Siegrid S. Yu

Temporal Dissection of Tumorigenesis in Primary Cancers

Timely intervention for cancer requires knowledge of its earliest genetic aberrations. Sequencing of tumors and their metastases reveals numerous abnormalities occurring late in progression. A means to temporally order aberrations in a single cancer, rather than inferring them from serially acquired samples, would define changes preceding even clinically evident disease. We integrate DNA sequence and copy number information to reconstruct the order of abnormalities as individual tumors evolve for 2 separate cancer types. We detect vast, unreported expansion of simple mutations sharply demarcated by recombinative loss of the second copy of TP53 in cutaneous squamous cell carcinomas (cSCC) and serous ovarian adenocarcinomas, in the former surpassing 50 mutations per megabase. In cSCCs, we also report diverse secondary mutations in known and novel oncogenic pathways, illustrating how such expanded mutagenesis directly promotes malignant progression. These results reframe paradigms in which TP53 mutation is required later, to bypass senescence induced by driver oncogenes.

A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: Creation and rationale for inclusion of tumor (T) characteristics

BACKGROUND The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing. Although most patients achieve complete remission with surgical treatment, those with advanced disease have a poor prognosis. The American Joint Committee on Cancer (AJCC) is responsible for the staging criteria for all cancers. For the past 20 years, the AJCC cancer staging manual has grouped all nonmelanoma skin cancers, including cSCC, together for the purposes of staging. However, based on new evidence, the AJCC has determined that cSCC should have a separate staging system in the 7th edition AJCC staging manual. OBJECTIVE We sought to present the rationale for and characteristics of the new AJCC staging system specific to cSCC tumor characteristics (T). METHODS The Nonmelanoma Skin Cancer Task Force of AJCC reviewed relevant data and reached expert consensus in creating the 7th edition AJCC staging system for cSCC. Emphasis was placed on prospectively accumulated data and multivariate analyses. Concordance with head and neck cancer staging system was also achieved. RESULTS A new AJCC cSCC T classification is presented. The T classification is determined by tumor diameter, invasion into cranial bone, and high-risk features, including anatomic location, tumor thickness and level, differentiation, and perineural invasion. LIMITATIONS The data available for analysis are still suboptimal, with limited prospective outcomes trials and few multivariate analyses. CONCLUSIONS The new AJCC staging system for cSCC incorporates tumor-specific (T) staging features and will encourage coordinated, consistent collection of data that will be the basis of improved prognostic systems in the future.

Memory regulatory T cells reside in human skin.

Regulatory T cells (Tregs), which are characterized by expression of the transcription factor Foxp3, are a dynamic and heterogeneous population of cells that control immune responses and prevent autoimmunity. We recently identified a subset of Tregs in murine skin with properties typical of memory cells and defined this population as memory Tregs (mTregs). Due to the importance of these cells in regulating tissue inflammation in mice, we analyzed this cell population in humans and found that almost all Tregs in normal skin had an activated memory phenotype. Compared with mTregs in peripheral blood, cutaneous mTregs had unique cell surface marker expression and cytokine production. In normal human skin, mTregs preferentially localized to hair follicles and were more abundant in skin with high hair density. Sequence comparison of TCRs from conventional memory T helper cells and mTregs isolated from skin revealed little homology between the two cell populations, suggesting that they recognize different antigens. Under steady-state conditions, mTregs were nonmigratory and relatively unresponsive; however, in inflamed skin from psoriasis patients, mTregs expanded, were highly proliferative, and produced low levels of IL-17. Taken together, these results identify a subset of Tregs that stably resides in human skin and suggest that these cells are qualitatively defective in inflammatory skin disease.

Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma

BACKGROUND The effects of primary tumor size on nodal involvement and of number of involved nodes on survival have not, to our knowledge, been examined in a national database of Merkel cell carcinoma (MCC). OBJECTIVE We sought to analyze a retrospective cohort of patients with MCC from the largest US national database to assess the relationships between these clinical parameters and survival. METHODS A total of 8044 MCC cases in the National Cancer Data Base were analyzed. RESULTS There was a 14% risk of regional nodal involvement for 0.5-cm tumors that increased to 25% for 1.7-cm (median-sized) tumors and to more than 36% for tumors 6 cm or larger. The number of involved nodes was strongly predictive of survival (0 nodes, 76% 5-year relative survival; 1 node, 50%; 2 nodes, 47%; 3-5 nodes, 42%; and ≥6 nodes, 24%; P < .0001 for trend). Younger and/or male patients were more likely to undergo pathological nodal evaluation. LIMITATIONS The National Cancer Data Base does not capture disease-specific survival. Hence, relative survival was calculated by comparing overall survival with age- and sex-matched US population data. CONCLUSION Pathologic nodal evaluation should be considered even for patients with small primary MCC tumors. The number of involved nodes is strongly predictive of survival and may help improve prognostic accuracy and management.

Immunohistochemical prognostication of Merkel cell carcinoma: p63 expression but not polyomavirus status correlates with outcome.

Merkel cell carcinoma (MCC) represents a cutaneous malignancy with high associated mortality. Numerous studies have attempted to define characteristics to more accurately predict outcome. Two recent studies have demonstrated that Merkel cell polyomavirus (MCPyV) seropositivity correlated with a better prognosis, while a third study revealed no difference. Expression of p63 by tumor cell nuclei has been shown to be associated with a worse prognosis in a European cohort. To better understand the relationship between prognosis and MCPyV or p63 status, we used immunohistochemistry to evaluate both attributes in 36 US patients with MCC. Our results show that when considered as a binary variable, p63 expression represents a strong risk factor (p < 0.0001, hazards ratio (HR) = ∞) for shortened survival. In addition, our results show that MCPyV status does not correlate with survival (p = 0.6067, HR = 1.27). Our study corroborates the European observation that p63 immunoexpression is useful as a prognostic tool. Larger studies will need to be performed in order to determine whether p63 status should be included in MCC staging, since our study is limited by its relative small size.

