We have read with great interest the review by Drs. Stratton and Culkin covering the various levels of human papillomavirus (HPV) research in penile cancer, including epidemiologic, clinical, pathologic, and molecular domains.[1] Our commentary aims to expand on the evolution and present state of the art in the pathology of HPV in penile cancer and precancerous lesions.

Since the recognition in 1995 of a relationship between subtypes of squamous cell carcinoma (SCC) and HPV,[2] the bimodal hypothesis of penile cancer pathogenesis-ie, that there are both HPV- and non–HPV-related etiologies-appears to be well established.[3] In fact, for the first time, a pathologic classification of penile cancer that has worldwide impact-such as the one proposed by the World Health Organization (WHO)-is based on these ideas (Table 1).[4] However, the interest in HPV has resulted in many studies that overlook the pathogenesis of the most common types of penile cancers, which are non–HPV-related. These squamous tumors are mostly characterized by maturation and gradual keratinization, and comprise a variety of architectural patterns designated as usual, verrucous, cuniculatum, pseudohyperplastic, papillary not otherwise specified (NOS), and pseudoglandular.[5] There is no explanation as to why some penile tumors are etiologically related to HPV and others are not. We performed an epidemiologic prospective study of 103 patients with penile cancer and classified their tumors, did whole-tissue-section (WTS) polymerase chain reaction (PCR) testing, and compared known risk factors in patients with HPV-positive and -negative tumors. Patients with HPV-related penile tumors had a past history of genital warts and more lifetime sexual partners than those patients with non–HPV-related cancers.[6] We also found a preferential relationship between certain subtypes of SCC and the presence of HPV in penile cancer, which has been a major area of interest for us over the last 15 years.[7-10]

Since our first HPV detection study of 117 penile cancer cases, in which we identified a preferential association of the virus with basaloid and condylomatous (warty) carcinomas,[2] we have examined about 1,300 cases of invasive penile carcinomas in the search for other types that may be related to HPV. The first group of tumors identified were HPV-positive usual carcinomas mixed with either warty or basaloid carcinoma. Despite the distinctive appearances of warty and basaloid carcinomas, some mixed tumors were entirely composed of warty and basaloid carcinoma, with an exophytic condylomatous surface and deeply invasive basaloid tumor components. We designated these tumors as warty-basaloid carcinomas, reflecting their morphologic makeup.[11] Another tumor that did not fit into either the warty or classical basaloid carcinoma classification, but which had a basaloid cell type with an exophytic surface outgrowth, was the papillary variant of basaloid carcinoma.[12] This tumor had to be separated from the morphologically distinct and etiologically different papillary NOS variant of SCC, also with an exophytic pattern but without condylomatous features and with HPV and p16 negativity.[13] Another unusual tumor, originally thought to be metastatic from the kidney, is the clear cell carcinoma primary in the penis. This is an aggressive tumor composed almost entirely of clear cells, but with a nesting growth pattern and comedonecrosis similar to what is seen in basaloid carcinomas (Figure A and B). Cytologically, these cells resemble warty carcinoma clear cells but lack the exophytic growth of warty carcinomas.[14] All of these neoplasms share a common characteristic: they are composed of either basaloid or warty-like cells in specific architectural configurations and are relatively easy to recognize. We also found a group of tumors which, when properly diagnosed, are consistently negative for HPV: these include verrucous, papillary NOS, pseudoglandular, pseudohyperplastic, and sarcomatoid carcinomas. Except for the latter, these neoplasms are keratinizing, mature, low-grade variants of penile SCC. It was puzzling to find some HPV-positive cases in the usual SCC category, since the prevalence of the virus in this tumor type is much lower than in classic HPV-related tumors. In an effort to discover more about these observations, and being fortunate enough to be collaborators on a survey of 1,000 patients from five continents,[15] we reviewed 60 (6%) HPV-positive tumors originally classified as usual SCC. There were only 26 (2.6 %) bona fide usual SCCs. The other HPV-positive tumors were represented by mixed usual warty/basaloid patterns and a variety of poorly differentiated tumors with unusual morphologic features, including solid, trabecular, small cell, medullary, lymphoepithelioma-like, and Hodgkin-like with marked eosinophilia. Among these unusual HPV-positive SCCs, there are two new distinct types-lymphoepithelioma-like carcinomas and medullary carcinomas-which are the most recently described HPV-related variants of penile SCCs.[16,17] These tumors, composed of larger poorly differentiated cells, are morphologically and cytologically different from those harboring basaloid or condylomatous cells. This leads us to conclude that HPV is very rare in usual penile SCC and that HPV-positive tumors are morphologically distinctive. It is now possible to identify HPV-positive tumors by observing the histology with hematoxylin and eosin staining, and p16 stain can also be used to distinguish between HPV-positive tumors and non–HPV-related tumors in difficult cases. The significance of separating HPV-related neoplasms into distinct morphologic types will not be well known until definitive molecular analyses are performed. The extremes of the spectrum, such as the condylomatous or warty carcinomas, which have an excellent prognosis, and the basaloid carcinoma, with a poorer prognosis, will justify this effort. Patients with HPV-related neoplasms at other sites carry a better prognosis than those with non–HPV-related tumors, but in penile cancer the studies are contradictory.[18,19]

Penile Intraepithelial Neoplasia (PeIN) Subtypes and HPV Genotypes

Geographic differences in the incidence of invasive penile cancer is well known: there are about 2 to 4 cases per 100,000 inhabitants in Asia, Africa, and Latin America, and 1 case per 100,000 in countries in North America and Europe. However, after examining cases from many countries, we found no differences in the distribution of subtypes of invasive carcinomas.[20] At the precancerous level, though, we found a higher prevalence of HPV-related subtypes of PeIN in Paris than in cases diagnosed in Paraguay, where differentiated PeIN (non–HPV-related) was the most common precancerous lesion.[15,21]

The new WHO classification of PeIN separates HPV-related from non–HPV-related precancerous lesions (Table 2)[4,22]: differentiated PeINs are usually HPV-negative warty, and basaloid PeINs are usually HPV-positive (Figure C and D). There are few studies of the genotypic composition of PeIN,[23,24] and similar to studies of invasive carcinomas, the methodology used in these studies has usually been WTS-PCR. Recently, we demonstrated that laser capture microdissection (LCM)-PCR is a better precision instrument than WTS-PCR, because lesions in which WTS-PCR showed just one genotype were found to actually have multiple HPV genotypes when the lesion was carefully dissected with the laser instrument.[25] Unlike invasive penile carcinomas, where few HPV genotypes are usually identified, many more genotypes exist in basaloid and warty PeINs. In 115 lesions from 43 patients, we found 18 different HPV genotypes, including both high- and low-risk types. One interesting finding was that HPV 16 was common in basaloid PeIN but rare in warty PeIN (70% vs 20%). Warty PeIN was found to have a heterogeneous array of multiple and variable HPV genotypes, unlike basaloid PeIN.[26] These findings strongly support the approach used[4] to classify HPV-related and non–HPV-related PeIN and in subtyping variants of PeIN.

