Skin cancer and parkinson's disease

Movement DisordersVol. 25, No. 2, 2010, pp. 139–148 Joaquim J. Ferreira, MD, PhD,1* Dulce Neutel, MD,1 Tiago Mestre, MD,1 Miguel Coelho, MD,1 Ma´rio M. Rosa, MD,1 Olivier Rascol, MD, PhD,2 and Cristina Sampaio, MD, PhD1 1Neurological Clinic Research Unit, Institute of Molecular Medicine, Lisbon School of Medicine, Lisbon, Portugal 2Departments of Clinical Pharmacology and Neurosciences, INSERM CIC-9302 and UMR-825, Abstract: The report of an increased frequency of melanoma cer occurrence in PD. The best data available suggest the risk during the clinical development of rasagiline prompted a of cancer is reduced in PD patients. However, specific cancers renewed interest in a possible association between skin cancer like thyroid and the female breast were reported at higher-than- and Parkinson’s disease (PD). The evaluation of this risk ended expected rates. Additionally, it was suggested that PD patients in a recommendation to perform a periodic dermatological ex- have a higher frequency of melanoma and non-melanoma skin amination as a follow-up measure of their treatment. The rec- cancers than the general population. The data on non-mela- ognition of this safety concern lead to the need to clarify if the noma skin cancer are less robust than the data on melanoma.
risk of skin cancer is indeed associated with PD and if levo- Causal factors remain unknown. Due to the weak association dopa or other anti-parkinsonian drugs might contribute to between skin cancer and PD, no robust recommendation can be increase such risk. To answer these questions, we critically made regarding the need for periodic dermatological screen- reviewed all clinical studies available concerning the associa- tion between skin cancer and PD. We found 26 studies on can- Key words: Parkinson’s disease; cancer; melanoma; skin Concern about an increased risk of skin cancer in vate a malignant melanoma, it should not be used in Parkinson’s disease (PD) patients was first raised by patients with suspicious, undiagnosed skin lesions or a Skibba (1972) based upon a case of recurrent malig- history of melanoma.’’3 The association between levo- nant melanoma in a PD patient treated with levodopa dopa therapy and melanoma was considered theoreti- (L-dopa).1 Since then, more than 50 cases of newly cally plausible because L-dopa is a substrate for the diagnosed melanoma, melanoma recurrence, or mela- noma metastasis were reported in L-dopa-treated PD The finding of an increased frequency of melanomas during the clinical development of rasagiline prompted These case reports were sufficient to raise safety a renewed interest in a possible association of skin concerns to an extent that, since 1976, a formal contra- cancer and PD. The evaluation of this risk ended in a indication exists for the use of L-dopa in PD patients recommendation to perform periodic dermatological with melanoma. For example, Sinemet and Madopar examinations in patients as follow-up measure of their yield the warning ‘‘(. . .) because levodopa may acti- treatment.7–9 A similar amendment was later added tothe safety labels of pramipexole,10 ropinirole,11 andselegiline.12 *Correspondence to: Dr. Joaquim Ferreira, Centro de Estudos Egas To review the association between skin cancers and Moniz, Faculdade de Medicina de Lisboa, 1649-028 Lisboa, Portugal.
E-mail: [email protected] PD, we critically analyzed the epidemiological and Potential conflict of interest: None reported.
clinical studies available. First, we reviewed data on Received 7 April 2008; Revised 28 September 2009; Accepted 29 the global risk of cancer in PD. As a second step, we focused on specific studies evaluating the risk of mela- Published online 8 January 2010 in Wiley InterScience (www. DOI: 10.1002/mds.22855 noma and other skin cancers in PD patients.
noma cases was low, but the number of cases of malig- nant melanoma was higher than expected.
