Matthew C. Fox

Raman active components of skin cancer

Raman spectroscopy (RS) has shown great potential in noninvasive cancer screening. Statistically based algorithms, such as principal component analysis, are commonly employed to provide tissue classification; however, they are difficult to relate to the chemical and morphological basis of the spectroscopic features and underlying disease. As a result, we propose the first Raman biophysical model applied to in vivo skin cancer screening data. We expand upon previous models by utilizing in situ skin constituents as the building blocks, and validate the model using previous clinical screening data collected from a Raman optical fiber probe. We built an 830nm confocal Raman microscope integrated with a confocal laser-scanning microscope. Raman imaging was performed on skin sections spanning various disease states, and multivariate curve resolution (MCR) analysis was used to resolve the Raman spectra of individual in situ skin constituents. The basis spectra of the most relevant skin constituents were combined linearly to fit in vivo human skin spectra. Our results suggest collagen, elastin, keratin, cell nucleus, triolein, ceramide, melanin and water are the most important model components. We make available for download (see supplemental information) a database of Raman spectra for these eight components for others to use as a reference. Our model reveals the biochemical and structural makeup of normal, nonmelanoma and melanoma skin cancers, and precancers and paves the way for future development of this approach to noninvasive skin cancer diagnosis.

Biophysical basis for noninvasive skin cancer detection using Raman spectroscopy

Raman spectroscopy (RS) is proving to be a valuable tool for real time noninvasive skin cancer detection via optical fiber probe. However, current methods utilizing RS for skin cancer diagnosis rely on statistically based algorithms to provide tissue classification and do not elucidate the underlying biophysical changes of skin tissue. Therefore, we aim to use RS to explore skin biochemical and structural characteristics and then correlate the Raman spectrum of skin tissue with its disease state. We have built a custom confocal micro-Raman spectrometer system with an 830nm laser light. The high resolution capability of the system allows us to measure spectroscopic features from individual tissue components in situ. Raman images were collected from human skin samples from Mohs surgical biopsy, which were then compared with confocal laser scanning, two-photon fluorescence and hematoxylin and eosin-stained images to develop a linear model of skin tissue Raman spectra. In this model, macroscopic tissue spectra obtained from RS fiber probe were fit into a linear combination of individual basis spectra of primary skin constituents. The fit coefficient of the model explains the biophysical changes spanning a range of normal and various disease states. The model allows for determining parameters similar to that a pathologist is familiar reading and will be a significant guidance in developing RS diagnostic decision schemes.

Defining recurrence of nonmelanoma skin cancer after Mohs micrographic surgery: Report of the American College of Mohs Surgery Registry and Outcomes Committee

BACKGROUNDnStandardized definitions and methods of surveillance for local recurrence of nonmelanoma skin cancer are critical in determining cure rates attributed to treatment modalities.nnnOBJECTIVEnWe sought to offer a standard definition of local recurrence after surgical treatment of nonmelanoma skin cancer and to propose an acceptable surveillance period and tracking methods.nnnMETHODSnA literature search was performed for background definitions of local recurrence and tracking methods. The American College of Mohs Surgery (ACMS) Registry and Outcomes Committee then conducted a modified Delphi process to arrive at consensus definitions.nnnRESULTSnWe define local recurrence as a tumor with comparable histology, with contiguity to the surgical scar after treatment, and that arises within the area of the previously treated tumor.nnnLIMITATIONSnThis project reports the results of a modified Delphi method process involving members of the ACMS. The model described may not be useful for nonexcision type treatments such as topical chemotherapy, electrodessication and curettage, or radiation treatment.nnnCONCLUSIONSnPrevious definitions of recurrence and surveillance methods after surgical treatment of nonmelanoma skin cancer are variable and nonstandard. We describe consensus standards for defining andxa0tracking recurrence that should allow for consistent scientific evaluation and development of performance data in skin cancer outcomes registries.