Clinical warts are common in young males and frequently reported as a risk factor for developing cancer; however, the mechanisms of this relationship remain obscure. The predominant thinking is that all condylomas are benign, exophytic, wart-like lesions with koilocytosis and related to infection with low-risk HPV strains, such as HPV 6 and HPV 11. These lesions are not considered precancerous, according to older or current classification schemes. However, emerging data indicate that some condylomas show cytologic atypias and harbor high-risk HPV.[27-29] In a recent unpublished study, we found that 20% of otherwise exophytic or acuminate condylomas associated with penile neoplasia showed focal cytologic atypias and harbored high-risk HPV, suggesting they were likely precancerous. More studies should be conducted comparing large numbers of common condylomas in younger patients with those associated with neoplasia in older patients. Another interesting finding in the study just mentioned was the presence of HPV-positive flat lesions with uncharacteristic morphologic appearances, which varied from hyperplasia-like, to acanthotic thickening with mild atypias, to flat lesions with superficial minimal koilocytosis. These unusual subclinical lesions were located near PeIN or invasive carcinomas, and many of them contained high-risk HPV similar to the virus types found in adjacent neoplasia. It may be that these lesions were flat condylomas or similar to the ones reported by Bleeker and Meijer[28,29] under the name of “acetowhite lesions” in male partners of women with cervical intraepithelial neoplasia. Another explanation may be that these lesions are, like atypical condylomas, a missing link between common condylomas, PeIN, and invasive cancer.

The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article

 Stratton KL, Culkin DJ. A contemporary review of HPV and penile cancer. Oncology (Williston Park). 2016;30:245-9, 252.

 Gregoire L, Cubilla AL, Reuter VE, et al. Preferential association of human papillomavirus with high-grade histologic variants of penile-invasive squamous cell carcinoma. J Natl Cancer Inst. 1995;87:1705-9.

 Rubin MA, Kleter B, Zhou M, et al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol. 2001;159:1211-8.

 Moch H, Humphrey PA, Ulbright TM, Reuter VE. WHO classification of tumours of the urinary system and male genital organs. 4th ed. Lyon: IARC Press; 2015. [In Press]

 Sanchez DF, Canete S, Fernandez-Nestosa MJ, et al. HPV- and non-HPV-related subtypes of penile squamous cell carcinoma (SCC): Morphological features and differential diagnosis according to the new WHO classification (2015). Semin Diagn Pathol. 2015;32:198-221.

 Chaux A, Netto GJ, Rodriguez IM, et al. Epidemiologic profile, sexual history, pathologic features, and human papillomavirus status of 103 patients with penile carcinoma. World J Urol. 2013;31:861-7.

 Chaux A, Cubilla AL, Haffner MC, et al. Combining routine morphology, p16(INK4a) immunohistochemistry, and in situ hybridization for the detection of human papillomavirus infection in penile carcinomas: a tissue microarray study using classifier performance analyses. Urol Oncol. 2014;32:171-7.

 Chaux A, Pfannl R, Lloveras B, et al. Distinctive association of p16INK4a overexpression with penile intraepithelial neoplasia depicting warty and/or basaloid features: a study of 141 cases evaluating a new nomenclature. Am J Surg Pathol. 2010;34:385-92.

 Cubilla AL, Lloveras B, Alejo M, et al. Value of p16(INK)(4)(a) in the pathology of invasive penile squamous cell carcinomas: A report of 202 cases. Am J Surg Pathol. 2011;35:253-61.

 Cubilla AL, Lloveras B, Alejo M, et al. The basaloid cell is the best tissue marker for human papillomavirus in invasive penile squamous cell carcinoma: a study of 202 cases from Paraguay. Am J Surg Pathol. 2010;34:104-14.

 Chaux A, Tamboli P, Ayala A, et al. Warty-basaloid carcinoma: clinicopathological features of a distinctive penile neoplasm. Report of 45 cases. Mod Pathol. 2010;23:896-904.

 Cubilla AL, Lloveras B, Alemany L, et al. Basaloid squamous cell carcinoma of the penis with papillary features: a clinicopathologic study of 12 cases. Am J Surg Pathol. 2012;36:869-75.

 Chaux A, Soares F, Rodriguez I, et al. Papillary squamous cell carcinoma, not otherwise specified (NOS) of the penis: clinicopathologic features, differential diagnosis, and outcome of 35 cases. Am J Surg Pathol. 2010;34:223-30.

 Sanchez DF, Rodriguez IM, Piris A, et al. Clear cell carcinoma of the penis: an HPV-related variant of squamous cell carcinoma: a report of 3 cases. Am J Surg Pathol. 2016 Feb 4. [Epub ahead of print]

 Alemany L, Cubilla A, Halec G, et al. Role of human papillomavirus in penile carcinomas worldwide. Eur Urol. 2016 Jan 4. [Epub ahead of print]

 Mentrikoski MJ, Frierson HF Jr, Stelow EB, Cathro HP. Lymphoepithelioma-like carcinoma of the penis: association with human papilloma virus infection. Histopathology. 2014;64:312-5.

 CaÃ±ete S, Clavero O, Sanchez DF, et al. Poorly differentiated solid (medullary) carcinoma: a distinctive HPV-related penile neoplasm. A report of 12 cases. Mod Pathol. 2016. [In Press]

 Bezerra SM, Chaux A, Ball MW, et al. Human papillomavirus infection and immunohistochemical p16(INK4a) expression as predictors of outcome in penile squamous cell carcinomas. Hum Pathol. 2015;46:532-40.

 Djajadiningrat RS, Jordanova ES, Kroon BK, et al. Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. J Urol. 2015;193:526-31.

 Chaux A, Lezcano C, Cubilla AL, et al. Comparison of subtypes of penile squamous cell carcinoma from high and low incidence geographical regions. Int J Surg Pathol. 2010;18:268-77.

 Soskin A, Vieillefond A, Carlotti A, et al. Warty/basaloid penile intraepithelial neoplasia is more prevalent than differentiated penile intraepithelial neoplasia in nonendemic regions for penile cancer when compared with endemic areas: a comparative study between pathologic series from Paris and Paraguay. Hum Pathol. 2012;43:190-6.

 Epstein JI, Cubilla AL, Humphrey PA. Tumors of the prostate gland, seminal vesicles, penis, and scrotum. Silverberg SG, editor. Washington, DC: American Registry of Pathology and AFIP; 2011.

 Ingles DJ, Pierce Campbell CM, Messina JA, et al. Human papillomavirus virus (HPV) genotype- and age-specific analyses of external genital lesions among men in the HPV Infection in Men (HIM) Study. J Infect Dis. 2015;211:1060-7.

 Sudenga SL, Ingles DJ, Pierce Campbell CM, et al. Genital human papillomavirus infection progression to external genital lesions: The HIM study. Eur Urol. 2015;69:166-73.

 Fernandez-Nestosa MJ, Guimera N, Sanchez DF, et al. Detection of HPV genotypes according to subtypes of penile intraepithelial neoplasia (PeIN). A study of 126 lesions in 43 patients using laser capture microdissection (LCM) PCR [abstr]. Mod Pathol. 2015;28:219-20A.

 Fernandez-Nestosa MJ, Guimera N, Sanchez DF, et al. Warty penile intraepithelial neoplasia: morphological and viral characterization in 24 cases using laser capture microdissection (LCM)-PCR [abstr]. Mod Pathol. 2016. [In press]

 Baydar DE, Kulac I, Ozagari A, Guler Tezel G. Occurrence of dysplasia and human papilloma virus typing in penile condylomas. Urology. 2013;81:211.e9-15.

 Bleeker MC, Hogewoning CJ, Van Den Brule AJ, et al. Penile lesions and human papillomavirus in male sexual partners of women with cervical intraepithelial neoplasia. J Am Acad Dermatol. 2002;47:351-7.

 Bleeker MC, Snijders PF, Voorhorst FJ, Meijer CJ. Flat penile lesions: the infectious “invisible” link in the transmission of human papillomavirus. Int J Cancer. 2006;119:2505-12.

Articles

Our commentary aims to expand on the evolution and present state of the art in the pathology of HPV in penile cancer and precancerous lesions.