We searched the database Medline (1966–2008) Elbaz et al.27 conducted a population-based case- with the terms ‘‘cancer,’’ ‘‘mortality,’’ ‘‘melanoma,’’ control study to investigate the association of PD with and ‘‘Parkinson’s disease’’. We also searched refer- nonfatal cancer. They used the medical records-linkage enced lists of identified studies on cancer and mela- system of the Rochester Epidemiology Project (1976– noma in PD and handsearched the abstract books of 1995). Each case was matched by age and sex to a international congresses of movement disorders. All general population control. The frequency of cancer in studies aimed at evaluating the frequency of any type general was lower in PD cases (19.4%) than in controls of cancer or cancer related mortality in PD were (23.5%) (OR 0.79; 95% CI 0.49–1.27). This pattern was more pronounced in women than in men and in Quality of published methodology data and related patients aged 71 years or younger at onset of PD. They susceptibility to bias were assessed through a check- did not find an association between PD and nonfatal list approach for study design, diagnostic criteria of cancer. However, they did find a decreased prevalence PD, type of cancer ascertainment, and statistical of smoking-related cancers and an increased prevalence of malignant melanoma. This latter finding was basedon 3 observed cases in the patient group.
The same authors28 used the same approach to investigate the risk of cancer after the diagnosis of PD.
They included 196 patients and 185 control subjects in The first comment about cancer in PD was made by this study. The risk of cancer was higher among Doshay in 1954 who concluded from the analysis of a patients than in controls (RR 1.64; 95% CI 1.15–2.35; case series that cancer was rare in ‘‘paralysis agi- P 5 0.007). The increased risk was significant for tans.’’13 Several other studies followed from other case non-melanoma skin cancers (RR 1.76; 95% CI 1.07– series, chart reviews, prospective cohorts, or case-con- 2.89; P 5 0.03). Among PD patients, there was no trol studies. In Table 1, we present all known studies relation between the risk of cancer and the cumulative for which the primary or secondary objectives were to dose of L-dopa or the use of other PD medications. No evaluate the frequency of cancer in PD patients.
other types of cancer were found to be associated with Hoehn and Yahr investigated the cause of death in PD. However, these analyses were hampered by the 194 patients with PD and found that 24 patients had small sample size and a potential surveillance bias.
died of malignant neoplasms.16 When compared with Moller et al.22 conducted a retrospective study in a the expected number calculated using the New York cohort of 7,046 patients with a primary diagnosis of population as reference (41 cases), they concluded that PD obtained from a Danish hospital discharge compu- a lower rate of death by malignant neoplasm occurred terised register (during 1977–89). Information on can- in PD patients (P < 0.001).16 Interestingly, 5 cases of cer incidence and death among cohort members from skin cancers from 69 cases of malignant neoplasms their first recorded admission for PD until the end of were reported. There was no description of the type of 1990 was obtained from the Danish cancer registry skin lesion and no comparison was made with the and from the Danish registry of deaths (the average expected prevalence of skin cancers in the reference duration of follow-up was 4.6 years). The Danish Can- cer Registry began reporting incidence data in 1943 Jansson and Jankovic19 retrospectively reviewed 406 and includes cases of non-melanoma skin cancers (ba- medical charts of PD patients and identified 18 patients sal cell and squamous cell carcinoma). The expected with cancer, when compared with an expected number numbers of cancer cases were calculated from the per- of 41.9. The exception to these lower cancer rates were son’s years at risk among cohort members and the malignant melanoma (2 cases observed vs. 0.3 expected, incidences of cancer in the Danish population. The P 5 0.04) and thyroid tumors (3 cases, all in women, overall incidence of cancer was lower than expected P < 0.001). Interestingly, non-melanoma skin cancers (relative risk 0.88, 95% CI 0.8–1.0). However, a sig- occurred less frequently than expected (10 cases nificant increase in relative risk was seen for skin mel- observed vs. 49.9 expected, P < 0.0001). The L-dopa anoma (relative risk 1.96, 95% CI 1.1–3.2). Relative dose, duration of treatment, and other risk factors related risks of other skin cancers also increased, although to the disease were not included in the analysis. The this was not statistically significant (relative risk 1.24, authors concluded that the rate of cancer and non-mela- An update of the Moller study22 was recently pub- noma and non-melanoma) with reasonable precision.
