JEADV
DOI: 10.1111/jdv.12907
ORIGINAL ARTICLE
Frequency of primary cutaneous lymphoma variants in Austria: retrospective data from a dermatology referral centre between 2006 and 2013 € gerer,3 R. Sedivy,3 F. Trautinger1,2 J. Eder,1,2,* A. Kern,1,2 J. Moser,1,2 M. Kitzwo €lten, Austria Karl Landsteiner Institute of Dermatological Research, St. Po €lten, Austria Department of Dermatology and Venereology, Karl Landsteiner University of Health Sciences, St. Po 3 €lten, Austria Institute of Clinical Pathology, Karl Landsteiner University of Health Sciences, St. Po *Correspondence: J. Eder. E-mail: [email protected] 1 2
Abstract Background Primary cutaneous lymphomas (PCL) are a heterogenous group of rare lymphoid neoplasms with incomplete information on global and regional prevalence. The recently introduced lymphoma classifications define distinctive clinicopathological disease entities that should allow for more accurate epidemiological assessment. Objective The aim of this study was to evaluate the prevalence and clinical spectrum of PCL diagnosed and treated at € lten, Lower Austria, a dermatology referral centre providing the Department of Dermatology and Venereology in St. Po secondary and tertiary care for a population of about 600 000. Methods In this retrospective study pathology reports, electronically archived between 2006 and 2013, were screened for the terms lymphoma, mycosis fungoides (MF) and lymphomatoid papulosis (LyP). Patients were diagnosed according to the current WHO-EORTC classification for cutaneous lymphomas and results were compared with data from European, US and Asian centres. Results Among 86 patients with PCL (age 58.3 17.35 years, mean SD; women 38%, n = 33; men 62%, n = 53) 83% (n = 71) were classified as cutaneous T-cell lymphomas (CTCL) and 17% (n = 15) as cutaneous B-cell lymphomas (CBCL). Nine patients with CTCL showed associated haematological disorders and malignomas. Among 47 MF patients following variants were observed: pilotropic MF (n = 2), follicular mucinosis (n = 1), unilesional MF (n = 1), large-cell transformation (n = 3), erythrodermic MF (n = 1), poikilodermatous MF (n = 2) and posttransplant lymphoproliferative disorder (CD8+ MF with gamma/delta phenotype after renal transplantation) (n = 1). One patient had MF concurrent with lymphomatoid papulosis. The group of CBCL comprised six cases (40%) of PCMZL and PCFCL each, 20% (n = 3) were classified as PCLBCL, LT. Conclusion This study for the first time provides data on the distribution of PCL clinicopathologic variants and stages according to the latest classification and staging systems in an Austrian referral centre. Received: 30 July 2014; Accepted: 4 November 2014
Conflicts of Interest The authors have no conflict of interest to declare.
Introduction Primary cutaneous lymphomas (PCL) are a diverse group of non-Hodgkin lymphomas (NHL) with initial presentation in the skin and no evidence of extracutaneous disease at the time of diagnosis. Their annual incidence is estimated to be 1 : 100 000.1 The skin is a common site of extranodal nonHodgkin lymphoma (NHL) manifestation ranking only behind the gastrointestinal tract. According to reports from the US and Europe cutaneous T-cell lymphomas (CTCL) account for about 71–77% and cutaneous B-cell lymphomas (CBCL) for about 23–29% of PCL.1,2 PCL show a variety of specific clinical,
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histological, immunophenotypical, cytogenetic and molecular features that discriminate them from their nodal counterparts. To find consensual criteria and unify classification and definition of PCL, a new classification of cutaneous lymphomas was defined in 1997 by the Cutaneous Lymphoma Study Group of the EORTC.3 At consensus meetings of experts from the World Health Organization and the European Organization for Research and Treatment of Cancer (WHO/EORTC) in 2003 (Lyon, France) and 2004 (Z€ urich, Switzerland) this classification provided the basis for the WHO/EORTC classification which was later incorporated into the current WHO Classification of
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Eder et al.
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Tumours of Haematopoietic and Lymphoid Tissues.1,4 Among CTCL the most common entities are mycosis fungoides (MF), Sezary syndrome (SS), CD30+ lymphoproliferative disorders (lymphomatoid papulosis, LyP, and primary cutaneous anaplastic large-cell lymphoma, C-ALCL), primary cutaneous peripheral T-cell lymphoma, unspecified (PCL, unspecified), subcutaneous panniculitis-like T-cell lymphoma (SPTL) and extranodal natural killer T-cell lymphoma, nasal type. Within CBCL three main subtypes were classified: primary cutaneous marginal zone B-cell lymphoma (PCMZL), primary cutaneous follicle centre lymphoma (PCFCL), both indolent types of CBCL, and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT), which represents a more aggressive variant of CBCL.1 In 2007, a revision of the MF and SS staging system and a proposal for a TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sezary syndrome were published by the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the EORTC with the intention to allow more accurate categorization and uniform staging of patients with PCL.5,6 These efforts not only aim at and most likely have already led to improvement of patient care and standardization of criteria for clinical studies, they also enable better and more accurate epidemiological studies hampered before by notoriously heterogenous disease definitions. Furthermore, they also allowed to establish consensus-based treatment recommendations for these rare diseases.7–9 Accordingly, epidemiological data based on the WHO/EORTC classification have been published recently.2,10–13 However, information about PCL prevalence still remains sparse with a high need for additional studies to improve our knowledge about the disease and to better allocate adequate specialist care. Here, we provide recent data retrospectively retrieved from electronic patient records between 2006 and 2013 from an Austrian dermatology referral centre.
