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32 P. G. Vaughan-Shaw and Y. Maeda
implicated in the etiology of stula-in-ano, given the associated increase in anal canal pressures and increased duration of time to defecate that are characteristic of obstruc­tive defecation syndrome (Wang et al. 2014). Neuromuscular abnormalities resulting in dyssynergic defecation such as dyskinetic puborectalis and nonrelaxing puborectalis may also encourage the formation or persistence of a stula tract, although this is not evidenced in the existing literature.
1.7 Anorectal Physiology Testing in the Context of Fistula
Assessment of anorectal physiology and anatomy has two principal functions within the context of stula-in-ano: rst, to help explore etiology of the stula and second, to determine baseline and/or postoperative function and anatomy (e.g., pressures, sphincter defects, etc.). A wide range of tests are available in modern colorectal units. They can broadly be considered as tests of function, tests of structure, and tests assessing both function and structure. Functional tests focusing on neuromuscular physiology, e.g., pudendal nerve terminal motor latency and electromyography, have limited relevance to stula. Anorectal manometry and vector volume manometry may provide important information in relation to the function of the anal sphincter which can help plan surgical intervention for stula, as described further below. Meanwhile, endoanal ultrasound or endoanal MRI provides an assessment of sphincter, pelvic oor, and rectal anatomy which can be hugely helpful in the investigation and preoperative planning of complex stula intervention.
1.7.1 Anorectal Physiology Testing in the Investigation of Fistula
Pathogenesis
The pathogenesis of stula is discussed in full later in this book but has been covered in relat ion to anorectal physiology in the sections above. One pertinent aspect yet to be discussed is the concept of high anal canal pressures in stula etiology. It is accepted that high pressures in the anal canal associated with straining to defaecate promote the formation of hemorrhoids. Subsequent lifestyle modications to reduce straining and pressures are provide symptomatic relief in the majority of patients and are rst-line management for hemorrhoid disease. It is thought that anal stula may develop due to increased anal canal pressure forcing feces or debris through the lining of the anorectum and into perianal or perirectal space, thus initiating stula formation (Hermann et al. 2015). This provides an alternative theory of stula pathogenesis to Parkscryptoglandular theory and may be most relevant to stulating Crohns disease. Pressures within the anorectum have been well studied, with the highest pressure found in the distal rectum and anal canal, consistent with the preponderance toward distal stulae (Tozer et al. 2018). As such, the importance of this high-pressure zone at the internal stula opening is supported by patterns of failure following stula surgery. It is clear that anorectal physiology testing will continue to help inform our understanding of stula etiology.
3 Anorectal Physiology Related to Anal Fistula and Abscess 33
1.7.2 Perioperative Anorectal Physiology Testing
The functional complication of primary concern following stula surgery is inconti­nence. Therefore, an assessment of anorectal physiology and in particular sphincter function in regard to continence is critical in both planning surgery and dening preoperative physiology in event of postoperative concerns or even litigation relating to impaired function. Accurate anal canal sphincter measurements of both anatomy and physiology are possible both at rest and when squeezing using anal vector volume manometry and 3-D anal endosonography (Schizas et al. 2016). These modalities allow the clinician to correlate structure and function, e.g., through dening sphincter length and pressure and identifying the exact part of the sphincter which are the most functionally important. This is valuable for the clinician in the decision-making and consent process in the surgical management of stula. For example, if anal vector volume manometry and 3D anal endosonography suggest that functionally relevant portion of the sphincter (i.e., the high-pressure zone) would be at risk by sphincter division stulectomy, the patient may defer this risk of functional decit and opt for sphincter preserving approaches such as ligation of stula tract (LIFT) or advancement ap surgery. Such approaches have shown to have less impact on squeeze pressure than stulotomy (Roig et al. 2009). Conversely, if assessment suggests that
stulectomy can be performed without clear concerns of incontinence, thenstulectomy may be the most effective and thus preferred management strategy.
Interestingly, recent evidence extends our knowledge in relation to pressures and function and suggests that adequate mean anal pressures alone should not falsely reassure the clinician considering sphincter division – profound low local pressure drops are seen in stula tract areas which may risk postoperative continence, despite normal mean pressures (Felt-Bersma et al. 2018).
It is clear that fecal incontinence is embarrassing and debilitating. As such it is essential that all necessary preoperative assessment and counseling is performed to most accurat ely predict and discuss the level of postoperative incontinence risk. Preoperative anal physiology will help dene this risk but may also provide an important objective measure of physiology that can be referenced against postoper­ative physiology. It may not be surprising for a patient with postoperative inconti­nence to consider complaining to their surgeon, and thus a baseline measure of physiology may protect the surgeon against unsubstantiated claims of impaired function as a direct consequence of the surgical intervention. Of course, it should be remembered that there is no single test that can assess the function of the pelvic oor and sphincters and the physiology and anatomy that are assessed may not correlate to function. Careful history in relation to continence, discharge, and leak is critical in counseling patients before stula surgery.

