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ORIGINAL ARTICLE
Year : 2022 | Volume
: 30
| Issue : 4 | Page : 102-107
Comorbidity analysis of turkish patients operated for dupuytren's contracture in a university hospital
Aydan Ayse Kose1, Bahadir Demirkan1, Adnan Sevencan2, Büsra Tokmak2, Can Ekinci1
1 Department of Plastic, Reconstructive and Aesthetic Surgery, School of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
2 Department of Orthopaedics and Traumatology, School of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
Correspondence Address:
Dr. Aydan Ayse Kose
Department of Plastic, Reconstructive and Aesthetic Surgery, School of Medicine, Eskisehir Osmangazi University, Meselik, Eskisehir 26480
Turkey
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/tjps.tjps_32_22
Background: Dupuytren's contracture (DC) is characterized by progressive fibroplasia of the palmar fascia resulting in significant impairment of hand function. Genetic factors and environmental factors are suspected in the etiology. Although the disease has a benign character, its formation and course follow a tumoral pattern. Several studies show that cancer-related mortality is higher in people with DC. Besides, various risk factors such as diabetes, smoking, and heavy handwork as triggers for DC led us to analyze the epidemiologic characteristics of our patients and search for the concomitance of chronic diseases and cancer. Methods: Seventy patients were operated for DC between 2009 and 2019. Information on occupation, dominant hand, diseased hand, family history, additional comorbidities, cancer, smoking, and drinking habits was sought. Results: A significant number of the patients were manual laborers. Most of the patients were active smokers at the time of the surgery. Dominant hand was predominantly right hand and the disease was mostly observed in the right hand but it was not significant (P > 0.05). Diabetes and cardiovascular disease (CVD) were the most common accompanying diseases. After surgery for DC, seven patients were diagnosed with cancer. Conclusions: This is the first Turkish study to show the relationship between DC and several comorbidities. Male gender and medium-heavy handwork were associated with DC. Although it was not statistically significant, the dominant hand was more affected by DC. Diabetes, CVD, smoking, and alcohol were significant comorbidities in our patients. The association between DC and cancer was remarkable.
Keywords: Cancer, cardiovascular disease, diabetes, Dupuytren's disease, smoking and alcohol
Dupuytren's contracture (DC) is a fibroproliferative disease of the palmar fascia characterized by fibroblast proliferation causing palmar nodules, bands, and finally flexion contractures of the digits. In a sense, it has a histological character similar to tumor formations; invades healthy mesenchymal tissues with infiltrative growth character and evolves into fibrous bands. The disease has no apoptotic feature; regression is not observed. Although there is a tendency to relapse; metastasis is never seen. In the early stages, the nodules are rich in type 3 collagen; as the disease progresses, it causes contractures like an unstoppable pathological scar tissue.[1]
When these findings are evaluated together, it can be thought that there is a defect in the control of cell proliferation in DC, as in malignancies. According to Kuo et al., when the defect in control of cell proliferation is not locally confined to palmar fascia, there may be a possible connection between DC and malignancies. They hypothesized a common genetic risk between DC and cancer development,[2] suggesting an increased risk of cancer in patients with DC.
There are important risk factors in the etiology of DC as alcohol consumption and smoking. Not only are these factors suspected to be causative factors for DC, but they may also be lowering the threshold for the development of malignancy in DC. It is not uncommon for diabetic patients to have various fibrosis-prone musculoskeletal disorders, primarily DC. This association was pointed out in many publications from different countries of the world.[3],[4]
In this study, retrospective screening of patients who have been operated for DC between 2009 and 2019 at the Departments of Plastic Surgery and Orthopedics in a university hospital was performed; occupation, alcohol intake, smoking addiction, and additional morbidities were investigated.
MethodsThe data from the medical records from 70 patients operated for DC in Plastic, Reconstructive and Esthetic Surgery, and Orthopedics and Traumatology Departments of our university hospital from January 2009 to December 2019 were retrospectively documented. The study was approved by the University Noninterventional Clinical Research Ethics Committee (May 12, 2020 date and 8 number). Ethical approval was waived in view of the retrospective nature of the study and all the procedures being performed were part of the routine care.
The records were examined for the dominant hand, diseased hand, family history, smoking and alcohol use, DC recurrence, and past and current health status including diabetes, cardiovascular disease (CVD), epilepsy, and cancer were investigated [Table 1].