lished, covering a longer period (1977–98).30 Among Overall, data available are consistent and sufficiently 14,088 patients with a primary diagnosis of PD (aver- robust to conclude that PD is associated with a age duration of follow-up of 5 years), 1,282 cancer decreased risk for cancer when compared with the gen- cases were subsequently recorded compared to 1,464 eral population. However, some cancer types have expected cases, with a standardized incidence ratio been reported to occur in excess of expected numbers (SIR) of 0.88 (95% CI 0.8–1.0), that is equivalent to a including malignant melanoma of the skin, other skin 12% reduction in the risk of cancer. Significantly cancers, and cancers of the thyroid and the female reduced risks were found for smoking-related cancers (e.g. lung (SIR, 0.38), larynx (SIR, 0.47), and urinarybladder (SIR, 0.52)) cancers. In contrast, increasedrisks were seen for malignant melanoma (SIR, 1.95; 95% CI 1.4–2.6), non-melanoma skin cancer (1.25; Recently, specific studies have investigated the prob- 95% CI 1.1–1.4), and breast cancer (1.24; 95% CI 1.0– lem of melanoma or other skin cancers in PD (Table 1.5). The association between PD and melanoma was 2). Different approaches were used to investigate the higher in the 1st year after PD diagnosis and decreased potential association: determination of the frequency of in subsequent periods. As in the first study, there was melanoma in PD patients’ cohorts; to investigate the also an increased relative risk for non-melanoma skin frequency of PD diagnosis in patients with a clinical cancers, which reached statistical significance in the history of melanoma; to investigate risk factors for the larger study. In both studies, there was no information development of skin cancers in PD patients (e.g., L- on treatment and the suspected role of L-dopa as a risk dopa treatment, other anti-parkinsonian treatments, or Driver et al.31 conducted a nested case-control study within a prospective cohort of 22,071 US male physi- cians to estimate the association between the diagnosis of PD and the development of cancer. During the 22 Olsen and coworkers33 conducted a population-based years of follow-up, 487 cases of PD were identified case–control study to investigate the prevalence of ma- and age-matched to 487 controls. The frequency of lignant melanoma, skin carcinoma, and other cancers any cancer was lower in PD cases (13.1%) than in con- before a first hospitalization or outpatient visit for PD.
trols (14.8%). The same research group conducted They identified 8,090 patients with a primary diagnosis another case-control study using the same cohort to of PD during the period of 1986–1998 from the evaluate cancer incidence following the diagnosis of National Danish Hospital Register. Each case was PD. A total of 487 cases of PD without cancer were matched with four population controls selected at ran- age-matched to reference participants who were alive dom from among inhabitants alive at the date of first and cancer-free at the time of PD diagnosis. A total of hospital contact with the patient. The number of cancer 121 cases of cancer were confirmed during a median cases since 1943 were obtained from the Danish Can- follow-up of 5.2 years (PD) and 5.9 years (reference).
cer Registry. The study found an increased prevalence Those with PD developed less cancer (11.0 versus of malignant melanoma and skin carcinoma before the 14.0%), with an adjusted RR of 0.85 [95% CI, 0.59– first hospital contact for PD, with overall odds ratios of 1.22]. Reduced risk was present for smoking-related 1.44 (95% CI 1.03–2.01) and 1.26 (95% CI 1.11– cancers such as lung (RR, 0.32), colorectal (RR, 0.54), 1.43), respectively. Cancers showed a reduced preva- and bladder (RR, 0.68), as well as for most non-smok- ing-related cancers such as prostate cancer (RR, 0.74).
A cross-sectional survey to assess the frequency and In contrast, PD patients were at a significantly characteristics of skin neoplasms in PD patients was increased risk for melanoma (RR, 6.15; 95% CI, 1.77– conducted in 12 medical centres in Israel.34 Of the 1,395 patients included, 9 patients (0.6%) had a histo- The most robust evidence concerning the global risk logically confirmed diagnosis of malignant melanoma of cancer in PD derives from the results of the Danish (1 invasive; 8 in situ), 14 patients (1.0%) had mela- PD cohort studies.22,30 All other epidemiological stud- noma in their medical history, and 6 patients had mela- ies have small samples and inadequate statistical power noma diagnoses before and 8 after their PD diagnosis.
to conclusively assess the risk for skin cancer (mela- The total number of patients with current or prior mel- anoma was 20 (1.4%). Occurrence of melanoma did with no history of melanoma or pigmented lesion- not correlate with PD duration, H&Y stage, or L-dopa related problems. Cases and controls were matched by treatment. Analysis of prevalence data (5-year limited age and gender. Cases of malignant melanoma were duration) for a comparable time period from the Israel collected from US academic dermatology clinics.