The Variegated Morphology of HPV-Related Neoplasms of the Penis

Chemotherapy-induced peripheral neuropathy (CIPN) is a common treatment-related side effect of several widely used drugs. Agents known to cause CIPN include platinum analogs, antitubulins (taxanes, vinca alkaloids, eribulin), proteasome inhibitors (bortezomib), immunomodulatory agents (thalidomide, lenalidomide, pomalidomide), and some of the newer biologics (alemtuzumab, ipilimumab, brentuximab).[1] In a recent meta-analysis of 31 studies of CIPN involving a total of 4,179 patients, the aggregate prevalence of CIPN was 48%. Within the first month after the patients completed chemotherapy, 68.1% had CIPN; the prevalence decreased to 30% after 6 months.[2] The reported proportion of patients affected by CIPN varies depending on the chemotherapy regimen administered, the duration of patient exposure to the neurotoxic agent(s), and the evaluation methods used.[3] For some patients, the side effects and deficits caused by CIPN are so severe that they impair daily function and diminish quality of life. CIPN can result in chemotherapy dose reductions or early treatment discontinuation, compromising effective cancer treatment and patient survival. Since cancer treatment advances have extended survival times for many patients, the long-term sequelae of CIPN have become increasingly important.

The classic clinical presentation is a symmetric, predominantly sensory, distal neuropathy (in a stocking-glove pattern). Common presenting symptoms are paresthesia (with positive symptoms including burning, tingling, and sharp pain), numbness (with negative symptoms including loss of sensation), and impaired balance. Occasionally, patients present with more prominent motor symptoms, autonomic involvement, or cranial neuropathies. The intensity and severity of the symptoms vary depending on the chemotherapeutic agent, the dosage and treatment schedule, the duration of therapy, coadministration of more than one known neurotoxic agent (eg, combination of carboplatin with paclitaxel), and comorbid conditions that predispose the peripheral nervous system to injury (Table 1).[4] The mechanisms of anticancer activity are usually well known and described for the specific chemotherapeutic agents used; however, their individual mechanisms of neurotoxicity may differ, making the onset and course of CIPN unpredictable.[5] There is great individual variability in the onset, severity, and duration of symptoms; recovery is often lengthy and frequently incomplete. With some chemotherapeutic agents, the patient’s symptoms continue to progress after treatment has ended; this so-called coasting phenomenon is observed with oxaliplatin, cisplatin, and vincristine.[6] Individual genetic variations or polymorphisms may explain the wide spectrum of vulnerability to CIPN from a given agent. Numerous genes have been investigated in an attempt to clarify this association, such as 

In practice, CIPN is graded based on subjective complaints from the patient and an examination by the oncologist. The most widely used tools to evaluate the degree of CIPN are questionnaires, either administered by healthcare professionals (such as the National Cancer Institute’s Common Terminology Criteria for Adverse Events grading scale) or completed by patients (such as the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity questionnaire). These tools are limited because they rely on the subjective report of symptoms. An important consideration is that healthcare providers and patients frequently have a different perception of CIPN severity.[1] This is especially important for patients who are engaged in professions or activities requiring intact sensory and motor functions, as well as fine control of the hands (eg, dentist, pianist, carpenter, jewelry maker) or feet (eg, professional driver).

There are no high-quality studies demonstrating effective prevention of CIPN using any agent. The latest guidelines from the American Society of Clinical Oncology (ASCO) acknowledge this limitation and recommend against offering any CIPN-preventive drug to patients undergoing neurotoxic cancer treatment.[8] Regarding treatment of CIPN, the ASCO guidelines state that clinicians may offer duloxetine to symptomatic patients[9] and should consider offering tricyclic antidepressants, gabapentin, or pregabalin to manage the positive symptoms associated with CIPN; however, these agents have no effect on the motor symptoms or the negative sensory symptoms. Patients should be informed of the limited scientific evidence of benefit from these anti-CIPN drugs, and of their potential harms and associated costs.[8]

Role of the Neurologist and Electro­Diagnostic Testing in Management of CIPN

Early and accurate diagnosis of CIPN is crucial, since it enables dose adjustment of chemotherapy to prevent worsening of peripheral neuropathy and possibly avert irreversible nerve damage. Prior to the initiation of neurotoxic chemotherapy, all patients should have laboratory testing to screen for diabetes (the hemoglobin A1c test), vitamin deficiencies (B12, B1), pyridoxine (B6) intoxication, and thyroid abnormalities, with correction of any underlying comorbidity. In addition, the treating physician should conduct a baseline neurologic examination, recording any sensory or motor abnormalities and documenting the patient’s deep tendon reflexes.[10] Loss of the Achilles tendon reflex is usually the first clinical sign of CIPN.

Notably, however, overdiagnosis of CIPN may compromise treatment with an otherwise beneficial chemotherapy regimen, negatively affecting cancer outcomes and survival. In a study of 55 breast cancer patients referred for electrodiagnostic studies due to symptoms suggesting possible taxane-related polyneuropathy, 33% had no electrophysiologic evidence of polyneuropathy or showed only focal entrapment neuropathy (carpal tunnel syndrome); 67% had a large fiber polyneuropathy.[11] Thus, neurologic evaluation can clarify when symptoms are unrelated to CIPN, allowing full oncologic treatment to continue.

Usually patients are referred to a neurologist only if symptoms of neuropathy persist for more than 6 months. In our opinion, a neurologist should be consulted early for patients with preexisting conditions or atypical presentations (Table 2). For patients with preexisting conditions, documentation of baseline neurologic deficits might prove invaluable if they develop neuropathic symptoms during cancer treatment. In addition, a careful neurologic examination of a patient with an atypical presentation should be enough to differentiate between CIPN and other entities (eg, cervical or lumbar radiculopathy, compression neuropathies). Nerve conduction studies (NCS) and an electromyogram (EMG) are well-tolerated electrophysiologic tests that are an invaluable complementary tool in the diagnostic evaluation of patients with suspected CIPN, especially when the timing and course of symptoms are unusual. NCS and EMG serve as an objective predictive measurement of the severity of peripheral nerve damage and therefore can be used to prognosticate neurologic recovery.[12]

The neurologist can also assist with treatment options. Despite the absence of strong evidence in favor of the available neuropathic medications, they may be helpful. In our practice, we frequently encounter patients for whom the available treatments failed, but often the doses were too low or inadequate time was allowed for the medication to take effect. Slow titration of gabapentin up to 600 mg three times a day is well tolerated and often provides moderate symptom relief. Alternatively, treatment with 30 mg of duloxetine daily for 1 week, followed by 60 mg daily, yields comparable symptom control. The neurologist will also be able to counsel the patient regarding expectations and limitations of the pharmacologic treatments. Patients should be offered physical or occupational therapy, and patient education should focus on lifestyle modifications to avoid falls and injury. Patients without laboratory-proven vitamin deficiencies should be reminded to avoid taking nutritional supplements, since they may worsen the neuropathy. Frequent neurologic examination should include reassessment of the need for symptomatic therapy.

Although CIPN is a common side effect of cancer treatment, physicians may not fully appreciate its impact on patients’ long-term quality of life.[13] Preexisting conditions should be taken into consideration prior to initiation of potentially neurotoxic agents. It is important that the treating physician collaborate closely with a neurologist in evaluating and managing high-risk patients. Symptom management, along with physical or occupational therapy, may benefit select patients.

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. 

 Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Curr Opin Neurol. 2015;28:500-7.

 Seretny M, Currie GL, Sena ES, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Pain. 2014;155:2461-70.

 Cavaletti G, Zanna C. Current status and future prospects for the treatment of chemotherapy-induced neurotoxicity. Eur J Cancer. 2002;38:1832-7.

 Kawakami K, Tunoda T, Takiguchi T, et al. Factors exacerbating peripheral neuropathy induced by paclitaxel plus carboplatin in non-small cell lung cancer. Oncol Res. 2012;20:179-85.

 Cavaletti G. Chemotherapy-induced peripheral neurotoxicity (CIPN): what we need and what we know. J Peripher Nerv Syst. 2014;19:66-76.