Table 1: Characteristics of the patients operated for Dupuytren's contractureStatistical analysis
The data were analyzed using IBM SPSS 21.0 (IBM Corp., Armonk, NY, USA). The Chi-squared test was performed to determine whether there is a statistically significant difference between the expected and observed frequencies. The significance level was set at P < 0.05.
ResultsThere were 70 patients in total and 62 of them were male (88.5%) while 8 were female (11.5%). The male-to-female ratio was 13/1 (P < 0.05). The age range was 33–83 years (mean 62.9 years). DC was in both hands in 23 of 70 patients, in the right hand in 30 patients, and in the left hand in 17 patients.
Palmar fasciectomy was the preferred operation technique. In patients with bilateral hand involvement, in five of them, palmar fasciectomy was performed in different sessions; in eight patients, palmar fasciectomy was performed on the one hand and percutaneous fasciotomy on the other hand in the same session. In the rest of the bilateral cases (ten patients), surgical intervention was not necessary for the other hand due to the early stages of the disease. Two patients had been operated before in another center; had recurrences and palmar fasciectomy was re-performed in our clinic. There were no major complications that is not resolved. Only in two cases, artery and nerve injury occurred as a complication and were repaired in the same session.
After surgery for DC, lung cancer was diagnosed in one patient, thyroid cancer in two patients, leukemia in one patient, prostate carcinoma in one patient, and basal cell carcinoma of the facial skin in two patients. The male patient with lung cancer died at the age of 79 years; 3.5 years after the DC operation, and the male patient with leukemia died at the age of 70 years; 4 years after the DC operation. Other patients with thyroid, prostate, and skin cancers were still alive during the study. When skin cancers were omitted, the incidence of cancer in our patients with DC was 7% according to our data.
Among the 70 patients, 47 patients (67%) were manual laborers doing medium to heavy work. Most patients were right-dominant (61/70%–87%). Fifty-six patients had dominant hand involvement, including bilateral cases (80%). Between 47 patients with DC only in one hand, dominant hand was involved in 33 of them (70%).
Thirty-eight patients were active smokers during the initial consultation (54%). Twenty-five patients (36%) have used alcohol at least once in their lifetime but regular alcohol intake was only present in four patients (6%). As for the comorbidities, 33 patients had diabetes (47%), 29 patients had CVD (41%); and 17 patients had both diabetes and CVD (24%). Two patients had epilepsy (3%). None of the patients had evidence for Peyronie or Ledderhose disease. Seven patients were healthy except for DC (10%).
DiscussionDC is known as a multifactorial disease and it is certain that genetic predisposition is one of the factors. It is more common in people of European origin. Especially in northwestern Europe, DC is present in approximately 20% of middle-aged men and 5% causing impaired hand function.[3],[5] In a 2004 study conducted in England, 34.3 new Dupuytren's cases were reported per 100,000 men.[2]
Historically, it was also referred to as Viking's disease because of the mention of DC in Viking epics. Indeed, northern European countries such as Sweden, Norway, Denmark, and Iceland are called Viking descendants and in epidemiological studies conducted in those countries, up to 40% DC presence has been reported in certain age groups.[6] Although there is no prevalence study on the frequency of DC in the Turkish people, it is possible to get some clues that it is particularly common in some regions.[7]
Cancer is the second-most common cause of death worldwide; with the increasing incidence, it is expected to be the most common cause of death in 2030. According to the 2012 data of the Ministry of Health, 175,000 new cancer cases were determined in Turkey in 1 year and new cases are expected in increasing numbers by 2023.[8]
Various publications draw attention to the increased likelihood of cancer in patients who are operated for DC. Wilbrand et al. identified 2151 of the 15,212 patients with Dupuytren's operated between 1965 and 1994 were later diagnosed with a malignancy.[9] Gudmundsson et al. classified 1297 male patients as having DC or not and followed up for 15 years. They observed an increase in cancer incidence among individuals who are in an advanced stage of DC and postulated that the excess mortality in those patients could be attributed to malignancy-related deaths.[10]
The fight against cancer should be multidisciplinary. Finding out the cancer incidence of our DC patients and raising awareness of this group of patients about possible health risks are the secondary outcomes of this surveillance. Although the number of interviewed patients was not sufficient to give meaningful information about our aim, some interesting data could be obtained.
