Extramammary Paget Disease. Part I. Epidemiology, Pathogenesis, Clinical Features, and Diagnosis.

Extramammary Paget disease (EMPD) is a rare skin cancer of apocrine-rich skin that mimics common inflammatory and infectious dermatoses, leading to delays in diagnosis and increased patient morbidity. Better clinical recognition of this entity, multidisciplinary patient assessment, and deeper understanding of the underlying pathophysiology are essential to improve patient care and disease outcomes. It is important to distinguish primary intraepithelial/micro-invasive EMPD from invasive EMPD or cases with adenocarcinoma arising within EMPD. This 2-part continuing medical education series provides a complete picture of EMPD. Part 1 of this continuing medical education series reviews the epidemiology, oncogenesis, clinical and histopathologic presentation, workup, and prognosis of this rare cancer.

Perifollicular linear projections: A dermatoscopic criterion for the diagnosis of lentigo maligna on the face.

BACKGROUND: Lentigo maligna (LM) can mimic benign, flat, pigmented lesions and can be challenging to diagnose. OBJECTIVE: To describe a new dermatoscopic feature termed "perifollicular linear projections (PLP)" as a diagnostic criterion for LM on the face. METHODS: Retrospective study on reflectance confocal microscopy and dermatoscopy images of flat facial pigmented lesions originating from 2 databases. PLP were defined as short, linear, pigmented projections emanating from hair follicles. Dermatoscopy readers were blinded to the final histopathologic diagnosis. RESULTS: From 83 consecutive LMs, 21/83 (25.3%) displayed "bulging of hair follicles" on reflectance confocal microscopy and 18 of these 21 (85.7%), displayed PLP on dermatoscopy. From a database of 2873 consecutively imaged and biopsied lesions, 252 flat-pigmented facial lesions were included. PLP was seen in 47/76 melanomas (61.8%), compared with 7/176 lesions (3.9%) with other diagnosis (P < .001). The sensitivity was 61.8% (95% CI, 49.9%-72.7%), specificity 96.0% (95% CI, 92.9%-98.4%). PLP was independently associated with LM diagnosis on multivariate analysis (OR 26.1 [95% CI, 9.6%-71.0]). LIMITATIONS: Retrospective study. CONCLUSION: PLP is a newly described dermatoscopic criterion that may add specificity and sensitivity to the early diagnosis of LM located on the face. We postulate that PLP constitutes an intermediary step in the LM progression model.

Jet-injection assisted photodynamic therapy for superficial and nodular basal cell carcinoma: A pilot study.

BACKGROUND: Photodynamic therapy (PDT) with topical δ-Aminolevulinic acid (ALA) has efficacy in treating basal cell carcinoma (BCC) but is limited by incomplete penetration of ALA into the deeper dermis. This prospective open-label pilot trial investigated the safety and efficacy of photosensitizer jet injection for PDT (JI-PDT) for BCC treatment. It was performed with 15 patients (n = 15) with histologically confirmed, untreated, low-risk nodular BCCs at a single institution. METHODS: For the intervention, JI-PDT patients (n = 11) received two sessions of jet-injected ALA with PDT separated by four to 6 weeks. To further understand treatment technique, another group of patients (n = 4) received jet-injected ALA followed by tumor excision and fluorescence microscopy (JI-E). Treatment tolerability was assessed by local skin responses (LSR) score at five distinct time intervals. Fluorescence microscopy assessed protoporphyrin IX penetration depth and biodistribution within the tumor. At the primary endpoint, tumor clearance was evaluated via visual inspection, dermoscopy and reflectance confocal microscopy. Postinjection and postillumination pain levels, and patient satisfaction, were scored on a 0-10 scale. RESULTS: Fifteen participants with mean age of 58.3, who were 15/15 White, non-Hispanic enrolled. The median composite LSR score immediately after JI-PDT was 5 (interquartile range [IQR] = 3) which decreased to 0.5 (IQR = 1) at primary endpoint (p < 0.01). Immunofluorescence of excised BCC tumors with jet-injected ALA showed photosensitizer penetration into papillary and reticular dermis. Of the 13 JI-PDT tumors, 11 had tumor clearance confirmed, 1 recurred, and 1 was lost to follow-up. 1/11 patients experienced a serious adverse event of cellulitis. 70% of patients had local scarring at 3 months. Patients reported an average pain level of 5.6 (standard deviation [SD] = 2.3) during jet injection and 3.7 (SD = 1.8) during light illumination. CONCLUSIONS: Jet injection of ALA for PDT treatment of nodular low-risk BCC is tolerable and feasible and may represent a novel modality to improve PDT.