 Cavaletti G, Alberti P, Frigeni B, et al. Chemotherapy-induced neuropathy. Curr Treat Options Neurol. 2011;13:180-90.

Alberti P, Cavaletti G. Management of side effects in the personalized medicine era: chemotherapy-induced peripheral neuropathy. Methods Mol Biol. 2014;1175:301-22.

 Hershman D, Lacchetti C, Dworkin R, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32:1941-67.

 Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309:1359-67.

 Hausheer F, Schilsky R, Bain S, et al. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol. 2006;33:15-49.

Chen X, Stubblefield M, Custodio C, et al. Electrophysiological features of taxane-induced polyneuropathy in patients with breast cancer. J Clin Neurophysiol. 2013;30:199-203.

 Kaley T, DeAngelis LM. Treatment of chemotherapy-induced peripheral neuropathy. Br J Haematol. 2009;145:3-14.

 Park S, Goldstein D, Krishnan A. Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin. 2013;63:419-37.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common treatment-related side effect of several widely used drugs. Agents known to cause CIPN include platinum analogs, antitubulins, proteasome inhibitors, immunomodulatory agents, and some of the newer biologics.

Chemotherapy-Induced Peripheral Neuropathy 

The promise of vaccine-based anticancer therapies has been explored for a number of years. However, the research met with little success in its early phases, largely because of a poor understanding of the biology of the immune system and its role in combatting cancer.[1] Recent years have seen an enormous expansion in our knowledge of immune mechanisms and their complex interactions, yielding insights that are now being exploited to develop therapeutic strategies. In fact, anticancer immunotherapy has now taken center stage in the war against cancer, with notable successes in the treatment of specific malignancies.[2] Among the various immunotherapy approaches, vaccines that utilize tumor-specific antigens provide a unique opportunity to harness the body’s natural immune responses to target malignancies.[3] However, for primary brain tumors such as gliomas, the promise of immunotherapy has yet to be realized. The comprehensive review by Desjardins and colleagues provides a concise overview of the rationale for the development of various vaccination strategies and of the promises and practical challenges of these approaches.[4] In particular, the authors focus on vaccines based on tumor protein peptides, heat shock proteins (HSPs), and dendritic cells (DCs), outlining the clinical studies that have explored the use of these various vaccines in adults with gliomas.

Immune surveillance is thought to be one of the major mechanisms for the identification and elimination of cancer cells. The emergence of cancer is partly attributed to the failure of the immune system to eliminate aberrant cells that have acquired tumorigenic potential.[5] The adaptation of the vaccination strategy from the prevention of infectious diseases to applications in cancer was based on the principle that the immune system can be induced to act against cancer cell neoantigens. However, most such proteins elicit weak immune responses, either because they are overexpressed normal proteins or because they are similar enough to their normal counterparts that they do not trigger the degree of immune activation needed to induce cytotoxic effects against cancer cells.[5] To overcome this, most trials of anticancer vaccines have used costimulatory molecules to enhance the immune response and raise it to cytotoxic levels.

Cancer-related peptide vaccine strategies, exemplified in this review by rindopepimut, an epidermal growth factor receptor (EGFR) variant III (EGFRvIII)-targeted peptide vaccine, falls into the category of active immunotherapy, which means it attempts to induce the immune system to act against the tumor by presenting the mutant peptide to the stimulated immune cells.[2] The in-frame deletion of exons 2–7 on EGFR generates a novel amino acid sequence and yields a truncated protein with an altered extracellular domain epitope that is identifiable by and accessible to the immune system; this novel tumor-specific epitope, conjugated to the keyhole limpet hemocyanin molecule, constitutes the vaccine.[6] Successful activation of the immune system to target EGFRvIII-expressing glioma cells would be expected to eliminate this subpopulation of cells from the tumor. This indeed appears to have been the case in the ACTIVATE and ACT II trials, which showed that the majority of the tumors that recurred after vaccine therapy demonstrated elimination of EGFRvIII-expressing glioma cells.[6] However, some studies of patient cohorts not treated with rindopepimut have reported a loss of EGFRvIII expression in recurrent glioblastoma (GBM) compared with tissue from primary resection, although the degree of loss was less than that reported in rindopepimut-treated patients.[7,8] Another issue is that, because of intratumoral heterogeneity, only a subset of cells in the tumor may express EGFRvIII, and such expression may be highly variable, as reported in a study using single-cell DNA analysis.[9,10] Such heterogeneity may result in the survival and regrowth of the non–EGFRvIII-expressing cells. Despite these concerns, trials of rindopepimut to date have shown promising results overall, which have led to an ongoing phase III trial (ACT IV; ClinicalTrials.gov identifier: NCT01480479). Favorable results have also been seen in a study of rindopepimut in combination with bevacizumab in patients with recurrent GBM (ReACT trial).[11] The results of the phase III study are expected to definitively answer the question of whether active immune targeting of a single antigen that is tumor-specific can yield a durable improvement in survival in patients with newly diagnosed EGFRvIII-expressing GBM. Rindopepimut has also been tested against diffuse intrinsic pontine glioma, a uniformly fatal primary pediatric brain tumor that also exhibits EGFRvIII expression.

Targeting single antigens restricts the use of vaccine-mediated approaches to only the relatively small subset of patients with gliomas that express those antigens; the heterogeneity of expression of such antigens can also potentially limit the utility of single-antigen vaccines. The need for wider application of vaccine therapies prompted the adoption of broader strategies, including the simultaneous use of multiple tumor-derived antigens, which could have the potential to more broadly activate the immune system against the tumor. In this context, the ability of chaperones, such as HSPs, to process polypeptides-including tumor antigens-in various cellular compartments has been of particular interest.[12] HSP gp96 is the primary resident chaperone of the endoplasmic reticulum and binds various client proteins that are involved in the antigen-presenting pathway.[13] Its ability to process peptides and to interact with professional antigen-presenting cells (APCs) enables HSP gp96 to function as a natural adjuvant that primes innate and adaptive immunity, allowing the complex formed when it is conjugated to tumor peptides to be internalized into APCs and the tumor peptides to be presented by class I and II major histocompatibility complexes (MHCs). Thus, HSP gp96–tumor peptide complexes can generate potent tumor-specific immune responses. This strategy is currently being studied in gliomas in a phase II clinical trial, in which HSP gp96–loaded antigens are extracted from patient-derived glioma tissue for use as a personalized anti-glioma vaccine. Some studies have reported that HSP gp96–based vaccines can stimulate both cytotoxic T lymphocytes and immunosuppressive regulatory T cells, particularly at higher doses[14]; the latter can potentially dampen the antitumor immune response. Thus, such immunotherapeutic approaches can prove to be a double-edged sword.

