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4 Unconventional Insights in the Pathogenesis and Etiology of Fistulas in... 43
In the transitional zone immediately above the dentate line rectal columns,
papillae and sinuses are formed (Fenger 1979). Some openings of the anal ducts,
connecting with the anal glands, are localized in the base of these sinuses, but others,
the more rudimentary forms, are found in between or outside the internal sphincter.
Most anal glands lay more proximal in the transitional zone. Up to 6–8 anal glands
are mentioned, producing mucus and facilitating fecal transport along the anal canal.
The lining epithelium of the anal ducts is as unpredictable as the lining of the
transitional zone and varies between columnar, goblet cell, transitional, pseudostratified, and sometimes fallopian tube epithelium, reminding the pluripotential
differentiation possibilities of the basal epithelial cells.
2.3 Histopathologic Concepts of Perianal Fistulas
The differences between anal tears, fissure , fistula, abscess, and fistula track lay
mainly in clinical presentation and localization, not in histopathology (Sugrue et al.
2017). Anal abscesses and fistulas are considered as different stages of the so-called
anal suppurative disease and believed to arise after obstruction of the anal duct,
followed by stasis of contents. Infection with the gut-microbiome causes an extensive local inflammatory process, rupture, abscess formation, and creating a connection from the anal transitional zone to the intermuscular perineal spaces (Kiehne
et al. 2007).
The main reason for the surgeon to ask for histopathology in patients with
perianal fistulas is to exclude an underlying malignancy; a luetic ulcer; infections
like HPV (human papillomavirus), HSV (herpes simplex virus), and LGV (lymphogranuloma venereum); or other causes of the inflammatory process (Appelman
2014). Since the pathogenic mechanism of fistula in IBD and especially in Crohn’s
disease patients is different and requires local as well as systemic treatment (Morson
and Lockhart-Mummery 1959; Sica et al. 2014), these fistulas have another phenotype and are not included in this chapter.
The histopathological substrate of the anorectal suppurative disease is nearly
always a nonspecific acute but mostly chronic inflammatory process with ulceration,
forming of (hyper)granulation tissue and reactive epithelial hyperplasia in the
neighborhood. Sometimes foreign body giant cells represent a local reaction on
fecal material in the fistula track; sometimes remnants of a squamous epithelial
lining are reported. Noteworthy is the lack of anal ducts or glandular tissue in the
numerous histopathological reports, circulating in the general pathology practice and
as such never mentioned in the sparse studies about histopathology of perianal
fistulas.
More important in this respect is the complete absence of clinical information
about the origin of the removed tissue, the localization of the fistula, the inner or
outer opening, predisposing diseases, or previous surgical interventions like a seton,
plug, or other, more invasive, procedures.
In spite of numerous different treatment strategies, the main unanswered question
remains why the inflammatory process will not heal properly and which underlying
44 C. B. H. Molenaar et al.
pathogenetic mechanisms as well as (predisposing) diseases sustain this process.
Several possibilities like persistent local infection with gut- and/or skin (anaerobic)
bacteria or their remnants and systemic conditions like autoimmune diseases, diabetes, obesity, and (congenital) alterations in the innate immune system are
suggested (Vossen et al. 2018).
3 New Concepts in Our “Out-of-the-Box” Unconventional
Approach and Hypothesis
3.1 Old Stories, New Histopathological Concepts?
In ancient, medieval, and modern times, the anorectal suppurative disease is a wellknown disease. In literature concepts about the etiology are sparse. Parks in 1961
suggested an important role for the anal ducts and glands, subsequently followed by
other authors (Parks 1961). But as mentioned above, in general practice and in
literature, the histopathologic substrate of anal suppurative disease related to the anal
ducts or glands is missing. This raises the question if after more than 60 years, this
theory is still tenable.
In between 1995 and 2012, a few consistent publications about squamous
epithelium in the inner or the outer fistula opening are found (van Koperen et al.