Materials and methods In a retrospective analysis, we evaluated the prevalence and the clinicopathological spectrum of PCL diagnosed and treated at the Department of Dermatology and Venereology in St. Poelten, Lower Austria. In 2006 electronic patient records were introduced in the hospital including also electronically searchable pathology reports. Accordingly our survey extended from 2006 to 2013. Pathology reports filed during this time were searched for the terms lymphoma, mycosis fungoides and lymphomatoid papulosis. The resulting patient list was manually checked for errors and duplicates, verified and correlated with patients’ records and history. All patients were classified and staged according to the classification systems of the WHO/EORTC and ISCL/EORTC as mentioned above. In all cases gender, age at initial diagnosis, associated other malignancies, therapy and survival status at last follow-up were recorded. Treatment response
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was not included in the survey due to lack of standardized documentation of treatment response in the electronic patient records and heterogenous and individual allocation of therapy. Kaplan–Meier plots were used for survival analysis, t-test assuming unequal variances and chi-squared tests were used as appropriate.
Results After excluding four patients with secondary cutaneous lymphomas and one patient with pseudolymphoma, the total study group consisted of 86 patients, 53 (62%) men and 33 (38%) women corresponding to a female to male ratio of 1 : 1.6. Frequency of PCL subtypes
CTCL constituted the major group accounting for 83% (n = 71) of PCL cases, 17% (n = 15) were classified as CBCL. Among CTCL MF was the most common subtype with 47 cases (66% of CTCL) followed by CD30+ lymphoproliferative disorders (21%; n = 15), primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (7%, n = 5), SS (4%, n = 3) and SPTL (4%, n = 3) of all CTCL cases. Subdividing MF, the following variants were observed: pilotropic MF (two women), follicular mucinosis (one man), unilesional MF (one woman), large-cell transformation (two men, one women), erythrodermic MF (one man), poikilodermatous MF (two men) and posttransplant lymphoproliferative disorder (one men CD8+ MF with gamma/delta phenotype after renal transplantation). One patient had MF concurrent with lymphomatoid papulosis. In the group of CBCL PCMZL and PCFCL accounted for 40% (n = 6) of all cases, each. 20% (n = 3) were classified as PCLBCL, LT (Table 1). Clinical stages at initial presentation are given in Table 2 and separately for MF in more detail in Fig. 1. Age and gender
The mean age of the total study group (n = 86) was 58.3 17.4 years (mean SD), consisting of 53 (62%) men aged 56.8 15.6 years (mean SD) (median 55; range 13–82) and 33 (38%) women aged 60.8 19.8 years (mean SD) (median 65; 9–89 years). Patients with CTCL (n = 71) had a mean age of 58.4 17.7 years (mean SD), with 45 (63%) men aged 58.3 15.6 years (mean SD) (median 59; range 13–82) and 26 (37%) women aged 58.9 21.1 years (mean SD) (median 63.5; range 9–89) (Fig. 2). Age distribution was also not significantly different between patients in early stages with a mean age of 59.8 14.3 years (mean SD) (median 58, range 13–82) and patients in the late stages aged 62.4 21.2 years (mean sd) (median 70, range 23–89) (P = 0.68). The group of CBCL (n = 15) showed a mean age of 57.9 16.2 years (mean SD). Of these males (n = 8, ages 49.5 14.2 years, median 49.5, range 32–70) were significantly
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Frequency of primary cutaneous lymphomas in Lower Austria
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Table 1 Demographic data of 86 primary lymphoma cases n
Type of lymphoma
Frequency (%)
Sex distribution F/M
Age distribution (years)
Ratio
n
Mean SD
Median (range)
PCL
86
100
1 : 1.6
33/53
58.3 17.4
59.5 (9–89)
CTCL
71
83
1 : 1.7
26/45
58.4 17.7
60 (9–89)
Mycosis fungoides
47
66
1 : 1.9
16/31
60.5 16.3
63 (13–89)
3
4
2:1
2/1
71.0 12.8
68 (60–85)
10
14
1:4
2/8
62.5 10.9
61.5 (48–79)
Sezary syndrome Lymphomatoid papulosis CD30+ primary cutaneous anaplastic large-cell lymphoma
5
7
1.5 : 1
3/2
41.2 23.6
49 (9–71)
Primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoma
5
7
1.5 : 1
3/2
55.4 15.1
58 (32–71) 22 (13–31)
2
3
0/2
22.0 12.7
15
17
1 : 1.1
7/8
57.9 16.2
58 (32–83)
Primary cutaneous marginal zone lymphoma
6
40
1:2
2/4
50.1 12.1
49.5 (34–70)
Primary cutaneous follicle centre lymphoma
6
40
1:1
3/3
59.3 20.3
64 (32–83)
Primary cutaneous diffuse large B-cell lymphoma, leg type
3
20
2:1
2/1
70.7 4.0
70 (67–75)
Subcutaneous panniculits-like T-cell lymphoma CBCL
CBCL, primary cutaneous B-cell lymphoma; CTCL, primary cutaneous T-cell lymphoma; F, female; M, male; n, number of patients; PCL, primary cutaneous lymphoma; SD, standard deviation.
