“Is this case of a very rare disease work-related?” A review of reported cases of Pacinian neuroma

this case of a very rare disease work-related?” A systematic review of reported cases of Pacinian Objective In response to a request for a medicolegal opinion from an orthopaedic technician with pacinian neuroma of the hand, we conducted a systematic review of reported cases designed to assess whether this rare disease could be considered to be work-related. Methods We used Medline, Embase, Google Scholar, Google, and a manual search to identify reports of histologically confirmed pacinian neuroma of the hand manifesting after 15 years of age. Cases with available information (from article/authors) on personal history were considered eligible. We tabulated information on age/ gender; localization and histopathologic features; signs/symptoms; history of local trauma; occupation, sports/ hobbies or other physical exposures; right- or left-handedness; and outcome. Results We found 44 eligible cases (including the present referral). Of these, 21 (48%) followed a trauma [<6 months from onset/presentation (N=7); 0.5–2 years from onset (N=6); ≥ 2 years from onset (N=7); and timing unknown (N=1)] involving the same anatomic site. Three of these 21 traumas definitely occurred at work, and a further 2 cases occurred at the site of definite work-related repetitive microtrauma. Conclusions The results reinforce the concept that pacinian neuroma of the hand can follow local trauma or repetitive microtrauma. Implicated traumas were either recent or remote, and they sometimes occurred while performing manual tasks at work. We concluded that the referred case could plausibly be considered work-related.

How should an occupational physician determine whether a specific case of a very rare disease could be considered to be of a work-related origin? When asked for a medicolegal opinion regarding a highly suspicious case of pacinian neuroma in the hand of an orthopaedic technician, we did not wish to avoid the question by giving the standard response of "insufficient evidence".
First described in 1952 (1), pacinian neuroma is a benign lesion involving proliferation of normal sized or enlarged pacinian corpuscles (cutaneous mechanoreceptors sensitive to rapid vibrations). Pacinian neuroma is mainly observed in the hand and foot and it can be excruciatingly painful and incapacitating. Trauma to digital nerves or normal (2) pacinian corpuscles has been postulated as a plausible risk factor (3,4). How-ever, knowledge of this rare entity is largely based on non-systematic reviews of case reports and small case series which may not provide strong enough evidence for many medicolegal contexts. To address the question whether onset of this rare disease can be attributed to work-related factors (within our own national medicolegal context), we decided to conduct a systematic review of reported cases of pacinian neuroma of the hand.

Case report
A 38-year-old man with a histopathological diagnosis of pacinian neuroma (figure 1) visited our unit to verify, for medicolegal purposes, whether the condition was likely of a professional origin. The patient had worked for 21 years as an orthopaedic technician preparing prosthetic limbs and strongly suspected that occupational use of solvents could have been responsible for the disease. In a clinical interview, it emerged that the patient (who is right-handed) used a hammer, blade, and handsaw to build the prosthesis, a pneumatic hammer to break the chalk mould, and milling machines for finishing. These tasks all produced many flying splinters of different materials (mainly carbon fibers and resins) that sometimes penetrated the patient's fingers (including the affected one) despite the use of latex gloves. He had regularly used various types of pliers to try to extract the splinters.
In 2003, the patient had experienced mounting pain, swelling and functional limitation of the right thumb. A rapidly growing nodule was evident at the level of the first interphalangeal joint. Despite X-ray and magnetic resonance imaging examinations, the nature of the lesion remained unclear. Following total body bone scintigraphy, which suggested a possible neoplastic lesion in the right thumb, the nodule was surgically excised in February 2004. At macroscopic examination, the lesion consisted of a well-defined, hard, whitish nodule (9 × 8 mm). Microscopically, it was composed of a clump of about a dozen adjacent, enlarged pacinian corpuscles, which appeared to be normally structured, exhibiting concentric lamellae around terminal nerve endings (figures 1 and 2).
Due to incomplete functional recovery, the patient was operated again to remove adhesions three months later. Despite resolution of functional limitations and pain, the patient subsequently experienced sensitivity loss between the first and second phalanx of the right thumb (plausibly due to nerve compression) and a new adhesion in the operated zone, restricting his professional dexterity. Having completed courses of physiotherapy and non-steroid anti-inflammatory drugs, the patient currently performs self-massage with gel to maintain elasticity of the skin.

