Patterns of Recurrence and Survival After Pelvic Treatment for Locally Advanced Penile Cancer.

Background: Penile cancer (PeCa) is rare, and the survival of patients with advanced disease remains poor. A better understanding of where treatment fails could aid the development of new treatment strategies. Objective: To describe the disease course after pelvic lymph node (LN) treatment for PeCa. Design setting and participants: We retrospectively analysed 228 patients who underwent pelvic LN treatment with curative intent from 1969 to 2016. The main treatment modalities were neoadjuvant chemotherapy, chemoradiation, and pelvic LN dissection. Outcome measurements and statistical analysis: In the case of multiple recurrence locations, the most distant location was taken and recorded as follows: local (penis), regional (inguinal and pelvic LN), and distant (any other location). A competing risk analysis was used to calculate the time to recurrence per location, and a Kaplan-Meier analysis was used for overall survival (OS). Results and limitations: The median follow-up of the surviving patients was 79 mo. The reason for pelvic treatment was pelvic involvement on imaging (29%), two or more tumour-positive inguinal LNs (61%), or inguinal extranodal extension (52%). More than half of the patients (61%) developed a recurrence. The median recurrence-free survival was 11 mo. The distribution was local in 9%, regional in 27%, and distant in 64% of patients. The infield control rate of nonsystemically treated patients was 61% (113/184). From the start of pelvic treatment, the median OS was 17 mo (95% confidence interval 12-22). After regional or distant recurrence, all but one patient died of PeCa with median OS after a recurrence of 4.4 (regional) and 3.1 (distant) mo. This study is limited by its retrospective nature. Conclusions: The prognosis of PeCa patients treated on their pelvis who recur despite locoregional treatment is poor. The tendency for systemic spread emphasises the need for more effective systemic treatment strategies. Patient summary: In this report, we looked at the outcomes of penile cancer patients in an expert centre undergoing various treatments on their pelvis. We found that survival is poor after recurrence despite locoregional treatment. Therefore, better systemic treatments are necessary.

F-18 Fluorodeoxyglucose Positron Emission Tomography with Computed Tomography Has High Diagnostic Value for Pelvic and Distant Staging in Patients with High-risk Penile Carcinoma.

BACKGROUND: For penile cancer patients with pelvic metastases, multimodal treatment is advised, but pelvic lymph node metastases are often found upon surgical resection only. Early selection for multimodal treatment requires reliable noninvasive staging. OBJECTIVE: To evaluate the diagnostic value of 18F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT) for staging pelvic lymph nodes and distant metastases in high-risk penile cancer patients. DESIGN, SETTING, AND PARTICIPANTS: FDG-PET/CT scans performed in patients with clinically overt inguinal lymph node metastases and/or high-risk primary tumors (bulky T3 or T4) were retrospectively analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All scans were reviewed by two independent nuclear medicine physicians staging the pelvic nodes and distant metastases. FDG-PET/CT findings were compared with histology after node dissection if available, or with positive imaging or follow-up of at least 1 yr. RESULTS AND LIMITATIONS: Between 2006 and 2016, 61 patients met the inclusion criteria. For staging of pelvic nodes, sensitivity was 85% (specificity 75%, negative predictive value [NPV] 90%, and positive predictive value [PPV] 65%). For the detection of distant metastases, FDG-PET/CT had a PPV of 93%. Results are limited by the retrospective design and the lack of direct comparison with CT scanning alone. CONCLUSIONS: FDG-PET/CT has high sensitivity and a high NPV for staging of pelvic lymph nodes in high-risk penile cancer. It also has a high PPV for the detection of distant metastases, which were found in 23% of patients. Therefore, FDG-PET/CT enables early selection for multimodal treatment of patients with pelvic metastases and may help avoid futile treatment of patients with distant metastases. PATIENT SUMMARY: We studied whether positron emission tomography with computed tomography (PET/CT) scans in patients with advanced penile cancer can detect metastases before lymph node surgery is done. PET/CT scans can detect or rule out pelvic lymph node metastases, and can detect distant metastases. This helps in making timely treatment decisions (before surgery).

Clinicopathological predictors of finding additional inguinal lymph node metastases in penile cancer patients after positive dynamic sentinel node biopsy: a European multicentre evaluation.