Table 2 Staging of primary cutaneous lymphomas n
%
Early stage disease (IA-IIA)
34
72
Advanced stage disease (IIB-IVB)
13
28
IIIA
2
67
IVB
1
33
T1N0M0*
9
60
T2N0M0
0
0
T3N0M0
6
40
T1N0M0
7
47
T2N0M0
6
40
T3N0M0
2
13
Stage Mycosis fungoides
Sezary syndrome
CD30+ lymphoproliferative disorders
Primary cutaneous B-cell lymphoma
*For PCL other than MF/SS the TNM staging system has not been translated into stage groups.
Figure 1 Mycosis fungoides stages at first presentation.
younger than females (n = 7, ages 67.6 13.2 years, median 70, range 43–83) (P = 0.02). Patients with PCMZL were non-significantly older than those with PCFCL aged 59.3 20.3 years (mean sd) and 50.1 12.1 (mean SD) respectively (P = 0.37). Three patients with PCLBCL, LT were aged 67.7 and 75.0 years respectively. Sex distribution was further analysed in MF where more men (n = 24) than women (n = 10) in our series had early stage disease (IA-IIA), whereas in the late stages (IIB-IV) sex distribution
was balanced (seven men and seven women). (P = 0.2, Chisquare).
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Comorbidities
In our study population six patients with MF showed at least one secondary malignancy. Patients suffered from melanoma (one male, MF stage IA, 76 years), primary myelopathic polycythaemia (one male, MF stage IA, 67 years), bladder cancer (one male, MF stage IIB, 70 years), gastric MALT lymphoma (one female, MF stage IB, 77 years), breast cancer (one female, MF
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Eder et al.
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78 years) had diffuse large B-cell lymphoma. Two of 10 patients with LP showed haemato-oncologic comorbidites: one 73 -yearold male had concurrent B-cell lymphoma, one 62-year-old male developed Hodgkin’s lymphoma.
(a)
Follow-up and survival
An overview about the various treatment modalities used and the current survival status is given in Tables 3 and 4. For patients with MF and SS survival curves (overall survival) were calculated (Fig. 3). In these patients follow-up periods varied from a minimum of 0.6 months to maximum of 217.3 months (median 37.6 months). Regarding the 47 MF patients, one patient died of melanoma, six patients were lost to follow-up and 40 were still alive at last follow-up. Of 34 patients presenting with early stage MF only one patient showed progression to advanced stage disease. Of the three patients with SS, two died due to infection related to immunosuppression and one patient is still alive.
(b)
Discussion
Figure 2 Prevalence of PCL (a) and CTCL (b) according to age and sex.
stage IIB, 89 years). One male patient with MF (stage IIB, 72 years) had coincident prostata carcinoma and myelodysplastic syndrome. One man with Sezary syndrome (stage IIIA,
Given the heterogenity and rarity of PCL and the limitations of available data, informations gained from small patient cohorts and from single-centre experience has contributed to our knowledge about PCL epidemiology.11,14,15 In the past, Austria already provided a patient cohort which in 2005, together with a large series from the Netherland registry, formed the basis for the WHO-EORTC classification for cutaneous lymphomas.1,16 In this study we add to this our data on 86 PCL cases and compare our results with data from other European countries, the US and Asia (see Table 5). The relative frequencies of different subgroups of PCL in our series were similar to previous studies from the US and Europe.1,2,11,12,17 Due to their rarity, no extranodal NK/T-cell lymphoma, nasal type, and a low number of SPTL were diagnosed in our centre since 2006. This is in agreement with former European and US studies but contrasts with reports from Japan and Korea where those entities appear to be much more common.1,2,11,13 Accordingly, extranodal NK/T-cell lymphoma is accounting for 5% and 16.7% of all PCL cases in Korea and
Table 3 Treatment and response in CTCLs. CTCLs
TS
UVB
SURG
PUVA
Retinoids
IFN
WM
Rad
Chemo
TSEB
MTX
ECP
ALIVE
Mycosis fungoides
36
15
0
16
8
9
1
4
0
2
2
0
39
7
Sezary Syndrome
2
1
0
2
2
0
2
0
0
0
1
2
1
0
LyP
LTFU
10
1
0
1
0
0
0
0
0
0
5
0
9
1
C-ALCL
0
0
4
0
0
0
0
0
0
0
2
0
5
0
SPTL
0
0
0
0
0
0
0
0
2
0
0
0
2
0
SM
0
0
5
0
0
0
0
0
0
0
0
0
2
0
Chemo, multiagent chemotherapy; ECP, extracorporal photoimmunotherapy; IFN, Interferon; LTFU, lost to follow-up; MTX, Methotrexate; Rad, localized radiotherapy; SM, primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma; Surg, surgery; TS, topical corticosteroids; TSEB, total skin electron beam; WM, Winkelmann-regime: Chlorambucil + oral corticosteroids.