Search strategy and selection criteria
We conducted a systematic search of the literature devised to retrieve reports ever published in any language of histologically diagnosed pacinian neuroma of the hand with onset/presentation after 15 years of age (a cut-off point based on the minimum working age in many countries). We used the following PubMed search string (applying the "humans" limit only when screening articles already indexed for Medline that were published since 1966): (pacini* NOT pacini[au]) OR (pacini [au] AND (pacini[tw] OR pacinian[tw])). We also used the terms "pacini" and "pacinian" to search Embase, Google Scholar and Google. Finally, we manually searched all the citations contained in the retrieved articles and obtained all potentially pertinent additional articles whenever possible. Electronic database searches were closed on 24 March 2010.
Specific eligibility criteria were: (i) histological confirmation of pacinian neuroma of the hand; (ii) presentation after 15 years of age; and (iii) some available information regarding personal history (other than age and gender).
One of the authors screened all retrieved articles for pertinence and eligibility in the present study, and doubtful cases were decided by discussion. Whenever appropriate and feasible, we solicited additional

Data extraction and case classification
Two authors performed data extraction and checked case classification. After piloting the extraction, we decided to record the following information: age/gender; localization of nodule and brief histopathological description; localized signs and symptoms; reported history of local trauma, specifying temporality (preferably time to onset, ie, latency); any information on occupation and sports/hobbies or other physical exposure information; right-or left-handedness; anatomically distant traumas; childhood onset; outcome of treatment, comorbidities (eg, glomus tumour). Finally, we classified the history of each case as "following a local trauma", and temporality in terms of (i) "very recent" (1 week to 6 months from onset/presentation), (ii) "recent" (6 months to 2 years) or (iii) "remote" (≥2 years); "following local repetitive microtrauma"; or "unclear". In cases where local trauma/repetitive microtrauma definitely (or presumably) occurred at work, we specified the occupational setting, whenever known. We classified as work-related cases, pacinian neuromas of the hand that arose at the site of a previous single trauma or repetitive microtrauma that was definitely reported to have occurred at work.

Cases identified
The PubMed search string evoked 953 publications. We were able to glean a further 21 potentially pertinent publications using Embase, and an additional article from Google. Manually searching all the citations led to retrieval of a further 22 accessible publications (the single inaccessible publication did not appear to report cases). Thus, we retrieved a total of 997 potentially pertinent articles. After eliminating articles not containing reports of cases (regarding plastic surgery techniques, associations with other pathologies or anatomical observations etc.), we identified 78 cases of pacinian neuroma diagnosed after 15 years of age (reported in 63 articles). Remarkably, only 29% (23/78) of cases concerned localizations other than the hand [foot (N=4), anogenital (N=3), intra-abdominal (N=3), oral cavity (N=2), sacrococcygeal region (N=3), buttocks (N=2), maxilla (N=1), arm (N=1), loin (N=1), neck (N=1), lymph node (N=1), retroperitoneal (N=1)].