2 Conclusion

Parks cryptoglandular hypothesis is the basis of understanding stula pathophysi­ology. In addition, there are emerging knowledge on complex interplay with molec­ular and cellular changes that may contribute to inammation and healing of perianal
34 P. G. Vaughan-Shaw and Y. Maeda
stula. Anorectal physiology testing is a useful adjunct to a detailed history of continence in delineating functional impairment and to dene the best management strategy for stula-in-ano and continues to provide data to inform our understanding of stula etiology, e.g., in regard to the inuence of anal canal pressures.

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affected in patients with fecal incontinence after stulotomy. World J Gastroenterol 21:4000–
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103:501–506 Eykyn SJ, Grace RH (1986) The relevance of microbiology in the management of anorectal sepsis.
Ann R Coll Surg Engl 68:237–239 Felt-Bersma RJF, Vlietstra MS, Vollebregt PF, Han-Geurts IJM, Rempe-Sorm V, Vander
Mijnsbrugge GJH et al (2018) 3D high-resolution anorectal manometry in patients with perianal
stulas: comparison with 3D-anal ultrasound. BMC Gastroenterol 18:44 Fry GA, Martin WJ, Dearing WH, Culp CE (1965) Primary actinomycosis of the rectum with
multiple perianal and perineal stulae. Mayo Clin Proc 40:296–299 Goligher JC, Ellis M, Pissidis AG (1967) A critique of anal glandular infection in the aetiology and
treatment of idiopathic anorectal abscesses and stulas. Br J Surg 54:977–983 Gordon-Watson C (1935) Fistula-in-ano arising from an intramuscular gland. Proc R Soc Med
28:216 Gosselink MP, van Onkelen RS, Schouten WR (2015) The cryptoglandular theory revisited. Color
Dis 17:1041–1043 Gupta PJ (2005) Ano-perianal tuberculosis–solving a clinical dilemma. Afr Health Sci 5:345–347 Hermann J, Eder P, Banasiewicz T, Matysiak K, Lykowska-Szuber L (2015) Current management
of anal stulas in Crohns disease. Prz Gastroenterol 10:83–88 Herrmann G, Desfosses L (1880) Sur la muquese de la region cloacale du rectum. C R Acad Sci
(Paris) 90:1301 Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:
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Stamos M, Wexner S (eds) The ASCRS textbook of colon and rectal surgery, 2nd edn. Springer,
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outcomes in different types of anorectal malformations. J Pediatr Surg 52:563–568 Lockhart-Mummery HE (1929) Discussion on stula-in-ano. Proc R Soc Med 22:1331 Mavrantonis C, Wexner SD (1998) A clinical approach to fecal incontinence. J Clin Gastroenterol
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Identication of epithelialization in high transsphincteric stulas. Tech Coloproctol 16:113– Parks AG (1961) Pathogenesis and treatment of stuila-in-ano. Br Med J 1:463–469
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logic and functional parameters after stula-in-ano surgery. Dis Colon Rectum 52:1462–1469 Sainio P (1984) Fistula-in-ano in a dened population. Incidence and epidemiological aspects. Ann
Chir Gynaecol 73:219–224 Schizas AM, Ahmad AN, Emmanuel AV, Williams AB (2016) Synchronized functional anal
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sonography. Neurogastroenterol Motil 28:1075–1082 Seow-choen F (2003) Topics in colorectal surgery. World Scientic Solmaz S, Korur A, Gereklioglu C, Asma S, Buyukkurt N, Kasar M et al (2016) Anorectal
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anorectal sepsis. Int J Color Dis 22:209–213 Tozer PJ, Rayment N, Hart AL, Daulatzai N, Murugananthan AU, Whelan K et al (2015) What role
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Assessment of microbiota and peptidoglycan in perianal stulas. Diagn Microbiol Infect Dis
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population-based follow-up study. Int J Color Dis 28:235–240

Unconventional Insights in the Pathogenesis and Etiology of Fistulas in the Perianal Region

C. B. H. Molenaar, M. E. Bos, and M. E. I. Schipper
Contents
1 Introduction . ..... . ............... ............................................................. 38
1.1 Etiology ................ ..................................................... ............ 38
1.2 Risk Factors for Development of Perianal Fistula ...................... ............... 39
1.3 Risk Factors due to the Type of Perianal Fistula ..................................... . 39
1.4 Treatment-Related Risk Factors for Failure ............................................ 40
1.5 Preliminary Conclusions ............................................................... 41
2 New Concepts in the Histopathological Approach of the Problem ......................... 42
2.1 Anatomy of the Anal Canal ....................... ..................................... 42
2.2 Histology of the Anal Canal . .......................................................... 42
2.3 Histopathologic Concepts of Perianal Fistulas . ......... . . . . . . . . . . .......... . . . . . . . . . . 43