Cell-based immunotherapeutic strategies using DC vaccines for the treatment of gliomas have been particularly exciting. Of the three cell types (DCs, macrophages, and B lymphocytes) that can process antigens and present them to naive T cells by means of MHC class I and II molecules, DCs are the most efficient at activating T cells; this makes DCs attractive candidates for therapeutic antitumor strategies,[15] as in the DCVax-L approach. DCs process antigens more slowly than the other cell types and are thus capable of preserving the peptides longer for sustained T-cell recognition, triggering a more efficacious antitumor effect.[16] The generation of tumor lysates allows multiple tumor-specific antigens associated with MHCs to be used to prime autologous DCs; the vaccine is then administered together with specific adjuvants. However, the ex vivo modification of DCs is a time-consuming, expensive, and labor-intensive process that must be undertaken in specialized facilities. In addition, some antigens from the tumor may vary in their ability to induce an immune response, resulting in variable and inconsistent responses. To circumvent this variability, tumor-specific proteins not expressed in normal tissue have been identified, and peptides representing these proteins have then been used as antigens to enhance tumor-specific cytotoxicity.[17] Another approach used an immunotherapeutic strategy to target glioma stem cells (GSCs), which have emerged as the putative source of tumor regeneration; in this approach, GSC-specific proteins are isolated and vaccines are then generated that can target these cells. An example of the latter strategy is ICT-107, a DC vaccine loaded with six synthetically generated GSC-associated peptides[18]; ICT-107 has shown promising results in phase II trials in GBM patients with a specific human leukocyte antigen (HLA) subtype (HLA-A2–positive).[19]

Approaches that utilize peptide vaccines such as rindopepimut allow for predictable and immediate availability of a commercially made product that can be readily accessed for treatment. In contrast, cell-based vaccines require extensive processing and the risk of failed vaccine production if a sufficient amount of good-quality tumor tissue is not available, which may preclude the generation of vaccine for some patients who would otherwise be candidates for this therapy. Additionally, similar to tumor heterogeneity and the problems it gives rise to, there is wide variation in immune responses among patients and additional variability induced by treatment-related immune changes; for all anticancer vaccines, these variations contribute to differences in efficacy independent of the variability of the tumor-specific antigen involved. These factors may determine which treated patients respond to immunotherapy and which do not.[16] Hence, the next major step in immunotherapy will be to identify the nuances of the complex immune responses that are patient-specific and tumor-specific in order to optimize the utilization of vaccine-based and other emerging immunotherapeutic strategies against gliomas in a personalized manner. This hopefully will allow full realization of the potential of vaccine therapies in the treatment of gliomas.

The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

 Parish CR. Cancer immunotherapy: the past, the present and the future. Immunol Cell Biol. 2003;81:106-13.

 Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-9.

 Melero I, Gaudernack G, Gerritsen W, et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat Rev Clin Oncol. 2014;11:509-24.

 Desjardins A, Vlahovic G, Friedman HS. Vaccine therapy, oncolytic viruses, and gliomas. Oncology (Williston Park). 2016;30:211-8.

 Finn OJ. Cancer immunology. N Engl J Med. 2008;358:2704-15.

 Gedeon PC, Choi BD, Sampson JH, Bigner DD. Rindopepimut: anti-EGFRvIII peptide vaccine, oncolytic. Drugs Future. 2013;38:147-55.

 Montano N, Cenci T, Martini M, et al. Expression of EGFRvIII in glioblastoma: prognostic significance revisited. Neoplasia. 2011;13:1113-21.

 van den Bent MJ, Gao Y, Kerkhof M, et al. Changes in the EGFR amplification and EGFRvIII expression between paired primary and recurrent glioblastomas. Neuro Oncol. 2015;17:935-41.

 Del Vecchio CA, Giacomini CP, Vogel H, et al. EGFRvIII gene rearrangement is an early event in glioblastoma tumorigenesis and expression defines a hierarchy modulated by epigenetic mechanisms. Oncogene. 2013;32:2670-81.

 Francis JM, Zhang CZ, Maire CL, et al. EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. Cancer Discov. 2014;4:956-71.

 Reardon DA, Schuster J, Tran DD, et al. ReACT: overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. J Clin Oncol. 2015;33(suppl):abstr 2009.

 McNulty S, Colaco CA, Blandford LE, et al. Heat-shock proteins as dendritic cell-targeting vaccines-getting warmer. Immunology. 2013;139:407-15.

 Amato RJ. Heat-shock protein-peptide complex-96 for the treatment of cancer. Expert Opin Biol Ther. 2007;7:1267-73.

 Liu Z, Li X, Qiu L, et al. Treg suppress CTL responses upon immunization with HSP gp96. Eur J Immunol. 2009;39:3110-20.

 Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012;12:265-77.

 Goyvaerts C, Breckpot K. Pros and cons of antigen-presenting cell targeted tumor vaccines. J Immunol Res. 2015;2015:785634.

 Berzofsky JA, Terabe M, Oh S, et al. Progress on new vaccine strategies for the immunotherapy and prevention of cancer. J Clin Invest. 2004;113:1515-25.

 Phuphanich S, Wheeler CJ, Rudnick JD, et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother. 2012;62:125-35.

 Wen P, Reardon D, Phuphanich S, et al. AT-60A randomized double blind placebo-controlled phase 2 trial of dendritic cell (DC) vaccine ICT-107 following standard treatment in newly diagnosed patients with GBM. Neuro Oncol. 2014;16(suppl 5):v22.

The promise of vaccine-based anticancer therapies has been explored for a number of years. However, the research met with little success in its early phases, largely because of a poor understanding of the biology of the immune system and its role in combatting cancer.

Vaccine Therapies Against Gliomas: Prime Time Yet?

The review by Pedersen and colleagues on ground-glass opacity (GGO) lung nodules[1] is timely, addressing a clinical scenario that clinicians are increasingly confronted with: how to appropriately manage the patient with an incidentally detected GGO nodule. I commend the authors for assembling a broad yet concise review of data that can help guide decision-making in this setting. However, I think that in reality, many of the concepts presented are not as clear-cut as depicted; we must be thoughtful and nuanced in our judgment when managing these patients.

The correlation between radiographic appearance and histologic diagnosis is far from reliable. Among resected pure GGO nodules, adenocarcinoma in situ (AIS) was diagnosed in 20% to 59%, minimally invasive adenocarcinoma (MIA) in 20% to 32%, and invasive adenocarcinoma in 39% to 48%.[2-4] Earlier studies of resected pure GGO nodules found that 10% to 30% were benign, 5% to 70% were atypical adenomatous hyperplasia, 20% to 70% were bronchioloalveolar carcinoma, and 10% to 30% were invasive adenocarcinoma.[5] There is moderate interobserver variability in the histologic classification: In a study evaluating the presence of invasion in 64 cases as assessed by 28 thoracic pathologists, complete agreement was seen in 10%, and less than 10% discordance in 29% (with use of a three-point scale: “probable and definite invasion,” “unclear,” “probably or definitely not invaded”).[6] Furthermore, radiographic appearance is significantly affected by many factors, such as CT section thickness, window settings, and radiation dose.[7] Thus, equating a pure GGO nodule with AIS and a part-solid GGO nodule that has a solid component of less than 5 mm with MIA is a gross oversimplification.

The underlying assumption in the review by Pedersen et al is that the diagnosis is black and white: benign or invasive lung cancer. Yet lung cancer exhibits a wide spectrum of behavior, from inconsequential to nonaggressive, typically aggressive, and very aggressive lung cancer. The proportion of “well-behaved” cancers has clearly been increased by the advent of CT screening.[8] The decision to treat must consider both the aggressiveness of the lung cancer and competing risks (comorbidities). Furthermore, the spectrum of nonaggressiveness/aggressiveness may confound the extent-of-resection data: for example, is survival after wedge resection for a pure GGO nodule good simply because the tumor was inconsequential anyhow? We have to learn to think of lung cancer in shades of gray rather than simply as malignant vs benign, or invasive vs noninvasive.

The view that it is only a matter of time until a GGO nodule progresses may not be correct. Kobayashi et al studied 108 GGO nodules that were followed for up to 10 years: only about one-third demonstrated progression (which manifested within 3 years in all cases).[9] Other research suggests that there may be two different populations of GGO nodules, with different mutational patterns; only about one-third are of the type that appears likely to progress.[10,11]

Observing a potentially nonaggressive lung cancer for a period of time is an appealing approach, since this allows the degree of change to guide management. However, small changes can be hard to assess. The appearance of a GGO nodule varies with the degree of inspiration and scanner parameters, and assessment is hampered by inter-/intraobserver variability. Even for solid tumors, data show that false-positive and false-negative assessments of growth are on the order of 10% to 50%,[12] and that inter- and intraobserver consistency are poor for size differences of less than 1.5 mm up to 2 mm.[13,14] GGO nodules are even more difficult to measure reproducibly, and volumetric programs generally do not work well (with interscan variability of ~35% and inter-/intraobserver variability of 20% to 40%).[15,16] Furthermore, growth must be evaluated in light of the time interval involved: Does a GGO nodule that has grown 1 to 2 mm over 5 years constitute a life-threatening lung cancer?