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Frequency of primary cutaneous lymphomas in Lower Austria
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Table 4 Treatment and response in CBCLs CBCLs
Surgery
Radiation
Rituximab
R-Chemo
Alive
LTFU
PCMZL
5
2
0
0
5
0
PCFCL
2
3
2
0
5
1
PCLBCL, LT
1
1
0
3
2
0
LTFU, lost to follow-up; R-Chemo, Rituximab-Chemotherapy.
Figure 3 Overall survival of 47 patients with MF and three patients with SS.
Japan, respectively, and Park et al. report 10 cases (10.5%) of SPLT in a single-centre study of 164 PCL cases in Korea.14,18 MF is unequivocally the most prevalent type of PCL. In our series more patients were diagnosed in early (IA-IIA) (72%) than in late stages (IIB-IVB) (28%) similar to data previously reported from the US (with 67% and 33% respectively) and by colleagues from Switzerland, Germany and Japan indicating a similar distribution of MF in different areas of the world.11,14,17,19 In our cohort, CBCL were much less common than CTCL accounting for 17% of all PCL which is consistent with the above-mentioned combined data from Austria and the Netherlands where CBCL counted for 23% of all PCL.1 However, regarding CBCL variants (subtypes) there is less agreement between studies. In our study, prevalence of PCFCL and PCMZL was equally frequent, whereas data from the Netherlands and Germany report PCFCL as the most frequent subtype and a recent study from Zurich shows a predominance of PCMZL.11,17,20 Interestingly PCLBCL, LT represents the most frequent CBCL subtype in the US and Japan.2,14 Besides the low prevalence of the disease group, which may lead to chance findings, it has to be considered that pathological classification of CBCL can be challenging and there is evidence for inter-rater disagreement among pathologists. Senff et al. showed by reclassifying 300 CBCL according to the new WHO-EORTC
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classification that of 167 patients with PCL initially classified as pcDLBCL using the WHO classification, 109 (65%) were reclassified as pcFCL.10 As with our study, the US and the Japanese studies cited above were conducted in a retrospective manner, and therefore, as the authors state themselves, it is possible that re-evaluation of CBCL pathology might lead to reclassification of a considerable number of cases. Consistent with previous reports we found a male predominance in the whole study population (female to male ratio 1 : 1.6) and also in CBCL and CTCL when evaluated separately.1,2,11,17,21 The major contribution to this gender imbalance came from MF patients with a female to male ratio of 1 : 1.9. From the reported age distributions in published lymphoma cohorts and epidemiologies a positive correlation of PCL incidence with increasing age is apparent, with the remarkable exception of CD30+ LPD. In our study, this was confirmed for PCL and CTCL. Interestingly, we found that women with CBCL were significantly older than men. The highest CBCL rates in men appeared in the group of the 30–40 -year olds, whereas women peaked between 70 and 80 years. Although this might well be a chance finding due to low patient numbers, a similar observation was reported by Bradford et al. in a large study from the US where particularly women with pcDLBCL-LT had a higher age at diagnosis.2 MF and particularly LyP are known to appear in concomitance with other haematological and lymphoproliferative disorders and accordingly this association was found in four MF and three LyP patients in our cohort.9,22,23,24,25 In addition, other malignancies were found to be increased in MF. Hahtola et al. described an increased risk of lung cancer in CTCL patients. Analysing genomic aberrations in CTCL-associated and reference lung cancer samples they found that cutaneous T-cell lymphoma-associated lung cancers show chromosomal aberrations differing from primary lung cancer.26 In our study, four patients had coincident melanoma, bladder, breast and prostata carcinoma respectively. In our study group, the occurence of these malignancies does not exceed expectance from the reported cancer rates in Austria.27 Although our results fit well into the current knowledge about PCL epidemiology and add new data to the existing body of evidence, certain limitations need to be emphasized: (i) This study was based on a single-centre experience and its results are therefore restricted to a limited geographic area. (ii) The investigated patient cohort was retrospectively defined with small subgroups
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Eder et al.