Lentigo maligna melanoma mapping using reflectance confocal microscopy correlates with staged excision: A prospective study.

BACKGROUND: Lentigo maligna/lentigo maligna melanoma (LM/LMM) can present with subclinical extension that may be difficult to define preoperatively and lead to incomplete excision and potential recurrence. Preliminarily studies have used reflectance confocal microscopy (RCM) to assess LM/LMM margins. OBJECTIVE: To evaluate the correlation of LM/LMM subclinical extension defined by RCM compared with the gold standard histopathology. METHODS: Prospective study of LM/LMM patients referred for dermatologic surgery. RCM was performed at the clinically defined initial surgical margin followed by margin-controlled staged excision with paraffin-embedded tissue, and histopathology was correlated with RCM results. RESULTS: Seventy-two patients were included. Mean age was 66.8 years (standard deviation, 11.1; range, 38-89); 69.4% were men. Seventy of 72 lesions (97.2%) were located on the head and neck with mean largest clinical diameter of 1.3 cm (range, 0.3-5). Diagnostic accuracy for detection of residual melanoma in the tumor debulk (after biopsy) had a sensitivity of 96.7% and a specificity of 66.7% when compared with histopathology. RCM margin assessment revealed an overall agreement with final histopathology of 85.9% (κ = 0.71; P < .001). LIMITATIONS: No RCM imaging beyond initial planned margins was performed. CONCLUSION: RCM showed moderate to excellent overall agreement between RCM imaging of LM/LMM and histopathology of staged excision margins.

In vivo imaging characterization of basal cell carcinoma and cutaneous response to high-dose ionizing radiation therapy: A prospective study of reflectance confocal microscopy, dermoscopy, and ultrasonography.

BACKGROUND: Radiation therapy (RT) is a treatment option for select skin cancers. The histologic effects of RT on normal skin or skin cancers are not well characterized. Dermoscopy, high-frequency ultrasonography (HFUS), and reflectance confocal microscopy (RCM) are noninvasive imaging modalities that may help characterize RT response. OBJECTIVES: To describe changes in the tumor and surrounding skin of patients with basal cell carcinoma (BCC) treated with RT. METHODS: The study was conducted between 2014 and 2018. Patients with biopsy-proven BCCs were treated with 42 Gy in 6 fractions using a commercially available brachytherapy device. Dermoscopy, HFUS, and RCM were performed before treatment and at 6 weeks, 3 months, and 12 months after RT. RESULTS: A total of 137 imaging assessments (RCM + dermoscopy + HFUS) were performed in 12 patients. BCC-specific features were present in 81.8%, 91%, and 17% of patients imaged with dermoscopy, RCM, and HFUS at baseline, respectively, before treatment. After treatment, the resolution of these features was noted in 33.4%, 91.7%, and 100% of patients imaged with the respective modalities. No recurrences were seen after a mean of 31.7 months of follow-up. LIMITATIONS: Small sample size and no histopathologic correlation. CONCLUSION: Dermoscopy and HFUS were not as reliable as RCM at characterizing BCC RT response.

Angulated small nests and cords: Key diagnostic histopathologic features of infiltrative basal cell carcinoma can be identified using integrated reflectance confocal microscopy-optical coherence tomography.

BACKGROUND: Accurate basal cell carcinoma (BCC) subtyping is requisite for appropriate management, but non-representative sampling occurs in 18% to 25% of biopsies. By enabling non-invasive diagnosis and more comprehensive sampling, integrated reflectance confocal microscopy-optical coherence tomography (RCM-OCT) may improve the accuracy of BCC subtyping and subsequent management. We evaluated RCM-OCT images and histopathology slides for the presence of two key features, angulation and small nests and cords, and calculated (a) sensitivity and specificity of these features, combined and individually, for identifying an infiltrative BCC subtype and (b) agreement across modalities. METHODS: Thirty-three RCM-OCT-imaged, histopathologically-proven BCCs (17 superficial and/or nodular; 16 containing an infiltrative component) were evaluated. RESULTS: The presence of angulation or small nests and cords was sufficient to identify infiltrative BCC on RCM-OCT with 100% sensitivity and 82% specificity, similar to histopathology (100% sensitivity, 88% specificity, kappa = 0.82). When both features were present, the sensitivity for identifying infiltrative BCC was 100% using either modality and specificity was 88% on RCM-OCT vs 94% on histopathology, indicating near-perfect agreement between non-invasive and invasive diagnostic modalities (kappa = 0.94). CONCLUSIONS: RCM-OCT can non-invasively identify key histopathologic features of infiltrative BCC offering a possible alternative to traditional invasive biopsy.

