Introduction
With an incidence of 0–1/100 000 inhabitants per year, Ormond’s disease is a rare
disease associated with chronic inflammatory fibrosis of the retroperitoneum and the
abdominal aorta. The disease peaks in the 5th-6th decade of life [1]. Vogt et al. provide a detailed description of the difficulties regarding terminology
in the German language. The term Ormond’s disease is often used synonymously with
chronic periaortitis which in turn includes idiopathic retroperitoneal fibrosis (IRF),
inflammatory retroperitoneal aortic aneurysm (IRAA), and perianeurysmatic retroperitoneal
fibrosis (PARF). The term Ormond's disease is often also used specifically for IRF
or retroperitoneal fibrosis [2]. In this article, Ormond's disease is described as idiopathic retroperitoneal fibrosis.
The symptoms are nonspecific and range from unclear abdominal and flank pain to classic
B-symptoms with fever, fatigue, and weight loss. 80–100 % of patients have an elevated
level of C-reactive protein [1]. The most common complication of retroperitoneal fibrosis is obstruction of the
urinary tract with subsequent hydronephrosis, which can be unilateral or bilateral.
One of the most significant challenges regarding diagnostic imaging is differentiation
with respect to other primarily inflammatory and malignant diseases of the retroperitoneum
[3]. In 75 % of cases, the etiology cannot be determined so that idiopathic fibrosis
(IRF) is diagnosed [4]. In recent years there has been an increasing focus on the theory of IgG4-associated
retroperitoneal fibrosis, which is based on the histological verification of IgG4-positive
plasma cell infiltrates. [5]
Etiology, disease course, and differential diagnoses
As a rule, a differentiation is made between a primary = idiopathic form (corresponding
to Ormond's disease) and a secondary form of retroperitoneal fibrosis. However, a
reliable classification is often not possible. Malignant diseases must be ruled out
as the cause of RPF.
Initially tissue edema, hypervascularization, and a multitude of mononuclear cells,
fibroblasts, and collagen bundles are primarily seen on histopathology. In the late
phase, increasing sclerosis and individual calcifications are seen [1]. Acquisition of a pretreatment histopathological specimen is controversial. Authors
like Cristian et al. postulate that morphological imaging is not sufficiently accurate
to rule out a malignant cause of RPF [6]. Other authors report the opposite and present significant correlations between
morphological criteria (extension above the vessels of the renal pedicle, retroperitoneal
extension with lifting of the abdominal aorta, additional detection of enlarged lymph
nodes) and functional parameters (very high tracer uptake with atypical distribution
on FDG-PET/CT) as criteria for a malignant cause of RPF [3]
[7]
[8]. Therefore, it is unclear whether histopathological confirmation is always necessary.
In the case of an atypical location, clinical or diagnostic indication of a malignant
origin and/or in the case of a lack of response to drug therapy, a histological specimen
should be acquired immediately.
The differentiation between a primary/idiopathic and a secondary form of fibrosis
is essential since the former responds extremely well to immunosuppresive treatment
while drug therapy is usually not effective in the case of a secondary form. Important
aspects for a more precise classification were presented by Fernando et al. and described
again in detail by Brandt et al. [9]
[10]
[11]:
1. Idiopathic RPF without the presence of cofactors.
In 75 % of cases, the etiology cannot be determined so that idiopathic fibrosis (IRF)
is diagnosed [4].
2. RPF as a consequence of or in combination with arterial vascular disease
Aneurysms or arteriosclerosis can be seen in approximately 10–20 % of patients with
RPF. The escape of antigens through the weakened media resulting in a local immune
reaction with inflammation and subsequent fibrosis has been discussed as the pathogenesis
[12].
3. RPF as a consequence of or in combination with an autoimmune disease or vasculitis
A correlation between RPF and autoimmune diseases (e. g. Hashimoto’s thyroiditis)
has been described by various authors in approx. 10–20 % of cases. Therefore, RPF
diagnosis should include investigation of a possible autoimmune origin [12]
[13]. An important differential diagnosis from the group of rheumatological diseases
is Erdheim-Chester disease (ECD), a rare form of non-Langerhans cell histiocytosis
with a poor prognosis in some cases and a high mortality rate. Multisystemic disease
typically includes involvement of the long bones, periarterial inflammation primarily
of the aorta, and retroperitoneal, usually perirenal, fibrosis. A typical sign on
CT is the so-called “hairy kidneys” [14]
[15].