2
DOI: 10.1111/jdv.12907
ORIGINAL ARTICLE
Frequency of primary cutaneous lymphoma variants in Austria: retrospective data from a dermatology referral centre between 2006 and 2013 € gerer,3 R. Sedivy,3 F. Trautinger1,2 J. Eder,1,2,* A. Kern,1,2 J. Moser,1,2 M. Kitzwo €lten, Austria Karl Landsteiner Institute of Dermatological Research, St. Po €lten, Austria Department of Dermatology and Venereology, Karl Landsteiner University of Health Sciences, St. Po 3 €lten, Austria Institute of Clinical Pathology, Karl Landsteiner University of Health Sciences, St. Po *Correspondence: J. Eder. E-mail: [email protected] 1 2
Abstract Background Primary cutaneous lymphomas (PCL) are a heterogenous group of rare lymphoid neoplasms with incomplete information on global and regional prevalence. The recently introduced lymphoma classifications define distinctive clinicopathological disease entities that should allow for more accurate epidemiological assessment. Objective The aim of this study was to evaluate the prevalence and clinical spectrum of PCL diagnosed and treated at € lten, Lower Austria, a dermatology referral centre providing the Department of Dermatology and Venereology in St. Po secondary and tertiary care for a population of about 600 000. Methods In this retrospective study pathology reports, electronically archived between 2006 and 2013, were screened for the terms lymphoma, mycosis fungoides (MF) and lymphomatoid papulosis (LyP). Patients were diagnosed according to the current WHO-EORTC classification for cutaneous lymphomas and results were compared with data from European, US and Asian centres. Results Among 86 patients with PCL (age 58.3 17.35 years, mean SD; women 38%, n = 33; men 62%, n = 53) 83% (n = 71) were classified as cutaneous T-cell lymphomas (CTCL) and 17% (n = 15) as cutaneous B-cell lymphomas (CBCL). Nine patients with CTCL showed associated haematological disorders and malignomas. Among 47 MF patients following variants were observed: pilotropic MF (n = 2), follicular mucinosis (n = 1), unilesional MF (n = 1), large-cell transformation (n = 3), erythrodermic MF (n = 1), poikilodermatous MF (n = 2) and posttransplant lymphoproliferative disorder (CD8+ MF with gamma/delta phenotype after renal transplantation) (n = 1). One patient had MF concurrent with lymphomatoid papulosis. The group of CBCL comprised six cases (40%) of PCMZL and PCFCL each, 20% (n = 3) were classified as PCLBCL, LT. Conclusion This study for the first time provides data on the distribution of PCL clinicopathologic variants and stages according to the latest classification and staging systems in an Austrian referral centre. Received: 30 July 2014; Accepted: 4 November 2014
Conflicts of Interest The authors have no conflict of interest to declare.
Introduction Primary cutaneous lymphomas (PCL) are a diverse group of non-Hodgkin lymphomas (NHL) with initial presentation in the skin and no evidence of extracutaneous disease at the time of diagnosis. Their annual incidence is estimated to be 1 : 100 000.1 The skin is a common site of extranodal nonHodgkin lymphoma (NHL) manifestation ranking only behind the gastrointestinal tract. According to reports from the US and Europe cutaneous T-cell lymphomas (CTCL) account for about 71–77% and cutaneous B-cell lymphomas (CBCL) for about 23–29% of PCL.1,2 PCL show a variety of specific clinical,
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histological, immunophenotypical, cytogenetic and molecular features that discriminate them from their nodal counterparts. To find consensual criteria and unify classification and definition of PCL, a new classification of cutaneous lymphomas was defined in 1997 by the Cutaneous Lymphoma Study Group of the EORTC.3 At consensus meetings of experts from the World Health Organization and the European Organization for Research and Treatment of Cancer (WHO/EORTC) in 2003 (Lyon, France) and 2004 (Z€ urich, Switzerland) this classification provided the basis for the WHO/EORTC classification which was later incorporated into the current WHO Classification of
© 2015 European Academy of Dermatology and Venereology
Eder et al.
1518
Tumours of Haematopoietic and Lymphoid Tissues.1,4 Among CTCL the most common entities are mycosis fungoides (MF), Sezary syndrome (SS), CD30+ lymphoproliferative disorders (lymphomatoid papulosis, LyP, and primary cutaneous anaplastic large-cell lymphoma, C-ALCL), primary cutaneous peripheral T-cell lymphoma, unspecified (PCL, unspecified), subcutaneous panniculitis-like T-cell lymphoma (SPTL) and extranodal natural killer T-cell lymphoma, nasal type. Within CBCL three main subtypes were classified: primary cutaneous marginal zone B-cell lymphoma (PCMZL), primary cutaneous follicle centre lymphoma (PCFCL), both indolent types of CBCL, and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT), which represents a more aggressive variant of CBCL.1 In 2007, a revision of the MF and SS staging system and a proposal for a TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sezary syndrome were published by the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the EORTC with the intention to allow more accurate categorization and uniform staging of patients with PCL.5,6 These efforts not only aim at and most likely have already led to improvement of patient care and standardization of criteria for clinical studies, they also enable better and more accurate epidemiological studies hampered before by notoriously heterogenous disease definitions. Furthermore, they also allowed to establish consensus-based treatment recommendations for these rare diseases.7–9 Accordingly, epidemiological data based on the WHO/EORTC classification have been published recently.2,10–13 However, information about PCL prevalence still remains sparse with a high need for additional studies to improve our knowledge about the disease and to better allocate adequate specialist care. Here, we provide recent data retrospectively retrieved from electronic patient records between 2006 and 2013 from an Austrian dermatology referral centre.