OBJECTIVE: To develop a predictive model for additional inguinal lymph node metastases (LNM) at inguinal lymph node dissection (ILND) after positive dynamic sentinel node biopsy (DSNB) using DSNB characteristics to identify a patient group in which ILND might be omitted. PATIENTS AND METHODS: We conducted a retrospective study of 407 inguinal basins with a positive DSNB in penile cancer patients who underwent subsequent ILND from seven European centres. From the histopathology reports, the number of positive and negative lymph nodes, presence of extranodal extension and size of the metastasis were recorded. Using bootstrapped logistic regression, variables were selected for the clinical prediction model based on the optimization of Akaike's information criterion. The area under the curve (AUC) of the receiver-operating characteristic curve was calculated for the resulting model. Decision curve analysis (DCA) was used to evaluate the clinical utility of the model. RESULTS: Of the positive DSNBs, 64 (16%) harboured additional LNM at ILND. Number of positive nodes at positive DSNB (odds ratio [OR] 2.19, 95% confidence interval (CI) 1.17-4.00; P = 0.01) and largest metastasis size in mm (OR 1.06, 95% CI 1.03-1.10; P = 0.001) were selected for the clinical prediction model. The AUC was 0.67 (95% CI 0.60-0.74). The DCA showed no clinical benefit of using the clinical prediction model. CONCLUSION: A small but clinically important group of basins harbour additional LNM at completion ILND after positive DSNB. While DSNB characteristics were associated with additional LNM, they did not improve the selection of basins in which ILND could be omitted. Thus, completion ILND remains necessary in all basins with a positive DSNB.

Distinct Patterns of Myeloid Cell Infiltration in Patients With hrHPV-Positive and hrHPV-Negative Penile Squamous Cell Carcinoma: The Importance of Assessing Myeloid Cell Densities Within the Spatial Context of the Tumor.

Comprehensive analysis of tumor infiltrating myeloid cells in the tumor microenvironment of penile squamous cell carcinoma (PSCC) is lacking. In this retrospective study, for the first time, PSCC resection specimens (N = 103) were annotated into the following compartments: intratumoral tumor (IT Tumor), intratumoral stroma (IT Stroma), peritumoral tumor (PT Tumor) and peritumoral stroma (PT Stroma) compartments. We then quantified CD14+, CD68+ and CD163+ myeloid cells within these compartments using an image analysis software and assessed their association with various clinical parameters, including high-risk human papillomavirus (hrHPV) status. In the total cohort, hrHPV status, grade of differentiation, age and tumor size were associated with myeloid cell densities. hrHPV+ tumors had higher infiltration rates of CD14+, CD68+ and CD163+ myeloid cells in the IT tumor compartment (p < 0.001, for all) compared to hrHPV- tumors. Furthermore, when examining the association between compartment-specific infiltration and differentiation grade, increased myeloid cell densities in the IT tumor compartment were associated with a more advanced histological grade (p < 0.001, for all). This association remained significant when the hrHPV- cohort (N = 60) was analyzed (CD14+ p = 0.001; CD68+ p < 0.001; CD163+ p = 0.004). Subgroup analysis in the hrHPV+ group (N = 43) showed that high infiltration rates of CD68+ and CD163+ cells in the PT tumor compartment were associated with lymph node (LN) metastasis (p = 0.031 and p = 0.026, respectively). Regarding the association between myeloid cell densities and disease-specific survival, the risk of death was found to decrease slightly as the number of myeloid cells in the IT tumor compartment increased (CD14+ p = 0.04; CD68+ p = 0.05; CD163+ p = 0.02). However, after adjusting for hrHPV, no independent association between myeloid densities and disease-specific survival were found. Altogether, these findings demonstrate the importance of assessing myeloid cell densities within the spatial context of the tumor. Further studies are needed to unravel the specific phenotype of myeloid cells residing in the different compartments, their effect on clinical parameters and the impact of hrHPV on the recruitment of myeloid cell populations in PSCC.

Management of the penile squamous cell carcinoma patient after node positive radical inguinal lymph node dissection: current evidence and future prospects.