4. IgG4-associated RPF
In recent years there has been a focus on the theory of IgG4-associated retroperitoneal
fibrosis which is based on the histological verification of IgG4-positive plasma cell
infiltrates. Moreover, elevated serum IgG4 levels are seen in up to 60 % of RPF patients.
Therefore, the percentage of IgG4-associated RPF cases among patients otherwise classified
as having idiopathic or primary RPF could by higher than previously assumed. [5]
[16]. The most common form of IgG4-associated disease is type 1 autoimmune pancreatitis.
IgG4-associated diseases have the following in common: good response to glucocorticoids
usually associated with rapid response of clinical and laboratory parameters. In the
case of a lack of response to steroids, tamoxifen, methotrexate (MTX), azathioprine,
and cyclophosphamide are available as alternatives [17].
Arora et al. showed that an IgG4-associated disease should be assumed also in the
case of negative histology and the presence of an elevated IgG4/total IgG ratio. They
emphasized the fact that the symptoms of patients with and without positive histology
do not differ and that the IgG4/total IgG ratio is the method of choice with the greatest
sensitivity in contrast to histology [8].
5. Drug-induced/toxic RPF
Smoking, ergotamine derivatives (primarily methysergide), opioid abuse, and exposure
to asbestos are risk factors for RPF. Smoking, ANA positivity, and lumbar pain were
associated with the recurrence of retroperitoneal fibrosis after initial remission
following steroid and/or MTX therapy [18]
[19]
[20].
6. RPF resulting from radiation or surgery
Since there is little correlation between this secondary form of RPF and Ormond's
disease, it should be classified and treated as radiation fibrosis or scarring [21].
7. Paraneoplastic/malignant RPF
It is not yet clear whether this form of secondary RPF is an independent entity or
rather represents (pseudo) fibrosis occurring as part of a malignant primary disease
(e. g. lymphoma, sarcoma) thus representing a differential diagnosis. However, it
has been shown that this form does not respond to drug therapy with immunosuppressants.
Therefore, the focus should be on diagnosis, e. g. via biopsy, and treatment of the
primary malignant disease [11].
Morphological characteristics
Radiological imaging plays a central role and is the gold standard in the diagnosis
and follow-up of RPF since it helps to determine whether, for example, double-J stents
can be removed or a medication can be paused, while the value of many laboratory parameters
for treatment monitoring is still unclear [11]
[22].
Morphological CT parameters, such as Hounsfield units during the venous and the late
phase, and the maximum fibrosis diameter, are considered predictive markers for improvement
or worsening of renal function in RPF after drug therapy [23].
1. Ultrasound
Ultrasound was considered inadequate. However, newer publications by authors like
Kamper et al. have shown that modern ultrasound can be used for follow-up under special
circumstances [24]. The images from 35 patients with MRI-confirmed RPF with typical extension were
correlated with four standardized ultrasound views (transverse at the level of the
renal pedicle, on the level of the aortic bifurcation and transverse through each
common iliac artery). Conventional B-mode “tissue harmonic imaging” and the wide-angle
function were used. In particular, “tissue harmonic imaging” could adequately visualize
the extent of RPF in 94.2 % (n = 33) patients and performed significantly better than
B-mode imaging.
2. CT/MRI
However, CT and MRI were used for imaging in most cases.
On CT, RPF appears as an isodense periaortic mass, typically under the renal pedicle
with common iliac extension. As a sign of active RPF, intense contrast enhancement
is often seen. Dilatation of the urinary tract can be effectively visualized and tracked.
The affected vessels can be sufficiently evaluated (see [Fig. 1], [5]).
Fig. 1 CT in arterial (a, b, axial MPRs) and portal venous (c, d, coronal MPRs) contrast medium phase. Classic image of an RPF with iso- to hypodense,
retroperitoneal, periaortic mass (blue arrow) under the kidney to the left iliac artery
(green arrow). Consecutive compression of the left ureter with urinary congestion,
which resulted in ureterolysis and application of a double-J catheter (red arrow).
Fig. 5 Coronal a, b and axial c, d CT reconstructions in the portal vein a, arterial c and urographic contrast medium phase b, d. One of the most common complications of RPF is compression and stenosis of the ureters.
In this example on the right side, with consecutive hydronephrosis on the right, delayed
contrast medium excretion and fornix rupture are seen.
MRI also allows precise evaluation of the extent of RPF and the associated complications.