3 New Concepts in Our Out-of-the-BoxUnconventional Approach and Hypothesis . .... . 44
3.1 Old Stories, New Histopathological Concepts? . ......... . . . . . . . . . . .......... . . . . . . . . . 44
3.2 Old Stories, New Clinical Concepts? . ...... . . . . . ...................................... 45
3.3 Based on Previous Medical History .............................. ...................... 47
3.4 Aspect and Localization of the Fistula Opening ....................................... 47
3.5 Phenotype 1 .................. ........................................................... 48
3.6 Phenotype 2 .................. ........................................................... 48
3.7 Phenotype 3 .................. ........................................................... 49
3.8 Phenotype 4 .................. ........................................................... 52
3.9 Phenotype 5 .................. ........................................................... 52
4 Discussion and Conclusions . ................................................................. 53
5 Cross-References .................. ............................. .............................. 58
References .................... ................................ ................................ .... 58
4
C. B. H. Molenaar (*) Department of Surgery, Proctos Clinic, Bilthoven, The Netherlands e-mail: cbh.molenaar@proctoskliniek.nl
M. E. Bos Department of Surgery, Proctos Kliniek, Bilthoven, The Netherlands
M. E. I. Schipper Department of Pathology, St. Antonius Ziekenhuis, Nieuwegein, The Netherlands
© Springer Nature Switzerland AG 2022 C. Ratto et al. (eds.), Anal Fistula and Abscess, Coloproctology,
https://doi.org/10.1007/978-3-030-76670-2_5
37
38 C. B. H. Molenaar et al.
Abstract
In this chapter we explore a new and different approach for the pathogenesis of a perianal stula (excluding those coexisting with inammatory bowel disease) in order to improve the understanding and treatment of this complex disease. We state that the cause of the reported disappointing success rates for the treatment of perianal stulas might be found in the fact that the approach to this disease is based on one theory that should t all different clinical features. In doing so we might compare apples and oranges. In clinical practice, we identied a couple of unanswered questions related to the etiology of perianal stulas. We substantiate our thoughts with basic concepts in histopathology. Continuously, we will focus on the identication of different types of stula given their different clinical presentation. Further research based on our hypothesis that a different clinical presentation probably is caused by a different etiology might lead to a better understanding and treatment of perianal stulas.
Keywords
Perianal stulas · Etiology · Risk factors · Anorectal abscess · Clinical phenotypes · Histopathology · Hidradenitis suppurativa · Epithelial remnants

1 Introduction

For decades the disappointing results in the treatment of perianal stulas have challenged physicians. Numerous studies are performed to obtain a better under­standing of the failure to control this disease. They focus on the development and persistence of perianal stula, as well as new treatment procedu res to deal with the complications of this disease. Unfortunately, the pathogenesis and etiology remain not fully determined and the ideal treatment procedure remains elusive.
1.1 Etiology
In 1961 Parks (Parks 1961) suggested the cryptoglandular origin. This theory pro­poses an initial infection of anal ducts and subsequently glands that lead to acute and chronic inammation, abscess formation, and granulation tissue, leading into a perianal stula. The bacteria from the gastrointestin al tract initiate the inammatory process and the persistence of the channel.
During the past years, research has been focusing on various aspects of the etiology of perianal stulas. For example, the pathophysiology of perianal stulizing disease in inammatory bowel disease has been investigated and reveals several theories about the development of these stulas (Tozer et al. 2015). This leads to a more suitable treatment strategyin these patients (Gosselink et al. n.d.; Tozer et al. 2009). But despite
4 Unconventional Insights in the Pathogenesis and Etiology of Fistulas in... 39
all efforts, in clinical practice these pathogenetic mechanisms do not fully explain the development of perianal stula in several other conditions.
1.2 Risk Factors for Development of Perianal Fistula
It is known that despite adequate drainage of anorectal abscess, up to 83% recurs, and on average 30% will result in a perianal stula, the majority developing within 12 months (Oliver et al. 2003). Meticulous preoperative diagnosis and concomitant antibiotics are attempts to reduce this undesirable course but evidence of its effect is scarce (Hamadani et al. 2009; Lohsiriwat et al. 2010).