National Cancer Registry suggested an overall relative Among the melanoma patients, 25 (2.9%) cases had rate of melanoma of 4.4 (95% CI 2.6–7.6) times PD compared with 11 (1.3%) controls with PD. The greater than expected based on an age- and sex- authors concluded that the odds of having PD was more than twofold greater in patients with malignant Bertoni et al.35 performed another cross-sectional melanoma than in the control subjects.
survey in 2,106 North American PD patients who Baade et al.39 conducted a cohort study of all patients underwent a full-body dermatological examination and diagnosed as having melanoma in Australia since 1982 biopsy of any suspicious skin lesions. Of the 346 (n 5 127,037). The subjects were followed through the patients with suspicious pigmented lesions, 20 had his- end of 2001. Their cohort had a risk of death due to thologically confirmed in situ melanomas (0.95%) and amyotrophic lateral sclerosis (ALS) that was 70% higher 4 had invasive melanomas (0.19%). No relationship (standardized mortality ratio 5 169.4, 95% CI 5 127– between the occurrence of melanoma (before or at ex- 221) than the general population, and nearly a threefold amination) and L-dopa usage was observed. Prevalence increased risk of dying from PD (standardized mortality (5-year limited-duration) of invasive melanoma in US ratio 5 266.3, 95% CI 5 222–317). These increased PD patients (n 5 1,692) was 2.2-fold higher (95% CI risks continued for long-term survivors, arguing against 1.21–4.17) than expected in age- and sex-matched pop- a surveillance effect (particularly for ALS).
ulations in the National Surveillance Epidemiology andEnd Results—US Cancer Statistics Review database(SEER). Compared with American Academy of Der- matology screening programs, age- or sex-adjusted rel- ative risk of any melanoma at screening was more than Since the early 1970s, a number of case reports have suggested that L-dopa therapy increased the risk of cu- A small cross-sectional survey found more neoplastic taneous malignant melanoma. However, this safety or pre-neoplastic lesions in PD patients (23.3%) when concern was based on a limited number of anecdotal compared to age matched controls (13.7%) (OR 95%CI reports, and on cases where melanoma preceded L- 1.92 [1.05, 3.51]). 36 Likewise, more cases of actinic ker- dopa treatment, in which a formal causal-relationship atosis (19%) and basal cell carcinoma (3%) were diag- evaluation would preclude such a link. There are also nosed in PD patients, suggesting that pre-neoplastic skin cases with no exacerbation or recurrence of melanoma lesions, such as actinic keratosis, could also play a role in in patients that were kept on L-dopa therapy. The data the increased risk of PD patients to develop melanoma.
from these case reports are also limited in terms of Constantinescu et al.37 evaluated the frequency of ma- patient characteristics that could be correlated with an lignant melanoma in the DATATOP clinical trial cohort.
increased risk for melanoma, such as sun exposure, The DATATOP cohort included 800 patients enrolled between September 1987 and November 1988, and fol- The only epidemiological study that has specifically lowed until 1994. Five cases of melanoma were found evaluated the role of L-dopa was conducted by Sober when compared with an expected number of 1.5 after et al.40 They conducted a prospective survey in 1,099 adjusting for age and gender (standardized event ratio 3.3 patients from the Melanoma Clinical Cooperative [95% CI 1.1–7.8]). Two cases of malignant melanoma Group. At the time of presentation of their primary mel- were diagnosed before the L-dopa treatment onset, and 3 anoma, only 1 patient had been taking L-dopa. The cases occurred after 1, 6, and 19 months. No conclusion authors concluded that L-dopa had no role in the induc- could be made about an association between L-dopa ther- tion of melanoma. No other formal epidemiological study has been conducted to test the hypothesis that L-dopa therapy for PD increases the risk of cutaneous ma-lignant melanoma. Interestingly, the hypothesis that L- dopa could be toxic to the melanocytes was raised in the 1970s.41 Although its efficacy was never demonstrated, Rigel et al.38 performed a case-controlled study in high doses of oral L-dopa were used in practice to treat 862 malignant melanoma patients and 862 controls one of the common causative factor is long-term sun exposure,48,49 it may be hypothesized that PD patients There are no epidemiological studies evaluating the frequency of skin cancer in PD patients treated with lesions. This may be due to a disease-specific suscepti- bility or to a photocarcinogenic potential of L-dopa or available are derived from adverse events reported in other anti-parkinsonian drugs. The increased rate of published clinical trials or registered in pharmacovigi- malignant melanoma and non-melanoma skin cancers before the diagnosis of PD weakens the hypothesis thatskin cancers may be caused by the treatment of PD.33 Furthermore, although exogenous L-dopa was sug- gested to have some effect on melanin synthesis, con- sequently, stimulating melanogenesis and melanoma From this analysis of all the data available regarding growth,50 it has not been demonstrated that L-dopa is the association between PD and skin cancer, melanoma carcinogenic. Other theories for L-dopa-induced mela- occurs at a higher frequency in PD patients when com- pared with the general population. Similarly, although increased plasma concentrations of growth hormone,52 not so robustly demonstrated, non-melanoma skin can- and mediation of immunosuppression by enhancing cers appear at an increased frequency in PD patients.
