variety of murine models have helped characterize LKB1s role in the pathogenesis of epithelial cancers. In some tumor types, LKB1 might function chiefly to suppress cell growth or invasion, while in other cases, it may serve to prevent metastasis. Moreover, molecular signatures of individual tumors likely influence LKB1s operational role, as multiple studies have shown that LKB1 can synergize with other tumor suppressors and/or oncogenes to accelerate tumorigenesis. To date, LKB1 has been considered mainly a tumor suppressor; however, some studies have suggested its potential oncogenic role, mainly through the suppression of apoptosis. In short, LKB1 is a tissue and context-specific kinase. This review aims to summarize our current understanding of its role in the pathogenesis of epithelial cancers.

Recognizing large-cell transformation of mycosis fungoides

BACKGROUND Although patients with mycosis fungoides (MF) typically experience an indolent disease course, a minority undergo a process of large-cell transformation (LCT), which often heralds more aggressive disease and shortened survival. Regrettably, most dermatologists are unfamiliar with LCT, and even fewer understand how to recognize it clinically. Because a diagnosis of LCT typically triggers more aggressive therapy and/or referral to cutaneous T-cell lymphoma (CTCL) centers, it is paramount for clinicians to be able to recognize suspect lesions visually. OBJECTIVE LCT is diagnosed histologically; however, diagnostic biopsy is performed only if transformed lesions are suspected clinically. Because the literature provides little information on what clinical features should lead to suspicion of LCT, we sought to identify and categorize the presentations of LCT to aid in its recognition. METHODS We identified 14 patients with biopsy-proven LCT confirmed by a board-certified dermatopathologist experienced with this diagnosis. The clinical presentations of LCT, timing of its evolution, and treatment regimens were evaluated by chart and photograph review. RESULTS We devised 3 categories that clinically represent LCT: (1) LCT occurring as a new, solitary nodule within a classic MF patch or plaque, (2) LCT occurring as abrupt onset of multiple scattered papules and/or nodules without spontaneous resolution, and (3) LCT occurring within new or enlarging tumors. LIMITATIONS A larger number of reviewed cases might reveal additional clinical presentations of LCT. CONCLUSIONS Dermatologists may use our categories of clinical indicators to recognize and diagnose LCT earlier, allowing implementation of more aggressive treatment regimens when appropriate.

Liver kinase B1 (LKB1) in the pathogenesis of UVB-induced murine basal cell carcinoma.

LKB1, a known tumor suppressor, is mutated in Peutz-Jeghers Syndrome (PJS). It is responsible for the enhanced cancer risk in patients with PJS. Dysregulation of LKB1-dependent signaling also occurs in various epithelial cancers. UVB alters the expression of LKB1, though its role in the pathogenesis of skin cancer is unknown. Here we describe upregulation of LKB1 expression in UVB-induced murine basal cell carcinoma (BCC) and in human skin tumor keratinocytes. AMP-kinase and acetyl Co-A carboxylase, the downstream LKB1 targets, are also enhanced in this neoplasm. In addition, p-Akt, a kinase which inactivates GSK3β by its phosphorylation, is enhanced in BCCs. Consistently, an accumulation of p-GSK3β and an increase in activated nuclear β-catenin are found. mTOR signaling, which is also inhibited by LKB1, remains upregulated in BCCs. However, a marked decrease in the expression of sestrins, which function as potent negative regulators of mTOR is observed. Metformin, a known chemical inducer of this pathway, was found effective in immortalized HaCaT keratinocytes, but failed to activate the LKB1-dependent signaling in human carcinoma A431 cells. Thus, our data show that the LKB1/AMPK axis fails to regulate mTOR pathway, and a complex regulatory mechanism exists for the persistent mTOR activation in murine BCCs.

Concomitant Mycosis Fungoides and Vitiligo: How Mycosis Fungoides May Contribute to Melanocyte Destruction

Background: Few reports have described vitiligo developing in patients with cutaneous T-cell lymphoma (CTCL). Objective: We sought to identify possible factors that might predispose patients with CTCL to vitiligo. Methods: Patient demographics, CTCL disease characteristics and treatments were analyzed in 25 patients with CTCL who developed vitiligo. Cox proportional hazards modeling was used to identify associations of risk factors with the development of vitiligo. Results: Younger age, later CTCL disease stage (stages IIB-IV) and presence of a CD8+CD4- mycosis fungoides phenotype were associated with the development of vitiligo. After adjusting for disease stage, increased risk of vitiligo was associated with methotrexate and CD4 antibody therapies (although the total number of patients with these was small), while decreased risk was associated with nitrogen mustard and PUVA therapies. Conclusions: No single feature was common to all of our patients, suggesting that multiple factors may contribute to the development of vitiligo in a patient-specific fashion.

Using better understanding of anatomy to improve surgical assistants' utility

SURGICAL CHALLENGE Surgical assistants are integral to conducting efficient procedures with good outcomes. Assistants position tissues to better expose lesions, apply counter-tension when excising and suturing, and aid in hemostasis by blotting with Q-tips and gauze. However, in certain anatomic locations, such as the central face, and in patients on multiple blood thinners, blotting alone may not provide adequate hemostasis. Simple compression of key adjacent vessels can aid markedly in field visualization, although proper execution requires some basic appreciation of facial anatomy.

Basal Cell Carcinoma Overlying a Cardiac Pacemaker Successfully Treated Using Mohs Micrographic Surgery

A 75-year-old man presented for treatment of a basal cell carcinoma (BCC) located on the left chest directly over a pacemaker that had been placed in December 2010 for atrial fibrillation with slow ventricular response. On physical examination, a 1.1by 0.5-cm poorly demarcated erythematous plaque was identified at the site of the previous biopsy, which had revealed superficial and nodular-type BCC transected at the deep margin (Figure 1). Treatment options including topical therapy and surgical management were discussed with the patient. Given the poorly demarcated Figure 3. After freezing of the specimen, additional optimum cutting temperature medium is placed on the chuck upside down and pressed over the specimen forming a rigid block ready to be cut in the cryostat microtome. LETTERS AND COMMUNICATIONS

Large-Cell Transformation of Mycosis Fungoides Occurring at the Site of Previously Treated Cutaneous B-Cell Lymphoma

The development of concomitant cutaneous B-cell and T-cell lymphomas is rare. In patients who develop both Band T-cell malignancies, a T-cell lymphoma, usually mycosis fungoides (MF), more frequently predates the B-cell lymphoma. In patients who develop a secondary B-cell lymphoma, progression of MF has been rarely reported. Herewe report thefirst caseofMFprogression in the formof a new tumor with large-cell transformation (LCT) developing at the site of a previously treated B-cell lymphoma tumor. When treating a second malignancy in patients with concomitant lymphomas, immune system preservation might be crucial in preventing progression of the first malignancy. In any patient with a history of concomitant Band Tcell lymphomas who develops a new tumor, repeat biopsy should be strongly considered to determine tumor origin, because MF tumors, including those with LCT might be clinically indistinguishable from cutaneous B-cell lymphoma.