Some studies showed that age younger than 40 years signicantly increased the risk of a chronic perianal stula or recurrent anal sepsis after a rst-time episode of perianal abscess. Patients with diabetes, on the other hand, may have a decreased risk compared with nondiabetic patients (Hamadani et al. 2009). Smoking is a know n risk factor for inammatory, stulizing cutaneous diseases. In a couple of studies, smoking is also identied as a risk factor for perianal stula development (Devaraj et al. 2011). It is therefore strongly recommended to quit smoking perioperatively assuming its also interfering with healing. Unfortunately reliable data showing additional positive effects in these patients after surgery are lacking.
1.3 Risk Factors due to the Type of Perianal Fistula
Low Versus High Perianal Fistulas
In general, the treatment of a low stula does have a higher success rate than
the treatment of a high stula.
A low stula includes less than one third of the anal sphincters. In daily practice the evalua tion of the involvement of the anal sphin cters is based rather on anatomical than on functional parameters. Based on these parameters, the low stula can be treated by stulotomy with a 95% rate of success (Göttgens et al.
2015). However, surgeons withhold to perform a stulotomy since a small risk of
incontinence remains after stulotomy.
Complexit y of the Perianal Fistula
The more complex the perianal stula, the lower the success rate. The deni­tions of complex stulas are multiple: high transsphincteric stula, anterior perianal stula in women, and stula with multiple tracks or stula with persistent cavities. It is assumed that the success rate of the treatment of the last two mentioned types of stula is lower (van Koperen et al. 2008; Sugrue et al.
2017). This might be due to the fact that not all tracks can be dealt with or the
persistence of a cavity maintaining the inammation.
Recurrent Perianal Fistula
In general, a recurrent stula has a lower success rate. Interestingly, there is no consensus about the denition of the recurrence of the disease. It can be stated in
40 C. B. H. Molenaar et al.
general that the same stula track persists after the failure of the treatment. Theoretically this should be referred to as a persistent stula and not a recurrent stula. Sometimes the stula can even recur after a period (sometimes years) of silence at the same location. It is known that after a LIFT procedure (Vander Mijnsbrugge et al. 2019), downgrading of the stula can occur, which means that the track of the stula is more supercial due to surgery. This tends to be an intersphincteric stula which can usually be treated by a stulotomy with a subsequently higher success rate.
1.4 Treatment-Related Risk Factors for Failure
Seton Drainage Prior to Perianal Fistula Surgery
There seems to be enough evidence that continuous drainage of the stula does calm down the inammation and might improve the results of the nal stula surgery. Therefore, it is generally accepted to place a seton prior to surgery. However, neithe r has been established how long the drainage ideally should take place nor its additional role in improving the success rate of stula treatment.
Seton Drainage as a Final Treatment Option
The seton can be left in place for several reasons. The patient is tired, because despite many interventions the stula persists, drainage is needed as part of the treatment of Crohns disease or simply because the patient isnt bothered by the seton and prefers to leave it in place instead of either being operated on without any guarantee or running the risk of soiling or incontinence.
In some cases the seton falls out spontaneously but isnt replaced because the patient doesnt present any symptoms, like the track of an ear piercing that has become obliterated by the surrounding brous tissue if it isnt used for a long time. However, nobody has reported yet the results of this wait-and-see policy.
Sphincter-Saving Procedures
In the last decades, several sphincter-saving procedures have been proposed. Most techniques focus on occlusion of the stula track sometimes in combination with the closure of the internal stula opening. Techniques like insertion of an anal plug, injection of brin glue, PRP (platelet-rich-plasma) or Permacol paste, ablation of the track with laser, and closure of the internal openin g with the OTSC (over-the-scope clip) initially reported high success rates. However, it has been hard for other clinicians to reproduce these positive results. In general, the success rate remains between 10% and 50% (Shawki and Wexner 2011).
Lately stem cell injections have gained more interest. In most countries this expensive procedure is exclusively performed in patients with Crohns disease, and reproducible results have to be awaited.
Invasive Procedures
So far the fistulotomy has the highest success rate (95%). The risk of passive incontinence and/or soiling is reported to be 40% in the long run, which obviously
4 Unconventional Insights in the Pathogenesis and Etiology of Fistulas in... 41
does withhold surgeons to perform this type of surgery (Bokhari and Lindsey
2010). Fistulotomy with immediate sphincteroplastyhas gained again more interest
lately, but more research needs to be done to know long-term effects on continence (Ratto et al. 2013). The mucosal advancement plasty remains the golden standard with a success rate of 60–80% although sphincter damage is likely to occur. The LIFT procedure has been introduced as a promising procedure, but the initially reported high success rate is up to the present not reproduced by others (Stellingwerf et al. 2019; Vander Mijnsbrugge et al. 2019).