Materials and methods In a retrospective analysis, we evaluated the prevalence and the clinicopathological spectrum of PCL diagnosed and treated at the Department of Dermatology and Venereology in St. Poelten, Lower Austria. In 2006 electronic patient records were introduced in the hospital including also electronically searchable pathology reports. Accordingly our survey extended from 2006 to 2013. Pathology reports filed during this time were searched for the terms lymphoma, mycosis fungoides and lymphomatoid papulosis. The resulting patient list was manually checked for errors and duplicates, verified and correlated with patients’ records and history. All patients were classified and staged according to the classification systems of the WHO/EORTC and ISCL/EORTC as mentioned above. In all cases gender, age at initial diagnosis, associated other malignancies, therapy and survival status at last follow-up were recorded. Treatment response
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was not included in the survey due to lack of standardized documentation of treatment response in the electronic patient records and heterogenous and individual allocation of therapy. Kaplan–Meier plots were used for survival analysis, t-test assuming unequal variances and chi-squared tests were used as appropriate.
Results After excluding four patients with secondary cutaneous lymphomas and one patient with pseudolymphoma, the total study group consisted of 86 patients, 53 (62%) men and 33 (38%) women corresponding to a female to male ratio of 1 : 1.6. Frequency of PCL subtypes
CTCL constituted the major group accounting for 83% (n = 71) of PCL cases, 17% (n = 15) were classified as CBCL. Among CTCL MF was the most common subtype with 47 cases (66% of CTCL) followed by CD30+ lymphoproliferative disorders (21%; n = 15), primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (7%, n = 5), SS (4%, n = 3) and SPTL (4%, n = 3) of all CTCL cases. Subdividing MF, the following variants were observed: pilotropic MF (two women), follicular mucinosis (one man), unilesional MF (one woman), large-cell transformation (two men, one women), erythrodermic MF (one man), poikilodermatous MF (two men) and posttransplant lymphoproliferative disorder (one men CD8+ MF with gamma/delta phenotype after renal transplantation). One patient had MF concurrent with lymphomatoid papulosis. In the group of CBCL PCMZL and PCFCL accounted for 40% (n = 6) of all cases, each. 20% (n = 3) were classified as PCLBCL, LT (Table 1). Clinical stages at initial presentation are given in Table 2 and separately for MF in more detail in Fig. 1. Age and gender
The mean age of the total study group (n = 86) was 58.3 17.4 years (mean SD), consisting of 53 (62%) men aged 56.8 15.6 years (mean SD) (median 55; range 13–82) and 33 (38%) women aged 60.8 19.8 years (mean SD) (median 65; 9–89 years). Patients with CTCL (n = 71) had a mean age of 58.4 17.7 years (mean SD), with 45 (63%) men aged 58.3 15.6 years (mean SD) (median 59; range 13–82) and 26 (37%) women aged 58.9 21.1 years (mean SD) (median 63.5; range 9–89) (Fig. 2). Age distribution was also not significantly different between patients in early stages with a mean age of 59.8 14.3 years (mean SD) (median 58, range 13–82) and patients in the late stages aged 62.4 21.2 years (mean sd) (median 70, range 23–89) (P = 0.68). The group of CBCL (n = 15) showed a mean age of 57.9 16.2 years (mean SD). Of these males (n = 8, ages 49.5 14.2 years, median 49.5, range 32–70) were significantly
© 2015 European Academy of Dermatology and Venereology
Frequency of primary cutaneous lymphomas in Lower Austria
1519
Table 1 Demographic data of 86 primary lymphoma cases n
Type of lymphoma
Frequency (%)
Sex distribution F/M
Age distribution (years)
Ratio
n
Mean SD
Median (range)
PCL
86
100
1 : 1.6
33/53
58.3 17.4
59.5 (9–89)
CTCL
71
83
1 : 1.7
26/45
58.4 17.7
60 (9–89)
Mycosis fungoides
47
66
1 : 1.9
16/31
60.5 16.3
63 (13–89)
3
4
2:1
2/1
71.0 12.8
68 (60–85)
10
14
1:4
2/8
62.5 10.9
61.5 (48–79)
Sezary syndrome Lymphomatoid papulosis CD30+ primary cutaneous anaplastic large-cell lymphoma
5
7
1.5 : 1
3/2
41.2 23.6
49 (9–71)
Primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoma
5
7
1.5 : 1
3/2
55.4 15.1
58 (32–71) 22 (13–31)
2
3
0/2
22.0 12.7
15
17
1 : 1.1
7/8
57.9 16.2
58 (32–83)
Primary cutaneous marginal zone lymphoma
6
40
1:2
2/4
50.1 12.1
49.5 (34–70)
Primary cutaneous follicle centre lymphoma
6
40
1:1
3/3
59.3 20.3
64 (32–83)
Primary cutaneous diffuse large B-cell lymphoma, leg type
3
20
2:1
2/1
70.7 4.0
70 (67–75)
Subcutaneous panniculits-like T-cell lymphoma CBCL
CBCL, primary cutaneous B-cell lymphoma; CTCL, primary cutaneous T-cell lymphoma; F, female; M, male; n, number of patients; PCL, primary cutaneous lymphoma; SD, standard deviation.