Most of the 70 patients (54%) had a smoking history, even the rest thought to be nonsmokers, it is clear that more than half of the total DC patients were exposed to an important carcinogen. Smoking is accused in the etiology of various cancers including lung, bladder, ovarian, nasopharyngeal cancers, and leukemia. In our study, 4 smoker patients operated for DC developed cancer; one had died of lung cancer and the other of biphenotypic acute leukemia. Referring to Turkey cancer statistics, cancer incidence, excluding skin cancers, among Turkish people is 212 over 100,000 (0.21%).[11] Whereas this rate is 7.1% among our patients with DC suggesting the difference is statistically very highly significant (P < 0.001). If there is a problem in controlling the cell proliferation mechanism in DC, any carcinogen may facilitate the possibility of malignancy.
Various studies show many common mechanisms between DC and malignancies. Bonnici et al. detected chromosomal instability such as trisomy and translocation in a cell culture study from palmar fascia specimens of a group of DC patients.[12] Also in a cohort study from Germany, England, and the Netherlands, comparison of DNA analysis of people with and without DC showed 9 chromosomal loci are thought to cause DC; while 4 of these loci have been shown to be related to the Wnt pathway, which enables the synthesis of proteins that stimulate cell proliferation. Wnt signal pathway is also a well-known pathway in cancer development.[13] Verjee et al. detected high levels of tumor necrosis factor (TNF) in DC tissues and they suggested that it might have been activating the Wnt pathway.[14] This hypothesis is supported by several reports of spontaneous and rapidly emerging DC cases during BRAF inhibitor therapy which is a cause of TNF upregulation.[15],[16] TNF is considered a double-edged sword in cancer biology; it stimulates proliferation, survival, migration, and angiogenesis in most cancer cells that are resistant to TNF-induced cytotoxicity, resulting in tumor promotion.[17]
Two patients in our series were diagnosed with thyroid cancer. In fact, the frequency of active smoking with thyroid cancer development is inversely proportional.[18] However, if DC patient has a cancer susceptibility, the risk-reducing effect of smoking on thyroid cancer in the normal population may not work in patients with DC.
Smoking is also a frequently accused factor in DC etiology. As stated above, 38 patients (54%) were active smokers at the time of the operation and four patients had quit smoking a few years ago. In a prospective study conducted in Denmark, 7254 people were screened with an interval of 10 years and smoking was found to have a dose-independent effect on the development of DC.[19] Whereas Hindocha emphasizes that smoking is not a precursor for DC; smokers suffer more seriously from DC, and the need for surgery and/or hand function disturbance is higher in smokers.[20] Smoking ratio in Turkish male population is as high as 42% and 31.2% in adults older than 15 years old.[21] In our study group which was composed of 62 male patients (88.5%), this ratio was 54%. Even compared to the Turkish male population, the smoking ratio was significantly higher (P < 0.05) in our patients. From this point of view, there may be a significant number of smokers who suffer from DC but do not seek medical advice for DC. Alcohol use, on the other hand, is also an etiological agent for DC, which confirms the data in our study. Twenty-five of our 70 patients (36%) reported alcohol consumption at least once in their lifetime; only four of them (6%) reported regular intake, whereas alcohol consumption at least once in Turkish population is 12%[22] demonstrating the difference is statistically very highly significant (P < 0.001).
Heavy-duty, heavy-lift, exposure to vibration, and intensive forearm rotation are also suspected of contracting DC.[23] The presence of these factors, together with genetic predisposition, has been suggested to lead to the emergence of the disease at an earlier age or an increase in the severity of the existing contracture. In a meta-analysis study that included nine studies - 60570 people - a prevalence of 9.8% of DC was found consistent with the previous literature. It has been observed that patients with DC were more exposed to handworks with vibration than their own control groups.[24] There are different opinions and conclusions on the association between occupation and DC. Burke et al. found no statistically significant correlation between vibration exposure and DC prevalence in 97,537 miners.[25] The peculiarity of this prospective study is that DC findings have been examined in a certain occupational group and a wide age range. Again Khan et al. screened 502,493 men in England and Wales; they identified 169 new DC cases. When they classified this population according to occupation, they could not find a significant correlation between manual occupation and DC. Nevertheless, the authors warned that this result should be read carefully because subclinical and mild form cases may have been overlooked.[26] In our study, not the whole society or a certain part of society but patients admitted for DC were evaluated. These patients were stage 2 or more according to Iselin and Tubiana classification and had contracture that interfered with their daily work. Forty-seven of our 70 patients (67%) stated that they use their hands extensively, lift heavily and were exposed to repetitive trauma with their hands. Although this is a high ratio that more than half of the patients are included, we could not obtain any data in Turkish population statistics to compare.