An international 3-center training and reading study to assess basal cell carcinoma surgical margins with ex vivo fluorescence confocal microscopy.

BACKGROUND: Novel solutions are needed for expediting margin assessment to guide basal cell carcinoma (BCC) surgeries. Ex vivo fluorescence confocal microscopy (FCM) is starting to be used in freshly excised surgical specimens to examine BCC margins in real time. Training and educational process are needed for this novel technology to be implemented into clinic. OBJECTIVE: To test a training and reading process, and measure diagnostic accuracy of clinicians with varying expertise level in reading ex vivo FCM images. METHODS: An international three-center study was designed for training and reading to assess BCC surgical margins and residual subtypes. Each center included a lead dermatologic/Mohs surgeon (clinical developer of FCM) and three additional readers (dermatologist, dermatopathologist, dermatologic/Mohs surgeon), who use confocal in clinical practice. Testing was conducted on 30 samples. RESULTS: Overall, the readers achieved 90% average sensitivity, 78% average specificity in detecting residual BCC margins, showing high and consistent diagnostic reading accuracy. Those with expertise in dermatologic surgery and dermatopathology showed the strongest potential for learning to assess FCM images. LIMITATIONS: Small dataset, variability in mosaic quality between centers. CONCLUSION: Suggested process is feasible and effective. This process is proposed for wider implementation to facilitate wider adoption of FCM to potentially expedite BCC margin assessment to guide surgery in real time.

Treatment of Extramammary Paget Disease and the Role of Reflectance Confocal Microscopy: A Prospective Study.

BACKGROUND: Extramammary Paget disease (EMPD) poses treatment challenges. Invasive and noninvasive treatment modalities exist with variable success reported. Reflectance confocal microscopy (RCM) is emerging as an adjuvant diagnostic tool. OBJECTIVE: To evaluate the treatment of EMPD patients and the role of RCM. METHODS: Prospective study. Demographic and tumor characteristics were recorded. Handheld-RCM was performed and correlated with histology. Treatment, clearance, pathology, and follow-up were all recorded. RESULTS: Thirty-six EMPD lesions in 33 patients were included. Mean age was 71.7 years, and 23 were men. Mean number of surgical stages needed to clear margins was 1.9 (SD, 0.9; 1.0-3.0 stages), and mean margin needed to clear was 1.8 cm. Reflectance confocal microscopy correlated well with scouting punch biopsies (kappa, 0.93; p < .001). Disruption of the dermoepidermal junction was associated with invasive EMPD versus in situ (83.3% vs 25.9%) on histology (p = .01). LIMITATIONS: Relatively small sample size. CONCLUSION: Extramammary Paget disease is challenging, and lesion demarcation is of the utmost importance. Using a staged surgical excision approach, the mean margins needed were 1.8 cm, less than previously reported. Nonsurgical modalities, including radiation therapy, imiquimod, or photodynamic therapy can be considered if surgery is not pursued. Reflectance confocal microscopy is a valuable noninvasive imaging modality for the management of EMPD.

Presurgical evaluation of basal cell carcinoma using combined reflectance confocal microscopy-optical coherence tomography: A prospective study.

BACKGROUND: Initial biopsy of basal cell carcinoma (BCC) may fail to show aggressive histologic subtypes. Additionality, the clinical evaluation of BCC before surgery can miss subclinical extension. Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) are emerging tools that can help in the presurgical evaluation of BCCs. OBJECTIVE: To assess the feasibility of a combined RCM-OCT imaging modality for presurgical evaluation of biopsy-proven BCCs for residual tumor, margin status, and depth. METHODS: Thirty-eight BCCs in 35 patients referred to a tertiary cancer center for Mohs micrographic surgery (MMS) were imaged with combined RCM-OCT. Images were correlated to MMS frozen sections. RESULTS: Thirty-eight BCCs were analyzed. The mean age of patients was 67.34 years (range, 36-84 years), and 20 patients were female (57.14%). Twenty four BCCs were located on the head (63.16%) , and the mean size was 8.58 mm (range, 3-30 mm). RCM-OCT showed an overall agreement of 91.1% with MMS frozen sections. A sensitivity of 82.6% (95% confidence interval [CI], 69%-92%), specificity of 93.8% (95% CI, 88%-97%), and receiver operating characteristic curve of 0.88 (95% CI, 0.82-0.94) was found. OCT depth was highly correlated with MMS depth (r2 = 0.9). LIMITATIONS: Small sample size and difficulty evaluating certain challenging anatomic sites. CONCLUSIONS: Combined RCM-OCT may emerge as a useful tool for presurgical evaluation of BCCs.