PURPOSE OF REVIEW: The level of evidence for current (adjuvant) treatment strategies after node positive inguinal lymphadenectomy is relatively low because of a paucity of prospective studies and controversy exist between the two major guidelines. The present review aims to provide a review of current literature on the available treatment options of patients after a tumor positive inguinal lymph node dissection. RECENT FINDINGS: Patients without inguinal extranodal extension or less than two tumor positive inguinal nodes are at low risk of ipsilateral pelvic nodal disease. Patients with pN1 disease are unlikely to benefit from adjuvant treatment, whereas patients with pN2 disease might benefit from adjuvant radiotherapy. For patients with high risk of pelvic nodal disease, prophylactic pelvic lymph node dissection (PLND) is advised by current guidelines. The InPACT study investigates whether adjuvant chemoradiotherapy could be used instead of prophylactic PLND. Subgroup analyses of retrospective cohorts suggest that patients with pN3 disease based on tumor positive pelvic nodes may benefit from adjuvant radiotherapy or chemotherapy. Given the weak level of evidence and substantial toxicity associated with current regimens, adjuvant chemotherapy cannot be generally recommended. SUMMARY: Despite current treatment strategies, patients with pN2-pN3 disease still have a poor prognosis. Prospective international multicenter studies are necessary to identify the best treatment options for patients with advanced node positive penile squamous cell carcinoma.

Defining the Tumor Microenvironment of Penile Cancer by Means of the Cancer Immunogram.

Current chemotherapeutic treatment for advanced penile squamous cell carcinoma has substantial side effects and no randomized data to support an overall survival benefit. Immunotherapy with checkpoint blockade is currently being tested in penile cancer patients in clinical trials. The high PD-L1 expression and CD8+ T-cell infiltration in penile cancer represent a promising prospect for immunotherapy response in the treatment of locally advanced disease. For efficacious immunotherapy treatment, a better understanding of the tumor microenvironment (TME) is critical. Here we use the structure revealed by cancer immunograms to define current knowledge of the penile cancer TME as a backbone for future research. PATIENT SUMMARY: Advanced penile cancer has a poor prognosis with a need for more effective therapy. In this manuscript we describe the potential of immunotherapy as a new treatment modality in penile cancer.

Surgical and Oncological Outcomes in Patients After Vascularised Flap Reconstruction for Locoregionally Advanced Penile Cancer.

BACKGROUND: Treatment of locoregionally advanced penile squamous cell carcinoma (LAPSCC) is challenging. The exact role (in terms of oncological benefit) of extensive surgery is not well established. Moreover, surgery invariably leads to large defects requiring reconstructive surgery. Rectus abdominis myocutaneous (RAM) and abdominal advancement flaps have an independent and constant blood supply, are easily harvested, and provide substantial skin coverage and soft tissue. OBJECTIVE: To determine the surgical and oncological outcomes in patients with LAPSCC undergoing surgical resection with RAM flaps. DESIGN, SETTING, AND PARTICIPANTS: From 2002 to 2016, a multi-institutional database identified 15 LAPSCC patients undergoing flap reconstructions. INTERVENTION: Local surgical resection with RAM or abdominal advancement flap reconstruction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Perioperative and pathologic data were collected. Postoperative complications were identified using the Clavien-Dindo classification for surgical complications. RESULTS AND LIMITATIONS: Fifteen patients (median age 61 yr) were treated, ten with curative intent. Thirteen patients received induction chemotherapy. Thirteen of the 15 patients (87%) experienced wound complications, including five Clavien-Dindo grade III complications. In 11/15 patients (73%), the disease recurred (median recurrence-free interval 106 d). The majority of recurrences (91%) were locoregional, and in four cases the patient also had lesions in distant organs. Ten of the 15 patients (67%) died of their disease. The overall median follow-up interval was 10.5 mo. The study was limited by its retrospective design, the absence of quality-of-life measurements, and the cohort size. CONCLUSIONS: The results of this study show that surgical resection with reconstruction is associated with a risk of perioperative complications, including high-grade Clavien-Dindo complications. With a cure rate of 27%, surgery must be carefully considered and there is a need for alternative treatments. Lack of robust quality-of-life-data is also a serious shortcoming in the decision process for this patient category. PATIENT SUMMARY: Surgery in locoregionally advanced penile cancer has a low cure rate. Reconstruction of defects is surgically feasible, albeit with a high risk of complications. Furthermore, decision-making lacks robust data on quality of life after surgery.

Laser ablation as monotherapy for penile squamous cell carcinoma: A multi-center cohort analysis.