secretion of melanocyte-stimulating hormone.51 Inter- The studies available were not designed to enable con- estingly, L-dopa and other precursors in the biosyn- clusions to be made regarding the causal relationship thetic pathway of melanin may have a toxic effect on melanoma in vitro.53 The two clinical surveys specifi- Due to the heterogeneity of study designs and out- cally conducted to evaluate the frequency of cutaneous come measures, no statistical pooling of the results lesions in PD patients concluded that an extremely was appropriate to be conducted. Nevertheless, a de- high prevalence of melanoma existed (1.4% in Israel scriptive analysis of the best data suggest a prevalence and 1.1% in North America). However, the interpreta- of melanoma in PD patients between 1.1 and 1.4 % tion of these rates is difficult without a parallel control and a 1.5–3-fold increase in the incidence of mela- group or a valid external database. This is even more noma. If we apply these estimates to the expected inci- difficult knowing both that the incidence of melanoma dence of melanoma in the United States for subjects has sharply increased in the last 70 years,54 and that 65–years-old and older (65.4 per 100.000 per year; the overall calculation of melanoma incidence in the SEER 2001–2005), we presume an approximate inci- general population is imprecise because rate figures are dence of 1 to 2 cases per 1000 PD patients per year calculated based on data collection systems that cannot find cases of less-invasive disease.
The theory linking L-dopa and melanoma was based The incidence of PD increases with age and the inci- on the shared biochemical pathways between the syn- dence of malignant melanoma has been increasing in thesis of both dopamine and melanin. The association recent decades. Consequently, it is expected that both between L-dopa and melanoma is therefore based on PD and malignant melanoma will coincidentally affect biological plausibility and a few case reports where several patients every year, even without a causal rela- data is too limited to determine the causality.1,45–47 In tionship between the two diseases. On the other hand, some cases, the short interval between the onset of L- if the increased risk in PD patients is caused by envi- dopa treatment and the diagnosis of melanoma makes ronmental or genetic factors common to both diseases, it somewhat implausible that a carcinogenic effect is it would be expected that the association between PD induced by L-dopa. On the other hand, the reported and skin cancer be bidirectional (i.e., that the risk for stronger association between PD and melanoma within malignant melanoma would also be increased before a the first years after PD diagnosis30 reduces the likeli- diagnosis of PD) that cannot be excluded with the data hood that these cases of melanoma are due to PD treat- available. In the scenario of an independent common ment and suggests the possibility of other pre-existing cause for PD and melanoma, we would expect either causal or confounding, unknown factors.
to have melanoma first and PD after or vice-versa.
Additionally, the association of PD with non-mela- Nevertheless, given that cancer has a much higher noma skin cancers counters the theory of L-dopa as a mortality it might happen that there is no time to de- causal factor, unless the biochemical pathway includ- velop PD once cancer occurs. In this situation, it would ing L-dopa is common to all types of skin cancer. As result that it should be more frequent to identify PD cases were cancer was found after the neurological di- Neuroscience, Lundbeck and UCB; Grants: Boehringer Ingel- heim, Eisai, GlaxosmithKline, Novartis, Solvay, Teva Neuro- So far all the melanoma reports refer to cutaneous science and Lundbeck. Cristina Sampaio, Consultancies: Inall cases the fees / honoraria due are paid to department and melanoma, with no data regarding the occurrence of not received personally: Lundbeck, Abbott, Bial, Boeringher ocular melanoma. This may be because of its rarity or be justified by its being more difficult to screen in pri- Author Roles: Joaquim Ferreira conceived and designed the review; collected, analyzed and interpreted the data; In summary, from the data available, there is: drafted the article; review and critique of manuscript; con-cepted, organised, and execution of the research project; 1. Consistent data supporting an association between designed, executed, and review and critique of statistical analysis. Dulce Neutel collected, analyzed and interpreted the 2. A possible association between non-melanoma skin data; help draft the article; organization and execution ofresearch project; review and critique of statistical analysis and manuscript. Tiago Mestre, Miguel Coelho and Ma´rio M.