Improvement of diagnostic confidence and management of equivocal skin lesions by integration of reflectance confocal microscopy in daily practice: Prospective study in 2 referral skin cancer centers.

BACKGROUND: Reflectance confocal microscopy (RCM) allows accurate, noninvasive, in vivo diagnosis for skin cancer. However, its impact on physicians' diagnostic confidence and management is unknown. OBJECTIVES: We sought to assess the physicians' diagnostic confidence and management before and after RCM of equivocal skin lesions. METHODS: Prospective, 2-center, observational study. During clinical practice, 7 dermatologists recorded their diagnostic confidence level (measured in a scale from 0 to 10), diagnosis, and management before and after RCM of clinically/dermoscopically equivocal lesions that raised concern for skin cancer. We also evaluated the diagnostic accuracy before and after RCM. RESULTS: We included 272 consecutive lesions from 226 individuals (mean age, 53.5 years). Diagnostic confidence increased from 6.2 to 8.1 after RCM (P < .001) when RCM confirmed or changed the diagnosis. Lesion management changed in 33.5% cases after RCM (to observation in 51 cases and to biopsy/excision in 31 cases). After RCM, the number needed to excise was 1.2. Sensitivity for malignancy before and after RCM was 78.2% and 85.1%, respectively. Specificity before and after RCM was 78.8% and 80%, respectively. LIMITATIONS: Small sample size, real-life environment, and different levels of expertise among RCM users. CONCLUSION: Physicians' diagnostic confidence and accuracy increased after RCM when evaluating equivocal tumors, frequently resulting in management changes while maintaining high diagnostic accuracy.

Using plasma cell-free DNA to monitor the chemoradiotherapy course of cervical cancer.

The liquid biopsy is being integrated into cancer diagnostics and surveillance. However, critical questions still remain, such as how to precisely evaluate cancer mutation burden and interpret the corresponding clinical implications. Herein, we evaluated the role of peripheral blood cell-free DNA (cfDNA) in characterizing the dynamic mutation alterations of 48 cancer driver genes from cervical cancer patients. We performed targeted deep sequencing on 93 plasma cfDNA from 57 cervical cancer patients and from this developed an algorithm, allele fraction deviation (AFD), to monitor in an unbiased manner the dynamic changes of genomic aberrations. Differing treatments, including chemotherapy (n = 22), radiotherapy (n = 14) and surgery (n = 15), led to a significant decrease in AFD values (Wilcoxon, p = 0.029). The decrease of cfDNA AFD values was accompanied by shrinkage in the size of the tumor in most patients. However, in a subgroup of patients where cfDNA AFD values did not reflect a reduction in tumor size, there was a detection of progressive disease (metastasis). Furthermore, a low AFD value at diagnosis followed a later increase of AFD value also successfully predicted relapse. These results show that plasma cfDNA, together with targeted deep sequencing, may help predict treatment response and disease development in cervical cancer.

Evaluation of soluble carbonic anhydrase IX as predictive marker for efficacy of bevacizumab: A biomarker analysis from the geparquinto phase III neoadjuvant breast cancer trial.

We analyzed the predictive potential of pretreatment soluble carbonic anhydrase IX levels (sCAIX) for the efficacy of bevacizumab in the phase III neoadjuvant GeparQuinto trial. sCAIX was determined by enzyme-linked immunosorbent assay (ELISA). Correlations between sCAIX and pathological complete response (pCR), disease-free and overall survival (DFS, OS) were assessed with logistic and Cox proportional hazard regression models using bootstrapping for robust estimates and internal validation. 1,160 HER2-negative patient sera were analyzed, of whom 577 received bevacizumab. Patients with low pretreatment sCAIX had decreased pCR rates (12.1 vs. 20.1%, p = 0.012) and poorer DFS (adjusted 5-year DFS 71.4 vs. 80.5 months, p = 0.010) compared to patients with high sCAIX when treated with neoadjuvant chemotherapy (NCT). For patients with low sCAIX, pCR rates significantly improved upon addition of bevacizumab to NCT (12.1 vs. 20.4%; p = 0.017), which was not the case in patients with high sCAIX (20.1% for NCT vs. 17.0% for NCT-B, p = 0.913). When analyzing DFS we found that bevacizumab improved 5-year DFS for patients with low sCAIX numerically but not significantly (71.4 vs. 78.5 months; log rank 0.234). In contrast, addition of bevacizumab worsened 5-year DFS for patients with high sCAIX (81 vs. 73.6 months, log-rank 0.025). By assessing sCAIX levels we identified a patient cohort in breast cancer that is potentially undertreated with NCT alone. Bevacizumab improved pCR rates in this group, suggesting sCAIX is a predictive biomarker for bevacizumab with regards to treatment response. Our data also show that bevacizumab is not beneficial in patients with high sCAIX.