Discussion
When asked to provide a professional opinion regarding the possible occupational etiology of a case of pacinian neuroma in the hand of a worker found to be exposed to repetitive microtrauma at the site of the lesion, we conducted a systematic review of reported cases in the literature. The results reinforce the concept that this rare disease can follow trauma in the same anatomical site. Remarkably, the implicated local trauma could be recent or remote. The trauma sometimes occurred while performing manual tasks at work, and at least one other documented case definitely followed repetitive microtrauma. Based on these findings, we expressed our professional opinion that the case referred to us for medicolegal purposes could plausibly be considered work-related.
Knowledge of whether a rare disease can be attributed to work-related factors can be of considerable medicolegal relevance to affected individuals. For instance, an employee who has experienced a pacinian neuroma of the hand that is deemed to be work-related may be able to claim financial compensation and more easily change job task. However, it is difficult to find evidence to determine whether cases of rare diseases can be considered to be of a work-related origin. Systematic reviews of cases can help gain reliable evidence on rare harms and other unusual occurrences (37). We adopted this study design as an evidence-based method of actively addressing a specific medicolegal question concerning the possible work-related aetiology of a clinically relevant rare disease.
In the context of an extremely rare disease, for which we were able to trace only 44 reported cases supplying some personal information about the patient (other than age and gender), the finding that a total of 23 cases could be strictly classified as directly following a trauma/repetitive microtrauma at the same anatomical site seems remarkable. Unsurprisingly perhaps, at least five of the implicated traumas were definitely workrelated. Even considering publication bias (in a disease widely suspected to be related to trauma, authors may be predisposed to search for and report traumas and suspect activities), the thematic consistency of the findings presented in table 1 seems to provide strong suggestive evidence that pacinian neuroma of the hand frequently has a direct, trauma-related aetiology. Remarkably, onset tended to occur at the exact site of trauma at varying times, ranging from a few weeks to decades after the original exposure. Thus, we think that it is reasonable on medicolegal grounds to classify as sequelae of an occupational injury those cases of pacinian neuroma of the hand that arise on the anatomical site of a work-related trauma, even if experienced many years previously.
The pathogenesis of pacinian neuroma is unclear. It has been postulated that any insult to the nerves or tendons, including repetitive traumas, could be a precipitating factor, promoting proliferation of the corpuscles (3,4,24,28,29). Case number 18, involving incidental finding of a non-symptomatic example in an expert reader of Braille, was originally interpreted as implying a causative link with increased demand for fine tactile perception; however, this claim was unsubstantiated (38), and since this blind man worked with power tools he would presumably have been exposed to hand-arm vibrations. Although the spectrum of the different types of trauma implicated was wide (ranging from fracture to contusion), we were somewhat surprised to find that hand-arm vibrations were not implicated in any of the reports under review even though this exposure can affect the function of pacinian corpuscles (39).
Regarding pacinian neuroma of the hand following repetitive microtrauma, we were able to locate a single definite reported case (occurring in a professional violinist) in addition to the one described herein. Nevertheless, on pathophysiologic grounds, repetitive local traumas can be considered a particular type of "local trauma" (adding insult to injury, one might say). Therefore, we think that local repetitive microtraumas, such as those encountered in these two cases, can also be considered a plausible causal factor.

Limitations
It might be tempting to conclude that pacinian neuroma of the hand may be considered a new work-related disease. However, a systematic review of reported cases has inherent methodological limitations. Indeed, the study design precluded definition of a clear-cut outcome measure to determine whether pacinian neuroma of the hand could be considered a work-related disease. Of particular concern is that a systematic review of reported cases cannot generate information regarding the strength of association -an important criterion for consideration of causality. Case-control studies would be necessary to evaluate risk analytically, but such an undertaking seems scarcely feasible due to the extreme rarity of the condition.
In addition to publication bias (see above), other forms of bias require consideration, including the "Texas sharpshooter fallacy", ie, fixing the hypothesis after collection of study data (many of the reported cases included in the present study had already been considered in earlier non-systematic reviews such as, most recently, reference 35). However, 7 of the 21 cases classified as following a local trauma (numbers 9, 30, 35, 37, 39, 40, 43) were not considered in earlier reviews. Classification of cases as being definitely trauma-and work-related was hampered by the scarce information regarding personal history (or ambiguous wording) in many of the eligible reports where it was not possible to gain additional clarification from the authors. It is plausible that a higher number of the implicated local traumas actually occurred at work.
It might be argued that this systematic review only helped "rediscover the wheel" given that many authors have already emphasized the relevance of a history of local trauma for onset of pacinian neuroma. Nevertheless, formal production of evidence is generally considered necessary in medicolegal contexts. To our knowledge, this is the first time that pacinian neuroma of the hand has been investigated as a putative new work-related disease.

Concluding remarks
The results of this systematic review of pacinian neuroma of the hand reinforce the concept that a causal link can be considered plausible for cases that arise in the anatomical site of past occupational or non-occupational traumas, including repetitive microtraumas. We think that possible Zanardi et al history of occupational (or non-occupational) traumas or repetitive microtraumas should be investigated and reported when painful pacinian neuroma of the hand is diagnosed in adult age. Documentation regarding any further cases linked to repetitive microtraumas may provide useful information on the spectrum of traumatic events that may be linked to the disease and indirectly to evaluate whether pacinian neuroma of the hand could be considered a new (albeit very rare) work-related disease. Such information may help provide a basis for medicolegal decisions within different national contexts. In the meantime, we think it is reasonable to suppose that painful cases of pacinian neuroma of the hand occurring even several years after a local trauma encountered at work can plausibly be considered clinically relevant sequelae of an occupational injury.