A growing body of data shows that prognosis correlates primarily with the solid component of a GGO nodule and with the invasive component of adenocarcinoma.[7,17-20] In fact, in the new (8th edition) American Joint Committee on Cancer staging system (due out in mid-2016), T will be determined by the solid (as determined by imaging)/invasive (as determined by pathology) component.[7] Thus, the development and the size of a solid component appear to be much more important than the GGO/lepidic component, calling into question the clinical importance of growth (typically slow) of a pure GGO nodule.

Data from CT screening show a marked increase in the proportion of patients with a long volume doubling time (VDT) compared with VDTs in patients with regularly detected lung cancers.[8] Among pure GGO lesions, 50% to 90% are tumors with a VDT of more than 400 days, and VDT is greater than 800 days in 20% to 50%.[8] Limited data are available regarding lung cancers incidentally detected on CT not associated with a screening program, but these data suggest a stage distribution and survival similar to the values seen in CT screening programs.[21,22]

In summary, I offer several thoughts regarding the management of GGO nodules:

This appears to correlate better with the more typical behavior of lung cancer, and the new stage classification will focus on the solid-appearing or invasive component of a cancer.

 There is a lot of variability in the assessment of small imaging changes. It is generally best to evaluate several scans over a period of time to be sure that a perceived change is real.

The spectrum of lung cancer, especially of cancer that presents as a GGO nodule, includes very indolent cancers. The rate of growth must be balanced against comorbidities and competing risks when making management decisions.

 Pedersen JH, Saghir Z, Winkler Wille MM, et al. Ground-glass opacity lung nodules in the era of lung cancer CT screening: radiology, pathology, and clinical management. Oncology (Williston Park). 2016;30:266-74.

 Son JY, Lee HY, Lee KS, et al. Quantitative CT analysis of pulmonary ground-glass opacity nodules for the distinction of invasive adenocarcinoma from pre-invasive or minimally invasive adenocarcinoma. PLoS One. 2014;9:e104066.

 Lim HJ, Ahn S, Lee KS, et al. Persistent pure ground-glass opacity lung nodules ≥ 10 mm in diameter at CT scan: histopathologic comparisons and prognostic implications. Chest. 2013;144:1291-9.

 Mimae T, Miyata Y, Tsutani Y, et al. What are the radiologic findings predictive of indolent lung adenocarcinoma? Jpn J Clin Oncol. 2015;45:367-72.

 Detterbeck FC, Homer RJ. Approach to the ground-glass nodule. Clin Chest Med. 2011;32:799-810.

 Thunnissen F, Beasley M, Borczuk AC, et al. Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study. Mod Pathol. 2012;25:1574-83.

 Travis D, Asamura H, Bankier AA, et al. The IASLC Lung Cancer Staging Project: Proposals for coding T categories for adenocarcinoma in situ and minimally invasive adenocarcinoma, and for measurement of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM Classification of Lung Cancer. J Thorac Oncol. 2016. [In press]

 Detterbeck F, Gibson C. Turning gray: the natural history of lung cancer over time. J Thorac Oncol. 2008;3:781-92.

 Kobayashi Y, Fukui T, Ito S, et al. How long should small lung lesions of ground-glass opacity be followed? J Thorac Oncol. 2013;8:309-14.

 Yatabe Y, Borczuk AC, Powell CA. Do all lung adenocarcinomas follow a stepwise progression? Lung Cancer. 2011;74:7-11.

 Kobayashi Y, Mitsudomi T, Sakao Y, Yatabe Y. Genetic features of pulmonary adenocarcinoma presenting with ground-glass nodules: the differences between nodules with and without growth. Ann Oncol. 2015;26:156-61.

 Jennings SG, Winer-Muram HT, Tarver RD, Farber MO. Lung tumor growth: assessment with CT-comparison of diameter and cross-sectional area with volume measurements. Radiology. 2004;231:866-71.

 Nietert PJ, Ravenel JG, Leue WM, et al. Imprecision in automated volume measurements of pulmonary nodules and its effect on the level of uncertainty in volume doubling time estimation. Chest. 2009;135:1580-7.

 Revel M-P, Bissery A, Bienvenu M, et al. Are two-dimensional CT measurements of small noncalcified pulmonary nodules reliable? Radiology. 2004;231:453-8.

 Oda S, Awai K, Murao K, et al. Computer-aided volumetry of pulmonary nodules exhibiting ground-glass opacity at MDCT. AJR Am J Roentgenol. 2010;194:398-406.

 Kim H, Park CM, Woo S, et al. Pure and part-solid pulmonary ground-glass nodules: measurement variability of volume and mass in nodules with a solid portion less than or equal to 5 mm. Radiology. 2013;269:585-93.

 Murakawa T, Konoeda C, Ito T, et al. The ground glass opacity component can be eliminated from the T-factor assessment of lung adenocarcinoma. Eur J Cardiothorac Surg. 2013;43:925-32.

 Tsutani Y, Miyata Y, Mimae T, et al. The prognostic role of pathologic invasive component size, excluding lepidic growth, in stage I lung adenocarcinoma. J Thorac Cardiovasc Surg. 2013;146:580-5.

 Tsutani Y, Miyata Y, Nakayama H, et al. Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma: a multicenter study. J Thorac Cardiovasc Surg. 2012;143:607-12.

 Maeyashiki T, Suzuki K, Hattori A, et al. The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer. Eur J Cardiothorac Surg. 2013;43:915-8.

 Raz DJ, Glidden DV, Odisho A, Jablons DM. Clinical characteristics and survival of patients with surgically resected, incidentally detected lung cancer. J Thorac Oncol. 2007;2:125-30.

 Kawachi R, Watanabe S, Asamura H. Clinicopathological characteristics of screen-detected lung cancers. J Thorac Oncol. 2009;4:615-9.

Lung cancer exhibits a wide spectrum of behavior, from inconsequential to nonaggressive, typically aggressive, and very aggressive lung cancer. The proportion of “well-behaved” cancers has clearly been increased by the advent of CT screening.

More Opaque Than Clear: Reality Is Always Cloaked in Shades of Gray

(co-authored with your daughter Elizabeth), you describe the early days of your career, and particularly how medical oncologists, surgeons, and radiologists were often at odds about the best way to treat cancer patients. Do you think that problem still exists to some extent, or are all disciplines working together now to provide comprehensive cancer care?

 Things have improved greatly, especially at major cancer centers where the essence of good care is provided by teams of physicians. But it’s not universal. I have recently seen some examples of marginal care for complex patients because the patient was seen by one physician at a time, a sequence resulting in lack of communication and, worse, unnecessary delays in starting treatment. And this was at a major university cancer center-they apparently have not gotten the message! It is good for patients to ask about whether a team of physicians will be involved. In private practice, assembling teams is more difficult so we still have work to do there.

Likewise, do you think oncologists are currently too constrained by treatment guidelines and standards of care, which may prevent them from trying new therapies or being more creative when it comes to treating their patients?

 Yes, I do. Guidelines are backward-looking in a rapidly changing field like cancer. But what worries me more are the constraints on innovation. New approaches to treatment in this era of targeted therapy need maximum flexibility to mix and match treatments in order to control the wily cancer cell.

What do you think needs to happen in order for the US Food and Drug Administration (FDA) to speed up the approval of new agents, which you indicate in your book is one of the biggest obstacles to patients receiving the treatment they need in the time they need it?