RPF is seen on non-contrast T1w sequences as a hypointense to isointense mass and
in the case of untreated active RPF additionally with a hyperintense signal in T2-weighted
sequences and intense contrast enhancement in T1w-fs sequences after IV application
of contrast agents containing gadolinium (see [Fig. 3]). With high signal intensities and a correspondingly low signal in the ADC map,
diffusion-weighted sequences also show typical signal behavior in the case of active
RPF [25]
[26]
[27]. In a study including 21 patients, Kamper et al. were able to show a significant
decrease in the b800 signal intensity and higher ADC values in DWI [28]. Particularly in patients with limited renal function or in young patients, MRI
can provide important information without radiation and potentially also without the
use of contrast since DWI sequences are very useful for evaluating acute RPF [27]
[29].
Fig. 3 MRI of the patient shown in [Fig. 1], [2], four years after initial diagnosis and currently under immunosuppressive therapy
(a, b: sequence: T1_fl2d_fs_tra_postKM). The RPF is smaller in size, with contrast medium
uptake still present in the marginal area. However, residual activity must be assumed.
3. Perfusion CT (VPCT)
Newer methods like perfusion CT (VPCT) can be used to evaluate fibrosis activity in
addition to the already identifiable morphological criteria such as extension and
density (see [Fig. 6]). Bier et al. evaluated the role of VPCT for determining inflammatory activity in
patients with acute and chronic periaortitis and undergoing immunotherapy. In a study
including 35 patients, the parameters of VPCT (blood flow, blood volume, volume transfer
constant k-trans, time to peak, mean transit time) in untreated patients correlated
significantly with serological markers (CRP, BSG) in relation to disease activity
but only correlated weakly in treated patients which emphasizes the value of VPCT
for initial diagnosis but leaves the question of its use for follow-up open [30]. A second study including 17 patients undergoing immunosuppressive therapy showed
a significant decrease in the parameters “blood flow” and “blood volume” during follow-up
via VPCT [31]. Therefore, it seems to effectively show the changes in hemodynamics with respect
to inflammation. However, a limitation regarding dynamic CT examination is that it
is associated with relevant radiation exposure and therefore should not be routinely
used for follow-up in the case of clinical improvement or in patients who are symptom-free.
Fig. 6 Perfusion CT of a patient with active RPF: contrast medium-affine, inhomogeneous
hyperperfused tissue proliferation around the infrarenal aorta and the proximal iliac
vessels on both sides, matching a highly active RPF (a–c axial MPRs; a: MIP; b: blood flow; c: blood volume).
4. Hybrid imaging
Hybrid imaging plays a special role (see [Fig. 2]). FDG-PET/CT or FDG-PET/MRI should be considered as an additional or primary modality
since hybrid imaging can evaluate both morphological changes and a decrease in inflammation
based on the reduced tracer uptake [32]. Therefore, for example, in a recent monocentric retrospective cohort study, Morin
et al. were able to again highlight the value of FDG-PET/CT in primary diagnosis and
particularly in follow-up. In their cohort (n = 23), all patients showed increased
tracer uptake on FDG-PET/CT at the time of diagnosis. In addition, the persistent
FDG uptake after treatment with steroids in the second follow-up examination was significantly
associated with the recurrence of IRF [33]. Other authors also highlight the importance of hybrid imaging, which allows differentiation,
for example, between RPF and lymphoma. In 2017, Fernando et al. included 78 patients
with RPF in a prospective study [3]. 0 % of patients with negative [18F]-FDG-PET (n = 24) had a malignancy in the subsequent biopsy (negative predictive
value 100 %). All malignant masses were correctly identified and subsequently histologically
verified (n = 4). The patients with malignant masses exhibited significantly increased
tracer uptake (SUV max ≥ 4) and an atypical distribution pattern. FDG-PET/CT was able
to show RPF activity in 50 % of patients with unremarkable lab results (19/38). Patients
with high activity on FDG-PET/CT responded significantly better to steroid therapy
than patients with low or no activity on FDG-PET/CT. An advantage of hybrid imaging
that should not be underestimated is the potential to dispense with the use of intravenous
contrast agent. Due to RPF and subsequent hydronephrosis, many patients have significantly
limited kidney function so that the administration of IV contrast agent is often contraindicated.
In such cases PET/CT can still provide useful information while maintaining good anatomical
resolution by applying FDG without IV contrast agent (low-dose CT should not be used
exclusively for attenuation correction) [34]. Individual case reports show that it is possible to remove stents or catheters
early in the case of a lack of FDG uptake in spite of morphological persistence of
RPF [35].