INTRODUCTION: Although the trend towards penile sparing therapy is increasing for penile squamous cell carcinoma, outcomes for laser ablation therapy have not been widely reported. We assessed the clinical outcomes of penile cancer patients treated with only laser ablation. MATERIALS AND METHODS: A retrospective review was performed on 161 patients across 5 multi-center tertiary referral centers from 1985 to 2015. All patients underwent penile sparing surgery with only laser ablation for squamous cell carcinoma of the penis. Laser ablation was performed with neodymium-doped yttrium aluminum garnet or carbon dioxide. Overall and recurrence-free survival was calculated using the Kaplan-Meier method and compared with the log rank test. RESULTS: A total of 161 patients underwent laser ablation for penile cancer. The median age was 62 (IQR: 52-71) years and median follow-up was 57.7 (IQR: 28-90) months. The majority of patients were pTa/Tis (59, 37%) or pT1a (62, 39%). Only 19 (12%) had a poorly differentiated grade. The 5-year recurrence-free survival was 46%. When stratified by stage, the 5-year local recurrence-free survival was pTa/Tis: 50%; pT1a: 41%; pT1b: 38%; and pT2: 52%. The inguinal/pelvic nodal recurrence was pTa/Tis: 2%; pT1a: 5%; pT1b: 18%; and pT2: 22%. There were no differences among stages with respect to recurrence-free survival (P = 0.98) or overall survival (P = 0.20). CONCLUSION: Laser ablation therapy is safe for appropriately selected patients with penile squamous cell carcinoma. Due to the increased risk of nodal recurrence, laser ablation coupled with diagnostic nodal staging is indicated for patients with pT1b or higher.

Surgical management of penile carcinoma in situ: results from an international collaborative study and review of the literature.

OBJECTIVES: To evaluate recurrence after penile-sparing surgery (PSS) in the management of carcinoma in situ (CIS) of the penis in a large multicentre cohort of patients. PATIENTS AND METHODS: We identified consecutive patients from five major academic centres, treated between June 1986 and November 2014, who underwent PSS for pathologically proven penile CIS. The primary outcome was local recurrence-free survival (RFS), which was estimated using the Kaplan-Meier method. RESULTS: A total of 205 patients were identified. Treatment methods included circumcision, glansectomy, wide local excision, laser therapy and total glans resurfacing. Over a median (interquartile range [IQR]) follow-up of 40 (26-65.6) months, there were 48 local recurrences, with 45.8% occurring in the first year and 81.3% occurring by year 5. The majority of recurrences were observed in the laser group (58.3%). The median (IQR) time to local recurrence was 15.9 (5.66-26.14) months. The 1- 2- and 5-year RFS rates were 88.4, 85.6 and 75%, respectively, and the median (IQR) RFS time was 106.5 (80.2-132.2) months. CONCLUSIONS: Among patients with penile CIS selected for surgical management, durable responses at intermediate- to long-term follow-up were noted. For those with glandular CIS, glans resurfacing offered the best outcomes.

Penile Sparing Surgery for Penile Cancer: A Multicenter International Retrospective Cohort.

PURPOSE: We evaluated recurrence outcomes of penile sparing surgery in what is to our knowledge the largest multicenter cohort of patients to date. MATERIALS AND METHODS: We retrospectively identified patients treated with penile sparing surgery from May 1990 to July 2016 at 5 tertiary referral institutions. Treatments consisted of circumcision, wide local excision, laser therapy with or without local excision, partial or total glansectomy and glans resurfacing. The study primary end point was local recurrence-free survival, defined from initial treatment to time of local recurrence and estimated with the Kaplan-Meier method. RESULTS: After applying study exclusion criteria 1,188 patients were included in analysis. During the median followup of 43.0 months there were 252 local recurrences (21.2%), of which 99 (39.3%) developed in year 1. Median time to local recurrence was 16.3 months and the 5-year local recurrence-free survival incidence was 73.6%. When stratified by stage, the 5-year local recurrence-free survival rate was 75.0%, 71.4% and 75.9% in Ta/Tis, T1 and T2 cases, respectively (log rank p = 0.748). Of the recurrences 58.3% were treated with repeat organ sparing procedures and the secondary partial (total) penectomy rate was 19.0%. Only margin status was significantly associated with local recurrence on multivariate analysis (p = 0.001). Study limitations included the retrospective design and the heterogeneous clinical approach. CONCLUSIONS: Penile sparing surgery can provide excellent local control for superficial penile tumors as well as for appropriately selected invasive lesions. Strict followup in the early postoperative period is highly recommended.

The role of PET/CT imaging in penile cancer.

Positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (FDG) combined with computed tomography (CT) provides functional imaging combined with anatomic information, improving diagnostic accuracy and confidence. Although virtually all primary penile tumors are FDG-avid, PET/CT is not recommended for primary tumor staging as it has limited spatial resolution and is hampered by urinary FDG excretion. The accuracy of PET/CT for lymph node staging seems to improve with the pretest likelihood of metastatic nodes. In groins with normal physical examination, sensitivity is only 57%. In groins with palpably enlarged lymph nodes, sensitivity of PET/CT reaches 96%. For pelvic lymph nodes and distant metastases, PET/CT is more accurate if inguinal metastases are present. However, these results are based on a very limited number of studies. Overall, the role of PET/CT imaging in penile cancer remains ambiguous, especially in inguinal lymph nodes. During staging and follow-up, it may be particularly useful in detecting pelvic lymph node metastases and occult distant metastases prior to systemic chemotherapy and/or extensive surgery, improving selection of patients that are most likely to benefit from such therapies.

Advancements in staging and imaging for penile cancer.

PURPOSE OF REVIEW: We review recent advancements in staging and imaging of penile cancer, including surveillance after therapy. RECENT FINDINGS: For cN0 patients, the sentinel lymph node biopsy is currently considered the preferred way for invasive staging. It has largely replaced other modalities such as staging inguinal lymphadenectomy. Its diagnostic value increases when combined with other staging modalities such as ultrasound with fine-needle aspiration cytology (US-FNAC) or fluorodeoxyglucose-PET with computed tomography (PET/CT). In patients with palpably suspicious nodes (cN+), imaging is more useful. PET/CT has shown good accuracy in a limited number of small studies. US-FNAC can confirm nodal metastatic disease. A staging inguinal lymphadenectomy is of therapeutic value but is associated with significant morbidity. Omitting staging inguinal lymphadenectomy was recently described; one study showed well tolerated use of sentinel lymph node biopsy combined with intraoperative ultrasound-guided resection of suspicious nodes in cN+ patients. Therapeutic inguinal lymphadenectomy was only performed in the 42% of groins with metastases confirmed by disorder. For M-staging, PET/CT has shown good sensitivity, and its role should be further evaluated. Follow-up and surveillance rely on physical examination and US-FNAC. SUMMARY: Over the past decade, staging and treatment of penile cancer have become less invasive, while survival tends to improve.

Glansectomy as Primary Management of Penile Squamous Cell Carcinoma: An International Study Collaboration.

OBJECTIVE: To analyze the recurrence and survival outcomes of glansectomy in patients with penile squamous cell carcinoma. MATERIALS AND METHODS: We performed a retrospective review of 410 patients across 5 international tertiary referral centers between 1999 and 2016. All patients had tumors involving the glans penis and underwent glansectomy as primary treatment. The Kaplan-Meier method and log-rank test were used to calculate survival and recurrence. Median follow-up was 42 months (interquartile range [IQR] 29-56). RESULTS: The median age was 64 years (IQR 53-72). Median tumor size was 2.2 cm (IQR 1.5-3.0). A total of 240 patients (58.5%) had pT2 disease, whereas only 43 patients (10.5%) had pT3 or pT4 disease. The majority of the cohort had poorly differentiated tumors (43.7%). Most recurrences were local at 7.6% (31 patients). Only 14 patients (3.4%) had regional recurrence and 9 patients (2.2%) had distant recurrence. When stratified by pathologic stage, tumors that were pT2 or higher were (P < .001) and were more likely to be poorly differentiated (P < .001). There were no differences in recurrence location among pathologic stages (P = .15). The 1-, 2-, and 5-year recurrence-free survival were 98%, 94%, and 78%, respectively. There were no differences in overall survival when stratified by stage (P = .67). CONCLUSION: Glansectomy is an oncologically safe treatment modality for squamous cell carcinoma of the glans in appropriately selected invasive tumors.

Clinical Outcomes of Perioperative Chemotherapy in Patients With Locally Advanced Penile Squamous-Cell Carcinoma: Results of a Multicenter Analysis.