 The FDA is approving drugs based on outdated methods. It should approve new cancer drugs based on their safety profile and their ability to hit important molecular targets. And I think cancer centers have matured enough to handle all the early trials by themselves. So, both the National Cancer Institute (NCI) and FDA should delegate responsibility for all phase I and II trials to NCI-approved cancer centers. This would not only increase the speed of developing new drugs tenfold, but it would cost less.

When writing this book, what did you hope oncologists (both experienced and new to the field) and patients alike would take away from it?

The mandate of the National Cancer Act of 1971 was “to support research and the application of the results of research, to reduce the incidence, morbidity, and mortality from cancer,” and we have done that. I would like people to know the war on cancer was a success and that the best is yet to come with the emergence of targeted therapy and immunotherapy. It’s a very exciting time to be entering the field of cancer research.

For patients, they need to know that for newly diagnosed cancer there is something that can be done for everybody. If a doctor tells you otherwise, find another doctor.

The mandate of the National Cancer Act of 1971 was “to support research and the application of the results of research, to reduce the incidence, morbidity, and mortality from cancer,” and we have done that.

Vincent T. DeVita on His New Book, “The Death of Cancer,” and the Current State of Cancer Care

Human papillomavirus (HPV) infection can be considered a major pandemic, causing both benign and malignant disease around the world. It is the most frequently acquired sexually transmitted disease, with more than 6 million new cases transmitted annually in the United States.[1] HPV is implicated in the oncogenesis of at least 5% of all cancers, including cervical, head and neck, anal, and penile cancers.

Recently, Alemany et al[2] undertook the largest epidemiologic study to date of HPV’s role in penile cancer, examining 1,010 penile cancer specimens from 25 countries. The team detected HPV DNA in approximately 40% to 50% of invasive penile cancer cases and in up to 90% of high-grade squamous intraepithelial lesions. The high-risk oncogenic subtypes 16 and 18 accounted for most of this disease and were detected in over 60% of HPV-positive specimens.

In this issue of ONCOLOGY, Drs. Stratton and Culkin provide an excellent in-depth review of HPV and penile cancer,[3] including both premalignant and malignant penile lesions. This review understandably did not mention lichen sclerosus as a further potential pathway leading to invasive penile cancer. Previously, controversy surrounded HPV’s role in conjunction with lichen sclerosus, but current evidence suggests that lichen sclerosus is an HPV-independent carcinogenic factor.[4,5]

As the review discusses, the College of American Pathologists’ most recent classification system for penile intraepithelial neoplasms (PeIN) has two distinct categories of PeIN: (1) “differentiated,” referring to PeIN with no HPV association and most commonly caused by lichen sclerosus, and (2) “undifferentiated,” referring to bowenoid/warty PeIN with a high association with HPV.[6] These distinctions are important, as future targeted therapies will depend on overall HPV status.

Over the past 5 years, several studies have investigated the molecular profiling of penile carcinomas, examining both genomic and epigenetic alterations. These studies have revealed distinct molecular pathways associated with HPV status. Recently, McDaniel et al[7] performed targeted genomic profiling of 60 fixed penile carcinomas and revealed several distinct recurrent mutations. In the HPV-positive cohort, low levels of 

 alterations were found, which were consistent with findings from genomic profiling of other HPV-induced malignancies, including oropharyngeal and cervical squamous cell carcinomas. One explanation for this is that during HPV infection, there is no genetic drive for alterations in these genes, as they become inactivated by the viral oncogenes E6 and E7, respectively. Feber et al[8] undertook methylome analysis of 50 cases of penile carcinoma and found that HPV infection was associated with widespread loss of DNA methylation. This methylation signature was distinct from that of the HPV-negative tumors. Furthermore, they found differentially methylated regions containing several candidate genes-eg, 

, a tumor suppressor gene. Gene ontology analysis found that a significant proportion of those genes found in differentially methylated regions belong to the Wnt signaling pathway.

Further work is needed to validate the potential targets uncovered in these molecular studies. Patients with penile cancer who have lymph node metastases still have only a few options, with mostly only platinum or taxane-based chemotherapeutic agents available, resulting in poor 5-year disease-specific survival rates. Future work should validate these targets, with targeted therapies in mind, such as epidermal growth factor receptor and mammalian target of rapamycin inhibitors.

The best method of combating HPV-related disease is to prevent it in the first place. This can now be achieved by routine vaccination using a quadrivalent or, more recently, a 9-valent HPV vaccine, which is routinely offered to young women in many countries. Stratton and Culkin highlight the important effect that HPV vaccination could have on the future epidemiology and treatment of penile cancer. HPV vaccination for high-risk HPV subtypes should now be considered in all young men as well as young women. It has the potential to improve herd immunity with regard to infection with all strains of HPV present in the vaccines, and thus to protect the population at large from both benign and malignant HPV-induced lesions.

In the near future, therapeutic HPV DNA vaccines will also be able to treat patients with HPV-positive disease. The first one in development, GTL001, is currently being evaluated in a phase II international randomized controlled trial across seven European countries.[9] We are awaiting these results, which will be published within the next 6 months. Further research is needed on HPV vaccination’s possible role in the treatment of HPV penile carcinomas. This affordable adjunct to treatment could potentially improve outcomes for all patients with HPV-associated penile carcinomas. The option of vaccination as treatment adds further weight to the argument that all penile tumors should be typed for HPV status, as we are now on the threshold of an era in which this information will directly affect the treatment and management of these patients.

The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

 Cates W Jr. Estimates of the incidence and prevalence of sexually transmitted diseases in the United States. American Social Health Association Panel. Sex Transm Dis. 1999;26:S2-S7.

 Gutierrez-Pascual M, Vicente-Martin FJ, Lopez-Estebaranz JL. Lichen sclerosus and squamous cell carcinoma. Actas Dermosifiliogr. 2012;103:21-8.

 Mannweiler S, Sygulla S, Winter E, Regauer S. Two major pathways of penile carcinogenesis: HPV-induced penile cancers overexpress p16ink4a, HPV-negative cancers associated with dermatoses express p53, but lack p16ink4a overexpression. J Am Acad Dermatol. 2013;69:73-81.

 Velazquez EF, Amin MB, Epstein JI, et al. Protocol for the examination of specimens from patients with carcinoma of the penis. Arch Pathol Lab Med. 2010;134:923-9.

 McDaniel AS, Hovelson DH, Cani AK, et al. Genomic profiling of penile squamous cell carcinoma reveals new opportunities for targeted therapy. Cancer Res. 2015;75:5219-27.

 Feber A, Arya M, de Winter P, et al. Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer. Clin Cancer Res. 2015;21:1196-206.

 EsquerrÃ© M, Momot M, Goubier A, et al. Bivalent adenylate cyclase (CYA)-based therapeutic vaccines: eradication of tumor cells expressing different antigens over time. Cancer Res. 2015;75(15 suppl):abstr 2507.

Over the past 5 years, several studies have investigated the molecular profiling of penile carcinomas, examining both genomic and epigenetic alterations. These studies have revealed distinct molecular pathways associated with HPV status.