Table 2 Staging of primary cutaneous lymphomas n
%
Early stage disease (IA-IIA)
34
72
Advanced stage disease (IIB-IVB)
13
28
IIIA
2
67
IVB
1
33
T1N0M0*
9
60
T2N0M0
0
0
T3N0M0
6
40
T1N0M0
7
47
T2N0M0
6
40
T3N0M0
2
13
Stage Mycosis fungoides
Sezary syndrome
CD30+ lymphoproliferative disorders
Primary cutaneous B-cell lymphoma
*For PCL other than MF/SS the TNM staging system has not been translated into stage groups.
Figure 1 Mycosis fungoides stages at first presentation.
younger than females (n = 7, ages 67.6 13.2 years, median 70, range 43–83) (P = 0.02). Patients with PCMZL were non-significantly older than those with PCFCL aged 59.3 20.3 years (mean sd) and 50.1 12.1 (mean SD) respectively (P = 0.37). Three patients with PCLBCL, LT were aged 67.7 and 75.0 years respectively. Sex distribution was further analysed in MF where more men (n = 24) than women (n = 10) in our series had early stage disease (IA-IIA), whereas in the late stages (IIB-IV) sex distribution
was balanced (seven men and seven women). (P = 0.2, Chisquare).
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Comorbidities
In our study population six patients with MF showed at least one secondary malignancy. Patients suffered from melanoma (one male, MF stage IA, 76 years), primary myelopathic polycythaemia (one male, MF stage IA, 67 years), bladder cancer (one male, MF stage IIB, 70 years), gastric MALT lymphoma (one female, MF stage IB, 77 years), breast cancer (one female, MF
© 2015 European Academy of Dermatology and Venereology
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78 years) had diffuse large B-cell lymphoma. Two of 10 patients with LP showed haemato-oncologic comorbidites: one 73 -yearold male had concurrent B-cell lymphoma, one 62-year-old male developed Hodgkin’s lymphoma.
(a)
Follow-up and survival
An overview about the various treatment modalities used and the current survival status is given in Tables 3 and 4. For patients with MF and SS survival curves (overall survival) were calculated (Fig. 3). In these patients follow-up periods varied from a minimum of 0.6 months to maximum of 217.3 months (median 37.6 months). Regarding the 47 MF patients, one patient died of melanoma, six patients were lost to follow-up and 40 were still alive at last follow-up. Of 34 patients presenting with early stage MF only one patient showed progression to advanced stage disease. Of the three patients with SS, two died due to infection related to immunosuppression and one patient is still alive.
(b)
Discussion
Figure 2 Prevalence of PCL (a) and CTCL (b) according to age and sex.
stage IIB, 89 years). One male patient with MF (stage IIB, 72 years) had coincident prostata carcinoma and myelodysplastic syndrome. One man with Sezary syndrome (stage IIIA,
Given the heterogenity and rarity of PCL and the limitations of available data, informations gained from small patient cohorts and from single-centre experience has contributed to our knowledge about PCL epidemiology.11,14,15 In the past, Austria already provided a patient cohort which in 2005, together with a large series from the Netherland registry, formed the basis for the WHO-EORTC classification for cutaneous lymphomas.1,16 In this study we add to this our data on 86 PCL cases and compare our results with data from other European countries, the US and Asia (see Table 5). The relative frequencies of different subgroups of PCL in our series were similar to previous studies from the US and Europe.1,2,11,12,17 Due to their rarity, no extranodal NK/T-cell lymphoma, nasal type, and a low number of SPTL were diagnosed in our centre since 2006. This is in agreement with former European and US studies but contrasts with reports from Japan and Korea where those entities appear to be much more common.1,2,11,13 Accordingly, extranodal NK/T-cell lymphoma is accounting for 5% and 16.7% of all PCL cases in Korea and
Table 3 Treatment and response in CTCLs. CTCLs
TS
UVB
SURG
PUVA
Retinoids
IFN
WM
Rad
Chemo
TSEB
MTX
ECP
ALIVE
Mycosis fungoides
36
15
0
16
8
9
1
4
0
2
2
0
39
7
Sezary Syndrome
2
1
0
2
2
0
2
0
0
0
1
2
1
0
LyP
LTFU
10
1
0
1
0
0
0
0
0
0
5
0
9
1
C-ALCL
0
0
4
0
0
0
0
0
0
0
2
0
5
0
SPTL
0
0
0
0
0
0
0
0
2
0
0
0
2
0
SM
0
0
5
0
0
0
0
0
0
0
0
0
2
0
Chemo, multiagent chemotherapy; ECP, extracorporal photoimmunotherapy; IFN, Interferon; LTFU, lost to follow-up; MTX, Methotrexate; Rad, localized radiotherapy; SM, primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma; Surg, surgery; TS, topical corticosteroids; TSEB, total skin electron beam; WM, Winkelmann-regime: Chlorambucil + oral corticosteroids.