Adnexal Carcinoma: Microcystic Adnexal Carcinoma and Sebaceous Carcinoma

Microcystic adnexal carcinoma (MAC) and sebaceous carcinoma (SC) are rare adnexal neoplasms. MAC most commonly presents as a poorly defined, firm, skin-colored papule, nodule, or plaque on the head and neck. Although locally destructive, MAC does not typically metastasize. Rates of misdiagnosis are high, due to incomplete, superficial sampling. Resection techniques with meticulous margin control, including Mohs micrographic surgery (MMS), are recommended in the management of MAC.

What do Patients Undergoing Mohs Micrographic Surgery Value? Results of a Patient Values Survey based on OAS-CAHPS

REFERENCES 1. Black N. Patient reported outcome measures could help transform healthcare. BMJ. 2013;346:f167. 2. McCormick Howard L. National Psoriasis Foundation: a patient-centric approach to improve access to psoriatic disease treatment. TSM J Manag Care. 2016;22(4 Suppl): s104-s107. 3. Kitchen H, Cordingley L, Young H, Griffiths CE, Bundy C. Patient-reported outcome measures in psoriasis: the good, the bad and the missing!. Br J Dermatol. 2015;172(5):1210-1221. 4. Puig L, Thom H, Mollon P, Tian H, Ramakrishna GS. Clear or almost clear skin improves the quality of life in patients with moderate-to-severe psoriasis: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2017;31: 213-220. 5. Armstrong AW, Robertson AD, Wu J, Schupp C, Lebwohl MG. Undertreatment, treatment trends, and treatment dissatisfaction among patients with psoriasis and psoriatic arthritis in the United States: findings from the National Psoriasis Foundation surveys, 2003-2011. JAMA Dermatol. 2013; 149(10):1180-1185. 6. Perez-Chada LM, Singh S, Callis-Duffin K, et al. International Dermatology Outcome Measures (IDEOM) Group 2016 New York Meeting: meeting summary and data from the Psoriasis Working Group. J Drugs Dermatol. 2017;16(8): 770-777. 7. Robinson A, Kardos M, Kimball AB. Physician Global Assessment (PGA) and Psoriasis Area and Severity Index (PASI): why do both? A systematic analysis of randomized controlled trials of biologic agents for moderate to severe plaque psoriasis. J Am Ac Dermatol. 2012;66(3):369-375.

Nodal Staging of High Risk Cutaneous Squamous Cell Carcinoma

BACKGROUNDnWhile progress has been made in defining the clinical and histopathologic features of high-risk cutaneous squamous cell carcinoma (HRcSCC), optimal staging guidelines remain elusive.nnnOBJECTIVEnWe seek to guide clinical practice regarding nodal staging options for patients with HRcSCC via review of evolving definitions of HRcSCC, nodal staging options, and how nodal staging may impact treatment and affect outcomes.nnnMETHODSnThis was a retrospective review of the published peer-reviewed literature regarding risk stratification, nodal staging, and treatment and outcomes for patients with HRcSCC via PubMed.nnnRESULTSnFor patients without clinical lymphadenopathy, based on literature from head and neck SCC, preoperative nodal staging with ultrasonography may be more useful than computed tomography or magnetic resonance imaging. Early nodal disease is usually curable, and therefore obtaining a sentinel lymph node biopsy specimen may be considered in those with negative imaging while we await studies of nodal staging outcomes.nnnLIMITATIONSnMore data are needed to validate the relationships between primary tumor stage and sentinel lymph node biopsy status and to determine if early detection of nodal disease impacts survival for patients with HRcSCC.nnnCONCLUSIONnIt is reasonable to consider nodal staging for patients with HRcSCC (Brigham and Womens Hospital stage T2b and T3) in the absence of clinically palpable lymphadenopathy via radiographic imaging and, if negative, sentinel lymph node biopsy.