2010; Lunniss et al. 1995; Mitalas et al. 2012). The lack of proper clinical informa-
tion about the localization of the fistula and the origin of the squamous epithelium
hampers the interpretation of the results, and this is never considered as an important
finding (van Koperen et al. 2010).
But recent literature about hidradenitis suppurativa (HS) did arise a new concept
of the ongoing inflammatory process in perianal fistula, comparable with HS (not in
etiology but in pathogenesis) (Ardon et al. 2019; Vossen et al. 2018).
Given the localization of the inner opening in the linea dentate, covered by
primitive, vulnerable, difficult to the distinct transitional epithelium, the inner
opening of the fistula could be covered by this epithelium, keeping this opening
patent and facilitating channel formation, a pathway for bacteria to the intermuscular
spaces. The bacterial and epithelial debris cause a simultaneous cascade of inflammatory cytokines, with the histopathological substrate of a mixed inflammatory
infiltrate, sometimes with multinucleated giant cells and followed by the formation
of granulation tissue (van Onkelen et al. 2016; Ratto et al. 2016).
Surgical intervention with the placement of a seton or closure of the track could
just result in seeding epithelial remnants in the track, thus “burying” these components in the inflammatory tissue. Sinus or track formation takes place caused by
these epithelial remnants, forming cavities and abscesses, promoting continuous
activation of the local immune system and an excellent habitat for bacteria of the
gut-microbiome.
This results not in degeneration, but on the contrary the numerous inflammatory
cytokines induce uncontrolled excessive epithelial proliferation, known as the
4 Unconventional Insights in the Pathogenesis and Etiology of Fistulas in... 45
feature of (pseudo) epithelial hyperplasia, ending up with keratinizing and as such
just maintaining the inflammatory reaction. Especially the role of inflammatory
cytokines is highlight ed in patients with HS, just indicating activation of the skin
immune system (Ardon et al. 2019).
In literature numerous schematic drawings are found about the possible localiza-
tion of the perianal fistula and abscesses, but in reality the correct position of the
fistula in between known anatomic structures is not documented. It’s well known
that tissue clefts surrounding penetrating neurovascular bundles and intermuscular
dissection planes around the different muscles are the preferential sites for spreading
inflammatory processes in general and subsequently also perianal fistulizing disease
(Fig. 1).
Fistula formation in Crohn’s disease patients is associated with an epithelial
barrier defect which enables to penetrate pathog en-associated peptides to enter the
gut mucous membrane (Siegmund et al. 2016). The local inflammatory response and
wound healing cytokines induce the so-called epithelial-mesenchymal transition, the
transformation of intestinal epithelial cells to invasive primitive myofibroblasts, as
such resulting in fistula formation and fibrosis (Bataille et al. 2008). This pathogenic
mechanism, related to the epithelial lining, could also play a role in the persistence of
the perianal fistula in other patients without IBD.
In perianal fistulas, formed on the above described pathogenetic mechanism, only
local radical surgical excision with removal of the whole process, like in HS and in
pilonidal disease, will interrupt the vicious circle.
3.2 Old Stories, New Clinical Concepts?
As above already mentioned, patients with perianal fistulas appear to have different
clinical features. In the following chapter, the diversity of disease symptoms and
courses are discussed, as encountered in clinical practice. Continuously we categorize
the different clinical presentations into the different so-called “clinical phenotypes.”
3.2.1 Basic Concepts
In clinical practice the term “fistula” is not only used for the connection between two
spaces but also for the track from the internal opening leading to the abscess or
pocket without the presence of an external opening. We prefer to exclusively use the
term “perianal fistula” if there is an internal and an external opening. In other cases
we would suggest to use the term “track.”
It is known that with an existing external opening, an internal opening is not
always identified. The general assumption is that the internal opening is too small to
identify but does exist. In this case we would suggest using the term “fistula with
unidentified internal opening.” Of course this remains debatable, for example, in
cases in which a hidradenitis suppurativa is suspected.
In this paragraph we refer to the aspect of fistulas that haven’t been operated on
before and exclude the iatrogenic fistulas.