HPV and Penile Cancer: Perspectives on the Future Management of HPV-Positive Disease

The goal of risk classification in prostate cancer should be to accurately characterize the likelihood of disease recurrence and the potential for prostate cancer–related death. Based on an individual patient’s risk, physicians can present him with appropriate treatment options to maximize survival and quality of life, in the context of his particular comorbid conditions and life expectancy. Accurate risk stratification is crucial, whether it is used to avoid overtreatment of very-low-risk or low-risk prostate cancer, or to identify subgroups of intermediate-risk patients who may benefit from more aggressive, and in some cases, multimodal therapy. The challenge in basing treatment on risk stratification is not at the far ends of the spectrum (very-low-risk or very-high-risk disease), where treatment paradigms are established, but rather in the middle, where intermediate-risk disease exhibits a broad range of behavior. The oncologic behavior of tumors in the intermediate-risk category is highly variable, demonstrating a wide range of prostate cancer–specific mortality, prostate-specific antigen (PSA) progression, and clinical disease recurrence across different treatment modalities.[1]

This review by Serrano and Anscher focuses on the substantial group of patients who fall into the intermediate-risk prostate cancer category as defined by the National Comprehensive Cancer Network; the authors advocate further subclassification of this group into favorable intermediate-risk (FIR) and unfavorable intermediate-risk (UIR) prostate cancer.[2] Studies from both surgical[3] and radiation[4,5] series have shown that men with UIR disease had inferior outcomes compared with men with FIR disease with regard to biochemical recurrence–free survival, distant metastasis, and cancer-specific survival. These varying outcomes suggest that FIR and UIR prostate cancer have different oncologic potentials and should be managed differently. The authors also point out that FIR prostate cancer behaves in a more indolent fashion than UIR disease and may not always warrant treatment. A recent update by Klotz et al on a large active surveillance (AS) cohort included a substantial percentage of patients (21%) with intermediate-risk prostate cancer (Gleason score 3+4 only).[6] After 15 years of follow-up, 85% of the initial 993 patients were still alive, and only 15 deaths (1.5%) were attributed to prostate cancer, even though 21% of the patients included were diagnosed with intermediate-risk prostate cancer.[6] Others have also suggested that there is a divide within intermediate-risk prostate cancer (Gleason score = 7), with the oncologic behavior of primary Gleason pattern 3 prostate cancer mimicking that of low-risk disease, and with primary Gleason pattern 4 prostate cancer mirroring high-risk disease.[7-9]

Risk stratification is further confounded by a heavy reliance on Gleason scoring from prostate biopsy specimens. Recent revisions to the Gleason scoring system have resulted in improved outcomes in both low-risk (Gleason score 6) and intermediate-risk (Gleason score 7) prostate cancer, as patients who were once considered low-risk have been reclassified into the intermediate-risk category. This phenomenon is known as the Will Rogers effect. The 2005 (and now 2014) International Society of Urological Pathology revision of Gleason scoring[10,11] may hamper efforts to study long-term outcomes of intermediate-risk prostate cancer patients, given that extended follow-up is required to recognize oncologic outcomes in prostate cancer on account of its slow growth pattern. Gleason scoring is also prone to interobserver variability by pathologists.[12] Finally, there are frequent discrepancies between prostate needle biopsy and radical prostatectomy Gleason scoring.[13] Most recently, Epstein et al have proposed and validated a new risk classification system that would replace the Gleason scoring system and take into account the distinction of FIR and UIR, as supported here by Serrano and Anscher.[11] In this new grading system, patients with Gleason 3+4=7 prostate cancer would be considered risk group 2, and those with Gleason 4+3=7 would be considered risk group 3. Of course, the adoption of an entirely new grading system, even if it is more accurate in terms of oncologic potential, will undoubtedly pose challenges for the study of intermediate-risk prostate cancer outcomes over time.

Evidence clearly suggests that UIR prostate cancer behaves similarly to high-risk prostate cancer.[14,15] The outcomes for radiation therapy are summarized nicely in this review; however, we believe that surgery should remain a fundamental management option for clinically localized UIR and high-risk prostate cancer. Recent studies suggest that surgery may lead to improved survival compared with radiotherapy in patients with intermediate- or high-risk localized prostate cancer.[16] Additionally, improvement in cancer-specific survival has been noted in high-risk patients undergoing surgery compared with those treated with external beam radiation therapy.[17] The results of the ProtecT trial (ClinicalTrials.gov identifier: NCT02044172) will provide additional insight into the role of surgical management in intermediate-risk prostate cancer.[18]

Conversely, with an armamentarium of treatment options available, it is also necessary to consider which patients truly do require treatment and which are suitable for AS. Intermediate-risk prostate cancer patients with favorable features (eg, low-volume Gleason 3+4=7 disease, PSA level < 10 ng/mL) may be more appropriately grouped with their low-risk counterparts in terms of treatment. Some large AS cohorts have included significant numbers of these intermediate-risk patients, and have demonstrated satisfactory outcomes, particularly in older patients,[6] suggesting that AS may be expanded to include carefully selected intermediate-risk prostate cancer patients with favorable features.

We have made great progress in stratifying the large and heterogeneous group of prostate cancer patients based on the oncologic potential of their cancers. However, we must now come to a uniform consensus regarding the descriptions of these risk groups in order to truly determine which treatments have the best oncologic efficacy, while minimizing overtreatment and optimizing patients’ quality of life.

The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article. 

 D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969-74.

 Serrano NA, Anscher MS. Favorable vs unfavorable intermediate-risk prostate cancer: a review of the new classification system and its impact on treatment recommendations. Oncology (Williston Park). 2016;30:229-36.

 Reese AC, Pierorazio PM, Han M, Partin AW. Contemporary evaluation of the National Comprehensive Cancer Network prostate cancer risk classification system. Urology. 2012;80:1075-9.

 Keane FK, Chen MH, Zhang D, et al. The likelihood of death from prostate cancer in men with favorable or unfavorable intermediate-risk disease. Cancer. 2014;120:1787-93.

 Zumsteg ZS, Spratt DE, Pei I, et al. A new risk classification system for therapeutic decision making with intermediate-risk prostate cancer patients undergoing dose-escalated external-beam radiation therapy. Eur Urol. 2013;64:895-902.

 Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol. 2015;33:272-7.

 Schiffmann J, Wenzel P, Salomon G. Heterogeneity in D’Amico classification-based low-risk prostate cancer: differences in upgrading and upstaging according to active surveillance eligibility. Urol Oncol. 2015;33:329.e13-9.

 Dinh KT, Muralidhar V, Mahal BA, et al. Occult high-risk disease in clinically low-risk prostate cancer with ≥50% positive biopsy cores: Should national guidelines stop calling them low-risk? Urology. 2016;87:125-32.

 Chan TY, Partin AW, Walsh PC, Epstein JI. Prognostic significance of Gleason score 3+4 versus Gleason score 4+3 tumor at radical prostatectomy. Urology. 2000;56:823-7.

 Epstein JI, Allsbrook WC Jr, Amin MB, et al. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005;29:1228-42.

 Epstein JI, Egevad L, Amin MB, et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 2016;40:244-52.

 Allsbrook WC, Mangold KA, Johnson MH, et al. Interobserver reproducibility of Gleason grading of prostatic carcinoma: urologic pathologists. Human Pathol. 2001;32:74-80.

 Sved PD, Gomez P, Manoharan M, et al. Limitations of biopsy Gleason grade: implications for counseling patients with biopsy Gleason score 6 prostate cancer. J Urol. 2004;172:98-102.

 Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367:203-13.

 Pierorazio PM, Walsh PC, Partin AW, Epstein JI. Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int. 2013;111:753-60.

 Sooriakumaran P, Nyberg T, Akre O, et al. Comparative effectiveness of radical prostatectomy and radiotherapy in prostate cancer: observational study of mortality outcomes. BMJ. 2014;348:g1502.

 Taguchi S, Fukuhara H, Shiraishi K, et al. Radical prostatectomy versus external beam radiotherapy for cT1-4N0M0 prostate cancer: comparison of patient outcomes including mortality. PLoS One. 2015;10:e0141123.

 Lane JA, Donovan JL, Davis M, et al. Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial. Lancet Oncol. 2014;15:1109-18.

We must now come to a uniform consensus regarding the descriptions of these risk groups in order to truly determine which treatments have the best oncologic efficacy, while minimizing overtreatment and optimizing patients’ quality of life.

Oncology Vol 30 No 3