1.5 Preliminary Conclusions
Looking at the current surgical techniques for the treatment of perianal stula, the success rate remains between 30% and 80%, excluding stulotomy for low stulas (Williams et al. 2007). Up till now this high rate of failure is not fully understood. Moreover, the initially reported high success rates of new surgical techniques are mostly difcult to reproduce by others.
W e like to hypothesize that the cause of the wide variation in reported positive results
and the overall low success rate for the treatment of perianal stulas might be found in the fact that the approach to this disease is based on one theory that should talldifferent clinical features. In doing so we might compare apples and oranges. As a starting point, we identied a couple of unanswered questions based on our clinical experience:
– Why does only 30% of the perianal abscesses develop a perianal stula (Oliver
et al. 2003)?
– What is the role of the various clinical presentations of patients with a perianal
stula?
– What is the link with other stulizing diseases such as hidradenitis suppurativa or
pilonidal sinuses/cysts (Principi et al. 2016)?
– Is there any relation with anal traumata that might be due to anal sexual inter-
course? Simply because there is no literature available on this last topic, we cannot explore this further.
Up until now we distinguish different types of perianal stulas, merely based on
anatomical features in respect to the anal sphincters and anatomy. From a clinical point of view, it is remarkable that we recognize a diversion in the clinical presentation of patients with a perianal stula but dont know the exact role. Because the clinical presentation somehow could be related to the etiology, it seems feasible to distinguish various types of perianal stulas based on their clinical presentation. In this chapter we will refer to these various clinical presentation types as clinical phenotypes.The analysis of the treatment results of these phenotypes might lead to the identification of the most successful treatment for that specic stula phenotype. We will substantiate our thoughts with concepts in pathogenesis, based on histopathology .
42 C. B. H. Molenaar et al.
2 New Concepts in the Histopathological Approach
of the Problem
2.1 Anatomy of the Anal Canal
The anal canal is the terminal part of the large intestine, starting on the narrowing point of the rectal ampulla and ending in the anus, the external outlet of the gastrointestinal tract. In time and literature, much confusion exists about the termi­nology used for the different parts: perianal skin, anal verge, anoderm, anal canal, dentate line, anorectum, anal transitional zone, and rectum. The oldsurgical anal canal has a quite different denition compared with the anatomical and the histo­pathological rectum and anal canal.
In embryology fusion of the ectodermal proctodeum with the endodermal prim-
itive hindgut results in the dentate line, the fusion line between the intestinal mucous membrane, and the squamous covering of the perianal skin. The anatomical com­plexity of this fusion area results in a dual arterial supply, venous and lymphatic drainage, and innervation. Last but not least, the comple x organization of the surrounding musculature (Shak 1980), for example, the internal and external sphincter, levator ani, and puborectalis muscle, gives rise to multiple inter- and extramuscular compartments and fossae, lined by fascia and playing an important role in the development of perianal abscesses.
2.2 Histology of the Anal Canal
In general, but especially relevant in tumor classication by, for example, the AJCC (American Joint Committee on Cancer), the histopathological concept of the anal canal is used for the fusion area, extending from the terminal rectal mucosa to the perianal skin (Appelman 2014). This includes the anal transitional zone and the dentate line.
From proximal to distal, the epithelial lining of the anal canal shows a gradual
transition between partly atrophic colonic crypts covered by mucus-producing rectal columnar epithelium to transitional” epithelium covering the irregular anal transi- tional zone with a length varying from 0.6 cm to 2.0 cm. This transitional epithelium looks like the urothelium, partly attened, umbrella-like, or with more squamous differentiation. This is mixed up with rectal crypts, lined by mucus-secreting columnar cells, with sometimes gastric differentiation and mature, keratinizing squamous epi­thelium. In the transitional zone, the smooth muscle layer of the muscularis mucosae, the normal border of the intestinal mucous membrane, is split up and will subsequently completely disappear in the dentate line (Morson 1978). The composition, amount, and distribution of the different epithelia in this transitional zone are completely unpredictable and macroscopically difcult to distinguish. The rectal mucosa tends to be more pink, and the transitional zone has a grayish glistening appearance, while the squamous covered dentate line is thicker and whitish, sometimes wrinkled with an unsharp transition in the more pigmented perianal skin.