JEADV 2015, 29, 1517–1523
© 2015 European Academy of Dermatology and Venereology
Frequency of primary cutaneous lymphomas in Lower Austria
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Table 4 Treatment and response in CBCLs CBCLs
Surgery
Radiation
Rituximab
R-Chemo
Alive
LTFU
PCMZL
5
2
0
0
5
0
PCFCL
2
3
2
0
5
1
PCLBCL, LT
1
1
0
3
2
0
LTFU, lost to follow-up; R-Chemo, Rituximab-Chemotherapy.
Figure 3 Overall survival of 47 patients with MF and three patients with SS.
Japan, respectively, and Park et al. report 10 cases (10.5%) of SPLT in a single-centre study of 164 PCL cases in Korea.14,18 MF is unequivocally the most prevalent type of PCL. In our series more patients were diagnosed in early (IA-IIA) (72%) than in late stages (IIB-IVB) (28%) similar to data previously reported from the US (with 67% and 33% respectively) and by colleagues from Switzerland, Germany and Japan indicating a similar distribution of MF in different areas of the world.11,14,17,19 In our cohort, CBCL were much less common than CTCL accounting for 17% of all PCL which is consistent with the above-mentioned combined data from Austria and the Netherlands where CBCL counted for 23% of all PCL.1 However, regarding CBCL variants (subtypes) there is less agreement between studies. In our study, prevalence of PCFCL and PCMZL was equally frequent, whereas data from the Netherlands and Germany report PCFCL as the most frequent subtype and a recent study from Zurich shows a predominance of PCMZL.11,17,20 Interestingly PCLBCL, LT represents the most frequent CBCL subtype in the US and Japan.2,14 Besides the low prevalence of the disease group, which may lead to chance findings, it has to be considered that pathological classification of CBCL can be challenging and there is evidence for inter-rater disagreement among pathologists. Senff et al. showed by reclassifying 300 CBCL according to the new WHO-EORTC
JEADV 2015, 29, 1517–1523
classification that of 167 patients with PCL initially classified as pcDLBCL using the WHO classification, 109 (65%) were reclassified as pcFCL.10 As with our study, the US and the Japanese studies cited above were conducted in a retrospective manner, and therefore, as the authors state themselves, it is possible that re-evaluation of CBCL pathology might lead to reclassification of a considerable number of cases. Consistent with previous reports we found a male predominance in the whole study population (female to male ratio 1 : 1.6) and also in CBCL and CTCL when evaluated separately.1,2,11,17,21 The major contribution to this gender imbalance came from MF patients with a female to male ratio of 1 : 1.9. From the reported age distributions in published lymphoma cohorts and epidemiologies a positive correlation of PCL incidence with increasing age is apparent, with the remarkable exception of CD30+ LPD. In our study, this was confirmed for PCL and CTCL. Interestingly, we found that women with CBCL were significantly older than men. The highest CBCL rates in men appeared in the group of the 30–40 -year olds, whereas women peaked between 70 and 80 years. Although this might well be a chance finding due to low patient numbers, a similar observation was reported by Bradford et al. in a large study from the US where particularly women with pcDLBCL-LT had a higher age at diagnosis.2 MF and particularly LyP are known to appear in concomitance with other haematological and lymphoproliferative disorders and accordingly this association was found in four MF and three LyP patients in our cohort.9,22,23,24,25 In addition, other malignancies were found to be increased in MF. Hahtola et al. described an increased risk of lung cancer in CTCL patients. Analysing genomic aberrations in CTCL-associated and reference lung cancer samples they found that cutaneous T-cell lymphoma-associated lung cancers show chromosomal aberrations differing from primary lung cancer.26 In our study, four patients had coincident melanoma, bladder, breast and prostata carcinoma respectively. In our study group, the occurence of these malignancies does not exceed expectance from the reported cancer rates in Austria.27 Although our results fit well into the current knowledge about PCL epidemiology and add new data to the existing body of evidence, certain limitations need to be emphasized: (i) This study was based on a single-centre experience and its results are therefore restricted to a limited geographic area. (ii) The investigated patient cohort was retrospectively defined with small subgroups
© 2015 European Academy of Dermatology and Venereology
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