Basal cell carcinoma: Epidemiology; pathophysiology; clinical and histological subtypes; and disease associations.

As the most common human cancer worldwide and continuing to increase in incidence, basal cell carcinoma is associated with significant morbidity and cost. Continued advances in research have refined both our insight and approach to this seemingly ubiquitous disease. This 2-part continuing medical education article will provide a comprehensive and contemporary review of basal cell carcinoma. The first article in this series describes our current understanding of this disease regarding epidemiology, cost, clinical and histopathologic presentations, carcinogenesis, natural history, and disease associations.

Basal cell carcinoma: Contemporary approaches to diagnosis, treatment, and prevention.

As the most common human cancer worldwide and continuing to increase in incidence, basal cell carcinoma is associated with significant morbidity and cost. Continued advances in research have refined both our insight and approach to this seemingly ubiquitous disease. This 2-part continuing medical education series provides a comprehensive and contemporary review of basal cell carcinoma. The second article in this series will present both the current standard of care and newly developed approaches to diagnosis, treatment, and prevention of this disease.

Reflectance confocal microscopy-guided carbon dioxide laser ablation of low-risk basal cell carcinomas: A prospective study.

BACKGROUND: Basal cell carcinoma (BCC) treatment modalities can be stratified by tumor subtype and recurrence risk. The main limitation of nonsurgical treatment modalities is the lack of histopathologic confirmation. Reflectance confocal microscopy (RCM) is a noninvasive imaging device that provides quasihistologic images. OBJECTIVE: To evaluate the feasibility and efficacy of RCM-guided carbon dioxide (CO2) laser ablation of low-risk BCCs. METHODS: Prospective study with biopsy specimen-proven low-risk BCCs imaged with RCM. RCM was performed on these sites before and after ablation. If residual tumor was found, a new series of laser passes were performed. The patients were then monitored for recurrence clinically and with RCM. RESULTS: Twenty-two tumor sites in 9 patients (5 men, 4 women) were imaged and treated. Median age was 59 ± 12.9 years (range, 30-74 years). Mean tumor size was 7.7 mm (range, 5-10 mm). Residual tumor was identified in 5 of 22 cases (22.7%) under RCM on immediate first-pass postablation sites, prompting additional laser passes. Median follow-up was 28.5 months (range, 22-32 months) with no recurrences found. CONCLUSIONS: Addition of RCM to laser ablation workflow can detect subclinical persistent tumor after initial ablation and may serve as an aid to increase the efficacy of laser ablation.

Reflectance confocal microscopy confirms residual basal cell carcinoma on clinically negative biopsy sites before Mohs micrographic surgery: A prospective study.

BACKGROUND: Biopsy specimens from patients with basal cell carcinoma (BCC) can present to surgery with no clinically residual tumor, complicating treatment decisions. OBJECTIVE: To evaluate reflectance confocal microscopy (RCM) for the assessment of residual BCC following biopsy. METHODS: Consecutive patients with biopsy-proven BCC and no clinical evidence of residual tumor who had been referred for Mohs micrographic surgery were included. Biopsy sites were imaged with a handheld RCM device. On the basis of RCM evaluation, cases were labeled RCM positive or RCM negative. Mohs micrographic surgery was performed in all cases; margins and 15-µm serial vertical sectioning were evaluated. RESULTS: A total of 61 patients were included (mean age, 61.7 years [standard deviation, 12.2 years]; range, 37-87 years); 60.7% were women. The mean lesion size was 5.1 mm (range, 3-12 mm); 73.8% of patients were positive on RCM, and 68.9% had residual BCC on histopathologic examination. The rates of RCM sensitivity, specificity, positive predictive value, and negative predictive value were 92.8%, 68.4%, 86.6%, and 81.2%, respectively. Three cases of BCC (high-risk, infiltrative, and basosquamous) were missed with use of RCM. When high-risk subtypes were excluded (n = 5), sensitivity and negative predictive value were both 100%. LIMITATIONS: RCM can miss deep-seated residual tumor. CONCLUSION: RCM is a valuable tool for the evaluation of residual BCC following biopsy, with the potential to reduce unnecessary surgical procedures.