Adenosquamous Carcinoma of the Skin: A Case Series

BACKGROUND Adenosquamous carcinoma is an uncommon cutaneous malignant neoplasm with mixed glandular and squamous differentiation and a propensity for aggressive clinical behavior. OBSERVATIONS Of 27 patients diagnosed as having adenosquamous carcinoma, 19 were men and 5 were immunosuppressed. The mean age was 74 years. The majority of tumors were located on the face and scalp (19 of 27 [70%]) or upper extremity (4 of 27 [15%]). Squamous and glandular differentiation was characteristic. Thickness of the primary lesion ranged from 1.2 to 9.2 mm, with all tumors extensively invading the reticular dermis. Perineural invasion was seen in 4 of 27 primary cases (15%). Although 3 of 6 patients treated with Mohs micrographic surgery had subsequent locoregional recurrences, there was no evidence of distant metastasis after a mean of 2.3 years of patient follow-up. CONCLUSIONS Adenosquamous carcinoma is best considered as a locally aggressive high-risk subtype of cutaneous squamous cell carcinoma. Tumor thickness and perineural invasion are high-risk histopathological attributes, and immunosuppression is an important clinical risk factor. Although Mohs micrographic surgery may be the best initial treatment, locoregional recurrence is common.

Organ transplant recipients with Merkel cell carcinoma have reduced progression-free, overall, and disease-specific survival independent of stage at presentation

BACKGROUND Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. Immunosuppression is associated with increased incidence of MCC. OBJECTIVE We sought to determine whether solid organ transplant recipients (SOTR) with MCC had decreased progression-free, disease-specific, and overall survival compared with immunocompetent patients. METHODS We conducted a retrospective cohort study examining 8 SOTR with MCC and 89 immunocompetent control subjects. Cox regression models were generated for outcomes of progression, disease-specific death, and death from any cause, adjusted for patient sex, age at diagnosis, and stage at presentation. RESULTS SOTR had a 4.1-fold increased hazard for progression (95% confidence interval 1.57-10.95, P=.004), a 10.5-fold increased hazard for all-cause mortality (95% confidence interval 3.06-35.98, P<.0001), and an 11.9-fold increased hazard for MCC-specific death (95% confidence interval 2.67-53.08, P=.001), adjusted for sex, age, and stage at presentation. SOTR had decreased 1-year overall survival, 46.8% versus 88.6%, and decreased 1-year MCC-specific survival, 56.3% versus 95.2%. LIMITATIONS This is a single-center study from a tertiary academic care center, and may not be generalizable to all patient populations. CONCLUSIONS SOTR have a significant reduction in overall, MCC-specific, and progression-free survival compared with immunocompetent patients. Further studies will determine whether aggressive treatment may improve outcomes in this high-risk population.

Tobacco smoking and dermatologic surgery

BACKGROUND Cigarette smoking is the leading cause of preventable death and a major public health concern. Numerous clinical and experimental studies have examined the effect of nicotine on wound healing and surgical procedures, but there are limited published reports in the dermatologic surgery literature. OBJECTIVE This article seeks to develop evidence-based recommendations regarding the effect of tobacco use in patients undergoing dermatologic surgery procedures. METHODS This article reviews the existing published English-language literature pertaining to the effects of tobacco on wound healing and surgical complications. RESULTS Tobacco use is associated with a higher incidence of postoperative complications including wound dehiscence, flap or graft necrosis, prolonged healing time, and infections. LIMITATIONS This review article only summarizes past reports and studies. CONCLUSION Recommendations for smoking cessation before dermatologic surgery are provided based on the available data.

18F-fluorodeoxyglucose positron emission tomography-computed tomography imaging in the management of Merkel cell carcinoma: a single-institution retrospective study.

Background Merkel cell carcinoma (MCC) is among the deadliest of cutaneous malignancies. A lack of consensus evaluation and treatment guidelines has hindered management of this disease. The utility of simultaneous positron emission tomography and computed tomography (PET/CT) has been demonstrated for a variety of tumors yet remains underinvestigated for MCC. Objectives To report the value of fluorodeoxyglucose PET/CT imaging in the initial staging and ongoing management of individuals with MCC and to determine whether any patient or tumor characteristics may predict when PET/CT is more likely to have greater influence on medical decision‐making. Materials and Methods A single‐institution retrospective chart review was conducted of all patients diagnosed with MCC who underwent FDG‐PET/CT scanning from 2007 to 2010. The outcome of each of these studies was evaluated as to the influence on patient staging and management. Patient clinical information and information on gross and microscopic tumor characteristics were collected and analyzed. Results Twenty patients underwent 39 PET/CT scans. Results of PET/CT imaging revealed previously unknown information related to MCC in four (20%) patients, leading to changes in management in three of these four cases. Three previously unknown neoplasms were detected. Conclusion Fluorodeoxyglucose‐positron emission tomography and computed tomography is a valuable tool for initial staging and to assess response to therapy of patients diagnosed with MCC. Larger prospective studies would be required to establish the optimal timing for this imaging modality.

Bleeding complications in dermatologic surgery.

Although the overall incidence is low, bleeding complications in dermatologic surgery can occur and be the source of significant patient morbidity. In this article, we summarize the key aspects of preoperative assessment of patients at risk for bleeding. A review of current issues and literature regarding safe continuation of anticoagulant and antiplatelet medications in dermatologic surgery patients is also presented. In addition, principles for management of bleeding events, should they occur, are also highlighted.