Fig. 2 [18F]-FDG-PET/CT of the patient described in [Fig. 1]. The retroperitoneal mass shows moderate metabolic activity with an SUVmean of 2.1
to 2.3, correlating with a florid RPF (a, b axial MPRs, c, d coronal MPRs).
FDG-PET/MRI hybrid imaging is unfortunately not universally available but represents
an alternative to PET/CT particularly in young patients due to the reduced radiation
exposure and to CT and MRI due to the additional information. In addition to the above-mentioned
morphological criteria in T2, T1_fs_contrast-enhanced, DWI and ADC sequences, it provides
additional functional information as a result of the FDG uptake. Ruhlmann et al. emphasize
the higher value of PET parameters compared to MRI parameters with respect to differentiating
between treated and untreated patients [27].
Hybrid imaging both with FDG-PET/CT and FDG-PET/MRI therefore plays a special role
in RPF imaging since it is highly suited for the quantification and prediction of
treatment response, allows corresponding drug therapy adjustments, and allows potentially
earlier removal of any foreign objects like stents and catheters. [3]
[35]
Differentiation from malignant disease
One of the most important challenges regarding diagnostic imaging is the differentiation
from other primarily inflammatory and malignant diseases of the retroperitoneum. Although
CT-guided histological verification of fibrosis prior to the introduction of drug
therapy is safe, it is still the topic of discussion [36]. Particularly differentiation with respect to malignant diseases is highlighted
by proponents of histological confirmation. However, primarily symptoms and lab results
in combination with precise imaging to be discussed in an interdisciplinary setting
can rule out malignancies in most cases (see [Fig. 4]). At this point we would like to make special reference to the study by Zhang et
al. which describes significant morphological CT differences like extension above
the vessels of the renal pedicle, retroaortic expansion, and pathological enlargement
of the lymph nodes, allowing the differential diagnosis of lymphoma, for example [7]. An overview of the criteria that indicate RPF or a malignant disease and an evaluation
of the individual modalities are shown in [Table 1].
Fig. 4 Axial CT reconstruction in the portal vein contrast medium phase: patient with histologically
confirmed follicular lymphoma after four cycles CHOP. Retroperitoneal mass resembles
an RPF, but spreads cranially over the renal pedicle.
Table 1
Morphological criteria for RPF.
|
modality
|
morphological criteria for RPF
|
potential indications of malignancy
|
|
ultrasound
|
determination of extent of cancer via “tissue harmonic imaging” in standard views,
extension typically below the renal pedicle
|
extension above the vessels of the renal pedicle
retroaortic extension
pathologically enlarged lymph nodes
|
|
CT
|
isodense periaortic mass, typically below the renal pedicle to periiliac
|
|
intense contrast enhancement can indicate active RPF
|
|
urinary retention
|
|
Calcifications as a possible sign of inactive RPF
|
|
MRI
|
T1w non-contrast hypointense to isointense
|
|
T2 non-contrast hyperintense in the case of activity
|
|
intense contrast enhancement in T1w-fs in the case of activity
|
|
high DWI signal or correspondingly low ADC signal in the case of activity
|
|
PET-CT/MRI
|
morphological criteria mentioned above
|
greatly increased (SUVmax ≥ 4) or atypically distributed FDG uptake can indicate malignancy
|
|
increased FDG uptake in terms of an increase in metabolic activity
|
Treatment
Since obstructive uropathy with resulting hydronephrosis and postrenal kidney failure
is the most common complication of RPF, preservation and protection of renal function
have the highest priority. Affected patients are treated with double-J stents and/or
nephrostomy tubes. Both methods result in a sufficient decrease in creatinine levels
and have comparable complication rates. However, in the long term some patients (approx.
18 %) experience atrophy of the previously affected organ [11].
Various immunosuppression drugs are available (cortisone, tamoxifen, infliximab, rituximab,
and tocilizumab) [11]
[37]
[38]
[39]
[40]. The surgical gold standard is ureterolysis with displacement of the ureter out
of the retroperitoneum into the omental fat performed via open surgery, laparoscopy,
or robot-assisted surgery. Depending on the degree of damage due to fibrosis, parts
of the ureter may need to be removed followed by reanastomosis or the compete ureter
must be replaced by the ileum or colon [6]
[11].