46 C. B. H. Molenaar et al.
tissue clefts around penetrating neurovascular bundles and intermuscular dissection planes. Illustration by Anne Simon
Fig. 1 The anorectum with different histopathological types of cellular lining at different levels. Perianal fistulas develop along the line of the least resistance:
4 Unconventional Insights in the Pathogenesis and Etiology of Fistulas in... 47
3.3 Based on Previous Medical History
Usually there is a previous history of a perianal abscess. An abscess can occur in
different locations. On the one hand, this raises the question if there might be a
different etiology. On the other hand, the technique used to drain the abscess might
also have a direct relation with the development of a fistula. Besides an abscess can
have a superficial and a profound location at the same time, for example, one
positioned in the levator muscle or intersphincteric space and one in the subcutaneous
or submucosal space. If the superficial abscess is drained,but the profound extension is
left untouched, this might lead to a deep chronic inflammatory process with the risk of
developing a fistula tract. Diagnostics are rarely used prior to drainage of a perianal
abscess, and the drainage is commonly performed outside office hours leaving it up to
the general surgeon or resident on call. Surprisingly enough, no research has been
done to understand the fact that in only 30% of these abscesses a fistula develops
(Hamadani et al. 2009; Oliver et al. 2003). So this definitely remains to be done.
A previous history of a chronic anal fissure is also mentioned (Deen-Molenaar
et al. 2016). We reported a patient with a chronic fissure who initially recovered with
conservative treatment using diltiazem ointment and defecation regulation but got a
relapse after a couple of weeks. He presented with an intersphincteric infection,
which was identified on endo-anal ultrasound. Despite oral antibiotics he developed
a postanal abscess. From our experience this is a quite common course.
Some patients present with a perianal fistula without any previous history of an
abscess. They might presents some complaints of itching or burning during the
previous weeks and then suddenly discover a pimple in the perianal region.
We reported a higher prevalence of perianal fistula in patients with HS localized
in the axillae and the groins, but HS can also occur in the perianal region (Ardon
et al. 2019). In our experience this is sometimes overseen by the clinician. Since HS
can be treated in a lot of cases with proper medication, this underdiagnosis might
lead to unnecessary invasive treatment.
There is also a trend towards previous histories with a proctologic treatment like
rubber band ligation, the drainage of a Bartholin cyst, or an episiotomy.
3.4 Aspect and Localization of the Fistula Opening
It is stated by Parks that the distance of the external opening from the anal verge does
give a clue to the complexity of the fistula. The larger the distance of the external
orifice to the anus, the higher the fistula is situated. In clinical practice this is not
always found. A low fistula can have a long subcutaneous track. Furthermore, an
external opening near the anal verge does not necessarily represent a low fistula,
since high intersphincteric fistulas do frequently end near the anal verge.
The external opening can present with hypergranulation tissue or can be
completely epithelialized, like the aspect of an ear piercing. The internal opening
is typically located at the level of the dentate line. However, in some cases the
internal opening is located in the anoderm or above the dentate line.
48 C. B. H. Molenaar et al.
We identifi ed the following groups of patients based on their clinical
presentation.
3.5 Phenotype 1
This type of perianal fistula is typically seen after an episode of an anal fissure as
described earlier in this chapter (Deen-Molenaar et al. 2016). Sometimes there are
previous sequelae of recurrence of the anal fissure over the pas t months or even
years. The patient can present with an anal abscess near to the anal verge.
Sometimes spontaneous rupture of the abscess already occurred before presentation, and they refer a periodically release of fluid from the small rupture site. The
resulting fistula is usually a low transsphincteric or intersphincteric fistula (Figs. 2,
3, 4, 5 and Table 1).
3.6 Phenotype 2
This type of perianal fistula is the classical one that persists 3 months after the
drainage of a perianal abscess. The patients usually present with a sudden onset of
pain and swelling without any previous signs of anal complaints. Frequently the
smell of the pus is strong due to an anaerobic infection. The abscess might be
located at a deep (intersphincteric, supralevator of ischiorectal space) and a superficial (subcutaneous) level. A horseshoe extension is common. The resulting fistula
is usually a high transsphincteric or intersphincteric fistula (Figs. 6, 7, 8 and
Table 2).