BACKGROUND: The prognosis of patients with locally advanced penile squamous-cell carcinoma is primarily related to the extent of lymph node metastases. Surgery alone yields suboptimal results, and there is a paucity of data on these patients' outcomes. PATIENTS AND METHODS: This retrospective study evaluated patients who received neoadjuvant or adjuvant chemotherapy from 1990 onward at 12 centers. Cox models were used to investigate prognostic factors for relapse-free survival and overall survival (OS). RESULTS: Among the 201 included patients, 39 (19.4%) had disease of T3-4 and N0 clinical stage; the remaining patients had clinical lymph node involvement (cN+). Ninety-four patients received neoadjuvant chemotherapy (group 1), 78 received adjuvant chemotherapy (group 2), and 21 received both (group 3). Eight patients for whom the timing of perioperative chemotherapy administration was unavailable were included in the Cox analyses. Forty-three patients (21.4%) received chemoradiation. Multivariate analysis for OS (n = 172) revealed bilateral disease (P = .035) as a negative prognostic factor, while pelvic cN+ tended to be nonsignificantly associated with decreased OS (P = .076). One-year relapse-free survival was 35.6%, 60.6%, and 45.1% in the 3 groups, respectively. One-year OS was 61.3%, 82.2%, and 75%, respectively. No significant differences were seen on univariable analyses for OS between the groups (P = .45). Platinum type of chemotherapy and chemoradiation were not significantly associated with any outcome analyzed. CONCLUSION: Benchmark survival estimates for patients receiving perioperative chemotherapy for locally advanced penile squamous-cell carcinoma have been provided, with no substantial differences observed between neoadjuvant and adjuvant administration. This analysis may result in improved patient information, although prospective studies are warranted.

Expression of Programmed Death Ligand 1 in Penile Cancer is of Prognostic Value and Associated with HPV Status.

PURPOSE: PD-L1 (programmed death ligand 1) inhibits T-cell function and prevents tumor eradication. This is facilitated by PD-L1 positive tumor cells and PD-L1 positive immune cells, and can be prevented by anti-PD-1 (programmed death 1)/PD-L1 immunotherapy. In advanced penile cancer there is a need for new therapeutic strategies. We investigated PD-L1 expression in penile cancers and compared PD-L1 expression with disease specific survival, lymph node metastases at diagnosis and high risk HPV status in a large patient cohort. MATERIALS AND METHODS: A total of 213 primary tumors were immunohistochemically stained for PD-L1 and scored for tumor (percentage), stroma (binary) and PD-L1 positive tumor infiltrating macrophages. Additionally, PD-L1 positive tumors were scored for expression pattern, that is diffuse or predominantly present at the tumor-stroma margin. RESULTS: Staining was successful in 200 tumors, of which 75% were high risk HPV negative. Median followup was 62 months. Of 200 tumors 96 (48%) were PD-L1 positive (scored 1% or greater), of which 59 (62%) had a marginal expression pattern and 79 (82%) were high risk HPV negative (p = 0.03). Compared to PD-L1 negative tumors, the PD-L1 expression patterns had different prognostic values in the whole cohort as well as in the high risk HPV negative subgroup. On multivariable analyses a marginal expression pattern was associated with absent lymph node metastases (OR 0.4) while diffuse expression was associated with poor survival (HR 2.58). These results were more prominent in the high risk HPV negative subgroup (OR 0.25, HR 3.92). CONCLUSIONS: PD-L1 was expressed in 48% of penile carcinomas and mainly in high risk HPV negative tumors. The pattern of expression was a prognostic factor as marginal expression was associated with absent lymph node metastases and diffuse expression was associated with poor survival.

Grade of dysplasia and malignant transformation in adults with premalignant laryngeal lesions.

BACKGROUND: The purpose of this systematic review was to determine the significance of the grade of dysplasia in the development of invasive carcinoma. METHODS: A systematic search was performed to identify all relevant evidence. Titles and abstracts were screened using predefined criteria. Remaining articles were critically appraised. Absolute risks and 95% confidence intervals (CIs) were calculated. RESULTS: Seven articles were included. Four studies demonstrated an increased risk for the development of laryngeal carcinoma from mild, moderate, and severe dysplasia. Three studies showed an increased risk between the categories of mild and moderate dysplasia. CONCLUSION: The risk of malignant transformation seems to increase with the grade of dysplasia, although percentages between studies are highly dissimilar. The wide variety and overlapping 95% CIs make it difficult to formulate a strong recommendation. However, moderate dysplasia is more prone for malignant transformation than previously thought, which might influence follow-up and treatment decisions in the future. © 2015 Wiley Periodicals, Head Neck 38: E2284-E2290, 2016.