Diabetes mellitus and DC co-occurrence are another remarkable detail. According to the data of the International Diabetes Federation, 15% of the adult population in Turkey is diabetic.[27] The prevalence of diabetes in our patients with DC is 47% suggesting a very highly significant difference (P < 0.001). Diabetes can cause a number of musculoskeletal disorders called diabetic hand syndrome characterized by limited joint movements such as stenosing tenosynovitis, carpal tunnel syndrome, and DC. Among all these conditions affecting hand function, the most researched relationship is among diabetes and DC and increased DC rate in diabetics was shown in many studies.[4],[28],[29] The basic mechanism is focused on upregulation of transforming growth factor-β (TGF-β), induced by glycated end-products. TGF-β plays a key role in the pathology of fibrotic diseases, and up-regulation has been associated with DC.[28] Zhang et al. showed increased TGF-β2 expression in cord tissue samples taken from DC in respect to healthy palmar fascia and they also supported this finding with polymerase chain reaction studies.[30] In our study, 47% of our DC patients were diabetic. Due to the scope of the study, we cannot comment about the exact rate of DC in diabetics but it is noteworthy that almost half of our patients with DC are diabetics indicating a significant relationship between DC and diabetes.
As shown before in both Dupuytren's disease and Non-Dupuytren's palmar fascial disease, CVD is a frequently encountered secondary risk factor. Poor cardiovascular profile is seen in these patients accounted for increased deaths due to CVD.[2],[31] In our study, 29 patients had CVD history (41%), whereas, this ratio was only 10.8% in the Turkish population[32] suggesting a highly significant difference (P < 0.001) in cardiovascular profile of patients with DC. Therefore, this finding could be very important to show increased incidence of CVD in DC patients and raise awareness of this group of patients about possible health risks. It might even be suggested for DC patients to have regular check-ups for their cardiovascular profile.
Although it was not statistically significant (P > 0.05), 53 of 70 patients had the dominant hand involvement including bilateral cases. In fact, dominant hand involvement itself can be interpreted as an evidence of micro or macro-trauma impact in the development of DC. There is no statistically significant support in this regard in the literature. However, Weinstein et al. investigated the prevalence of DC in the Hispanic population and they found out 10 patients out of 16 operated for DC on single hand had dominant hand involvement while 4 dominant hand surgeries were undertaken in 5 bilateral cases. They did dominant hand surgery in 67% of the patients;[33] whereas, in our study, this ratio was 76% although it was not statistically significant.
ConclusionsThis is the first Turkish study to show the relationship between DC and several comorbidities. Our findings suggest a closer relationship between Dupuytren's disease with diabetes, CVD, cancer, smoking and alcohol intake in the Turkish population (P < 0.05). DC patients should be warned about the co-occurrence of these several health issues. What is more interesting is cancer status of DC patients. Cancer development in 7 of 70 patients is worth noting. Since the study is not a prospective cohort study, we cannot reach a conclusion regarding the incidence of cancer in DC patients compared to similar-age individuals in Turkish society. However, compared to the general Turkish population, the cancer incidence is significantly higher in our DC group (P < 0.001). Furthermore, as a multifactorial disease with some pathophysiological and molecular features mimicking tumor formation, DC patients may be susceptible to various types of cancer which also are multifactorial. Carcinogens, such as smoking, may increase the likelihood of cancer in these individuals with predisposition. Screening of patients with DC and increasing their awareness will be beneficial both in the early diagnosis and treatment of additional morbidities. More research should be done on molecular/biochemical/genetical association between cancer and DC.
Acknowledgment
There is no contributor who does not meet the criteria for authorship. Hence, the section of acknowledgment is none.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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