Fig. 2 (a) Transversal) and (b) sagittal. Endo-anal ultrasound in a patient with an acute anal fissure
which appears as a hypoechogenic thickening of the internal anal sphincter at 7 o’clock on the
transversal transection
4 Unconventional Insights in the Pathogenesis and Etiology of Fistulas in... 49
Fig. 3 (a) Transversal and (b) sagittal. Endo-anal ultrasound with the suggestion of an
intersphincteric infection which appears as a bigger hypoechogenic area on the transversal transection compared to the ultrasound that was made 4 weeks before (Fig. 2a, b)
Fig. 4 (a) Transversal and (b) sagittal. Endo-anal ultrasound showing an abscess in the
intersphincteric area
3.7 Phenotype 3
The patient who presents with this type of perianal fistula does not reveal a previous
history of a perianal abscess. They might present some complaints of itching or
burning during the previous weeks and then suddenly discover a pimple in the
perianal region. The resulting fistula is usually a high transsphincteric or
intersphincteric fistula. The track of the fistula is usually transsphincteric and
sometimes with a long subcutaneous track (Figs. 9, 10, 11 and Table 3).
50 C. B. H. Molenaar et al.
Fig. 5 Transversal. Endoanal ultrasound after drainage
of the abscess and immediate
fistulotomy showing an
incomplete defect in the
internal anal sphincter
Table 1 Features of phenotype 1
Anal pain for more than 6 weeks previous to the presentation of the abscess
Known with chronic anal fissure
Recurrent periods with an intersphincteric infection (hypoechogenicity on the endo-anal
ultrasound)
Abscess predominantly located postanal
External opening of the fistula at 0.5 to 1 cm from the anal verge in the midline
Internal opening of the fistula in the bottom of the fissure
Fig. 6 Showing a persisting
wound 3 months after
drainage of a perianal abscess.
The wound shows
hypergranulation tissue and at
8o’clock is a slight swelling
palpable. With slight
compression at this swelling
bloody fluid comes out of the
wound at 3 o’clock. This
finding is typical for a
persistent ischiorectal pocket
after abscess drainage
4 Unconventional Insights in the Pathogenesis and Etiology of Fistulas in... 51
Fig. 7 Endo-anal ultrasound at different levels with a presenting a distal level, b an intermediate
level, and c a proximal level. There is an area with hypo-echogenicity visible from 8 o’clock (a)to
3o’clock (b). The internal opening of the fistula is visible 6 o’clock at a high (or deep) level (c)
Fig. 8 Endo-anal ultrasound
in rendering mode showing
the hypoechogenic area in 3D
seen in Fig. 7a–c
52 C. B. H. Molenaar et al.
Table 2 Features of
phenotype 2
Fig. 9 External fistula
opening at 7 o’clock and
1.5 cm from the anal verge
with no hypergranulation
tissue and therefore hardly
recognizable
Sudden onset of anal pain
Perianal abscess with anaerobic infection (strong smell)
Horseshoe abscess common
Hypergranulation tissue at the external opening
Internal opening at the dentate line
3.8 Phenotype 4
We meant to include patients with a perianal hidradenitis suppurativa in the classification of the phenotypes, because the fistula can have an opening in the anal canal.
Therefore, this type of fistula should be identified in an early stage in order to offer
the nonsurgical treatment available to treat HS. In our example we show a clear case
of HS in a young woman. She was referred to us after HS treatment had failed, and
here abscesses recurrently appeared (Figs. 12, 13, 14, 15 and Table 4).
3.9 Phenotype 5
The patient presents with a previous history of a recurrent abscess with pus or
yellowish fluid that doesn’t have the typical smell of an anaerobic infection. The
fistula is usually a high transsphincteric fistula and anteriorly located (Figs. 16, 17
and Table 5).