3. Insufficient data to conclude on the association Rosa helped draft the article, analyzed and interpreted the between L-dopa and melanoma in PD patients; data and critically revised it; organization and execution of 4. Insufficient data to conclude on the association the research project; review and critique of statistical analysis between rasagiline, selegiline, ropinirole, pramipex- and manuscript. Olivier Rascol and Cristina Sampaio ana- ole or other anti-parkinsonian drugs and melanoma lyzed and interpreted the data; critically revised the article;conception of research project; and review and critique of 5. Insufficient data about the risk factors for skin can- 1. Skibba JL, Pinckley J, Gilbert EF, Johnson RO. Multiple primary Physicians and PD patients should be made aware of melanoma following administration of levodopa. Arch Pathol1972;93:556–561.
the association between PD and skin cancers.
2. Pfutzner W, Przybilla B. Malignant melanoma and levodopa: is No robust recommendation can be made regarding there a relationship? Two new cases and a review of the litera- the need for periodic dermatological screening.
ture. J Am Acad Dermatol 1997;37:332–336.
3. Medical Economics Company, Inc. Physicians’ desk reference.
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In our opinion, there is a clear need to understand the risk factors for the association between melanoma and 5. Siple JF, Schneider DC, Wanlass WA, Rosenblatt BK. Levodopa therapy and the risk of malignant melanoma. Ann Pharmacother other non-melanoma cancers and PD. To investigate the putative role of medications requires a prospective, case- 6. Fiala KH, Whetteckey J, Manyam BV. Malignant melanoma and control study designed to examine the main risk factors levodopa in Parkinson’s disease: causality or coincidence? Par-kinsonism Relat Disord 2003;9:321–327.
for the development of skin cancers in PD patients. This 7. Parkinson Study Group. A randomized placebo-controlled trial of study should be a large study focused on patients with rasagiline in levodopa-treated patients with Parkinson disease and more than 5 years of disease treatment and without any motor fluctuations: the PRESTO study. Arch Neurol 2005;62:241–248.
restriction in terms of anti-parkinsonian drugs. It will be 8. Parkinson Study Group. A controlled trial of rasagiline in early crucial to have parallel prospective controls using the Parkinson disease: the TEMPO Study. Arch Neurol 2002;59: 9. Teva Pharmaceutical Industries Ltd. Azilect1 package insert.
Any clinical survey or pharmacoepidemiological Kfar Saba, Israel: Teva Pharmaceutical Industries Ltd; 2006.
study about this safety problem should also include a 10. Boehringer Ingelheim International GmbH. Mirapex1 package balanced effort to identify not only melanoma but also insert. Ridgefield, CT: Boehringer Ingelheim International GmbH;2006.
all neoplastic and pre-neoplastic skin lesions.
11. GlaxoSmithKline. Requip1 package insert. Research Triangle Financial Disclosure: In the past 12 months, the authors 12. Valeant Pharmaceuticals International. Zelapar1 package insert.
have the following information to disclose. Joaquim Ferreira, Costa Mesa, CA: Valeant Pharmaceuticals International; 2006.
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detection, and treatment in the 21st century. CA Cancer J Clin


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Estradiol (E2) Enzyme Immunoassay Intended Use the color formed is proportional to the amount of enzyme present and is inversely For the quantitative determination of estradiol (E2) concentration in human related to the amount of unlabeled E2 in the sample. A standard curve is obtained serum. For in vitro diagnostic use only. by plotting the concentration of the standard versus


«LA CELESTINA» PROBLEMAS TEXTUALES DE LA CELESTINA : EDICIONES, TÍTULO Y AUTOR La Celestina , una de las obras cumbres de la literatura española, presenta importantes problemas en cuanto al texto y sus ediciones se refiere y también en lo concerniente al título y a su autor. Veamos, con detalle, cada una de estas n Aunque está datado en el siglo XV no se sabe cual es la fecha ex

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