Raman spectroscopy reveals biophysical markers in skin cancer surgical margins

The recurrence rate of nonmelanoma skin cancer is highly related to the residual tumor after surgery. Although tissueconserving surgery, such as Mohs surgery, is a standard method for the treatment of nonmelanoma skin cancer, they are limited by lengthy and costly frozen-section histopathology. Raman spectroscopy (RS) is proving to be an objective, sensitive, and non-destructive tool for detecting skin cancer. Previous studies demonstrated the high sensitivity of RS in detecting tumor margins of basal cell carcinoma (BCC). However, those studies rely on statistical classification models and do not elucidate the skin biophysical composition. As a result, we aim to discover the biophysical differences between BCC and primary normal skin structures (including epidermis, dermis, hair follicle, sebaceous gland and fat). We obtained freshly resected ex vivo skin samples from fresh resection specimens from 14 patients undergoing Mohs surgery. Raman images were acquired from regions containing one or more structures using a custom built 830nm confocal Raman microscope. The spectra were grouped using K-means clustering analysis and annotated as either BCC or each of the five normal structures by comparing with the histopathology image of the serial section. The spectral data were then fit by a previously established biophysical model with eight primary skin constituents. Our results show that BCC has significant differences in the fit coefficients of nucleus, collagen, triolein, keratin and elastin compared with normal structures. Our study reveals RS has the potential to detect biophysical changes in resection margins, and supports the development of diagnostic algorithms for future intraoperative implementation of RS during Mohs surgery.

Tumor margin assessment in Mohs surgery using reflectance, fluorescence and Raman spectroscopy

Mohs surgery is the current gold standard to treat large, aggressive or high-risk non-melanoma skin cancer (NMSC) cases. While Mohs surgery is an effective treatment, the procedure is time-consuming and expensive for physicians as well as burdensome for patients as they wait for frozen section histology. Our group has recently demonstrated high diagnostic accuracy using a noninvasive “spectral biopsy” (combination of diffuse reflectance (DRS), fluorescence (FS) and Raman spectroscopy (RS)) to classify NMSC vs. normal lesion in a screening setting of intact tissue. Here, we examine the sensitivity of spectral biopsy to pathology in excised Mohs sections. The system is designed with three modalities integrated into one fiber probe, which is utilized to measure DRS, FS, and RS of freshly excised skin from patients with various NMSC pathologies including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), where each measurement location is correlated to histopathology. The spectral biopsy provides complimentary physiological information including the reduced scattering coefficient, hemoglobin content and oxygen saturation from DRS, NADH and collagen contribution from FS and information regarding multiple proteins and lipids from RS. We then apply logistic regression model to the extracted physiological parameters to classify NMSC vs. normal tissue. The results on the excised tissue are generally consistent with in vivo measurements showing decreased scattering within the tumor and reduced fluorescence. Due to the high sensitivity of RS to lipids, subcutaneous fat often dominates the RS signal. This pilot study demonstrates the potential for a spectral biopsy to classify NMSC vs. normal tissue, indicating the opportunity to guide Mohs excisions.

New Yellow Plaques in a Patient Taking Pembrolizumab

A woman in her 70s presented with a new 4-cm left upper lobe lung mass with hilar lymphadenopathy. Biopsy results demonstrated a squamous cell carcinoma (SCC) of the lung, and chemoradiotherapy with carboplatin and paclitaxel for stage 3A disease was initiated. An allergic reaction prompted a change to cisplatin-etoposide, which continued as adjuvant chemotherapy after the radiation was complete. At first restaging, a recurrence of disease in the lung was detected, which was treated with cisplatin and gemcitabine for 4 months before she enrolled in a clinical trial (NCT02009449) in which she received combination therapy with pembrolizumab, 2 mg/kg intravenously for 21 days, and an investigational agent, AM0010 (pegylated recombinant human interleukin-10), 10 μg/kg subcutaneously on days 1 through 14 of the 21-day cycle. Three months into treatment, she developed multiple thick, mildly pruritic, yellow hyperkeratotic plaques on her lower extremities (Figure, A). A referral to a dermatology expert was initiated. Clinical image A Histopathologic image B Histopathologic image C