The Complex Relationship between Mesenteric Panniculitis and Malignancy — A Holistic Approach is Still Needed to Understand the Diagnostic Uncertainties

Mesenteric panniculitis is an idiopathic, localized inflammation involving the adipose tissue of the small bowel mesentery. The association of mesenteric panniculitis with malignancy, predominantly lymphomas, has been widely reported in the medical literature. In this review article, we will discuss the clinical guidelines in the diagnosis and management of mesenteric panniculitis and the clinical association between mesenteric panniculitis and malignancies.


Introduction And Background
Mesenteric panniculitis (MP) is an idiopathic, localized inflammation involving the adipose tissue of the small bowel mesentery. The association of mesenteric panniculitis with malignancy, predominantly lymphomas, has been widely reported in the medical literature. The majority of patients with mesenteric panniculitis are asymptomatic and are picked up incidentally while performing radiological examinations, but MP patients with a high risk of malignancy warrant a thorough investigation [1]. There is a lack of clear clinical guidelines on the management and follow-up of MP. Table 1 shows the five cardinal radiological signs of MP [1].

Pathology
MP is an inflammatory disorder of the mesenteric root with two distinct pathological subgroups: mesenteric panniculitis and retractile mesenteritis. The differential diagnosis of these two conditions is based on histological criteria; fat necrosis predominates in MP whereas fibrosis and retraction predominate in retractile mesenteritis [2].

Objectives of this literature review
To discuss the clinical features and association between mesenteric panniculitis and malignancy, the diagnostic dilemmas, and their treatment plan.

Materials and methods
We conducted a literature search of articles using the US National Library of Medicine PubMed database, PubMed, MEDLINE, Embase, Cochrane Library and Google Scholar databases, ClinicalTrials.gov for studies, and the ISI Web of Science. No date restrictions were placed on the search. A thorough search for controlled clinical trials and cohort studies was conducted. Since the rarity of condition, case reports were also included.
Included studies were those published in English that assessed the association between mesenteric panniculitis and malignancy. Reference lists were also screened. From the search results, articles with irrelevant titles were discarded, with the remaining abstracts examined for relevance.
The authors of this review independently determined the eligibility of the studies and assessed the methodology of included studies. In this review article, we will discuss the aetiology, pathogenesis, and clinical studies related to MP, as well as case studies and their management per the latest clinical guidelines.

Review of clinical studies
The findings of the literature review are summarised in Table 2, but we will discuss a few of the studies that are more relevant to the association between mesenteric panniculitis and malignancy.

ID Findings
Akram et al. [5] 17478346 Patients with symptomatic MP may benefit from a combination of tamoxifen and prednisolone. Out of 259 patients with confirmed MP, 78 were diagnosed with malignancy (54 with a current cancer and 33 with a past cancer or both); the most common primary sites were colorectum (19), lymph nodes (17), kidney (6), and prostate (4).
Daskalogiannaki [9] 10658720 CT evidence of MP was observed in 49 patients. MP coexisted with malignancy in 34 patients, and it coexisted with benign disorders in 11 patients.

Ehrenpreis et al. [3] 28082812
A total of 359 patients had CT scans with signs of MP-like abnormalities; 81 patients had a known history of cancer at the time and 19 had a new cancer diagnosis at the time of their CT. Fourteen of these patients were undergoing CT as part of a malignancy evaluation. The most common cancer associated with MP-like signs on the CT was lymphoma with 36 cases (17 of which were follicular lymphoma).
Gögebakan et al. [10] 23906444 Out of 13,485 CT patients, 77 were diagnosed with MP; of these, 51% were also diagnosed with malignancy vs. 60% of the control group (those without MP).
Khasminsky et al. [11] 28712750 Among MP patients, 1.8% were found to have NHL, which is about how prevalent it is in the general population.
Küpeli et al. [12] 29914254 Out of the 22,033 patients in this study, 309 were diagnosed with MP; 58% of them also had a malignancy.
Mahafza et al. [13] 28917065 Of the 4,758 patients in the study who underwent abdomino-pelvic MDCT, 90 patients had MP-like features.
Twenty-eight of those patients were also diagnosed with malignancy, which represented a risk more than two times higher than for those without MP.  (14), lymphoma (13), and urogenital tract (7). Malignancies were diagnosed after the detection of mesenteric panniculitis in 13 patients. Univariate analysis of demographic, clinical, and radiological features revealed that lymph node size >12 mm (relative risk 4.5 (CI 1.4-14.6); p = 0.0266) and the absence of the fat ring sign (relative risk 0.6 (0.3-1.1); p = 0.047) were associated with the subsequent diagnosis of malignancy in patients with mesenteric panniculitis.  Although prior studies have described the association of MP and malignancy, a recent study shows that only 1.4% of patients with a computed tomography (CT) scan finding of MP will be found to have a previously undiagnosed or suspected cancer [3]. The higher rate of association of MP and cancer described in prior studies likely indicates the inclusion of patients with a known history of cancer.
Additionally, this study shows that a follow-up abdominal CT in patients with cancer suggests stability and not a worsening of MP. Finally, findings indicated that positron emission tomography scans are not recommended in the evaluation of cancer patients with mesenteric panniculitis-like findings on a CT [3].
One retrospective study of 4,758 patients with 90 identified cases of mesenteric panniculitis found that the likelihood of associated malignancy (mostly intra-abdominal malignancy) was 2.1 times higher in patients with MP than those without it [13].
The crude ratio of mesenteric panniculitis patients with colon cancer is less than 10% from our studies (refer Table 4), which is worth looking into. Bigger studies with good sample size and proper research are necessary to further assess it. Even though this is simply a crude ratio, it holds promise for better understanding of the co-occurrence of MP and colon cancer.

Follow-up
Computed tomography scan is optimal for accurate, non-invasive diagnosis of MP and follow-up of sclerosing mesenteritis and any complications. The presence of some radiological findings, such as lymph node size of more than 12 mm and the absence of the fat ring sign, should raise the concern of subsequent malignancy in patients with MP [23].

Treatment
There are no well-established treatment plans for this rare condition. Thus, any treatment prescribed is mainly for symptom relief and to address any complications. Commonly used agents include steroids and other immunosuppressants [24].
One study found that symptomatic patients with idiopathic mesenteric panniculitis responded to treatment with antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) [9]. Patients with obstructive or compressive symptoms may require surgery.

Strengths of the studies
This is one of the most comprehensive literature reviews discussing the association between mesenteric panniculitis and malignancy. The studies in this literature review have been done in multiple centres which will increase the generalisability of the results within a population. Studies also represent a wide range of malignancies like colorectal cancer, lymphoma, breast cancer, etc.

Limitation of clinical studies
Most clinical studies performed on MP lacked histological biopsies. Generally, a biopsy is not justified due to the incidental asymptomatic nature of the disease in most patients. For the majority of patients, the diagnosis was based on the CT appearance and on follow-up CT studies that revealed no additional findings or changes [6].
Most of studies are retrospective and details regarding standardisation of CT scan protocol like intravenous contrast and oral contrast were not available.
Various aspects of interest are not included such as race/ethnicity, medications, chemotherapy and are not discussed in detail.

Discussion
Mesenteric panniculitis is a rare clinical entity that can occur independently or in association with other disorders. Diagnosis of this nonspecific, benign inflammatory disease presents a challenge to gastroenterologists, radiologists, surgeons, and pathologists.
In most cases, MP is self-limiting and regression can even be observed during follow-up in the absence of medical treatment. Clinical symptoms can subside without surgery and with the use of drugs such as corticosteroids, colchicine, cyclophosphamide, and tamoxifen. MP is considered not to be precancerous, and hence long-term follow-up is not needed [20].
There is a lot of dilemma clinicians facing regarding follow-up CT imaging in patients with mesenteric panniculitis. The clinicians should also not subject the patient to unnecessary imaging which also puts the patients at increased risk of radiation-induced gastrointestinal malignancies. The main dilemma clinicians face after diagnosis of MP is how to follow it up and what should be the frequency of scanning. As such CT remains the most widely used and cost-effective modality for adult patients. The frequency of scanning should be guided by clinical symptoms and aetiology of MP. For MP associated with benign causes and in asymptomatic patients, frequency of scanning can be less, unless there is change in clinical symptoms. It would be practically prudent to suggest yearly follow-up CT at first instance but we need clinical guidelines and clinical studies to support this.
Radiological imaging like magnetic resonance imaging may be a reasonable option but it may be expensive and ultrasound may not be the best modality as it can miss findings which CT scan can identify. Ultrasound and magnetic resonance imaging can be used as follow-up modalities for paediatric patients and patients with renal impairment.
Histopathological confirmation is usually not needed to establish the diagnosis of MP as radiological features often suffice. Biopsy should be reserved for cases where there is suspicion of associated malignancy, for example in a scenario where follow-up CT scans are showing progressively enlarging mesenteric nodes on the background of MP, hence raising suspicion of lymphoma. Wait and watch approach can be used for MP secondary to benign causes Physicians should have a broad differential diagnosis when encountering a patient with mesenteric panniculitis and not subject the patient routinely to undergo CT-guided biopsy to establish the diagnosis.
Physicians should also not order multiple radiological investigations and still a conservative approach is needed. The challenges faced are whether an aggressive approach of surgical intervention is needed. But it would be worth watching and a holistic approach of wait and watch is desired.
At the moment, as per our literature review, we cannot find a confirmed certain link between mesenteric panniculitis and subsequent malignancy.
The prevalence of MP appears to be much higher than previously reported, and the reason for this is likely the major technological evolution in imaging during the last decade. This high prevalence may explain the spontaneous association with the numerous and probably unrelated clinical situations found in the literature. Finally, the vast majority of cases are considered idiopathic, benign, and asymptomatic [8]. Furthermore, referring clinicians are often unfamiliar with MP and therefore look-up to the reporting radiologist for management guidance [25].
Lymph node size (>12 mm) and the absence of the fat ring sign were identified as predictors of subsequent diagnosis of malignancy in patients with MP. Identification of MP via imaging should prompt awareness for possible malignancy in these patients [19].

Conclusions
High-quality research linking mesenteric panniculitis imaging features and subsequent malignancy is needed. The lack of consensus regarding the clinical significance of MP thus presents clinicians with a diagnostic dilemma, because MP is encountered frequently as an apparently incidental finding on crosssectional imaging, usually abdomino-pelvic CT scan. There is no consensus on the treatment of MP. Treatment approaches in the literature mostly consist of supportive procedures intended to relieve the symptoms of MP. Physicians should apply holistic approach when they encounter mesenteric panniculitis which includes thorough physical examination, detailed history for red flag signs for malignancy and age-related appropriate screening for malignancy tailored to individual patients.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.