Pancreatic panniculitis: Getting spooked by ghost cells

By Warren R. Heymann, MD, FAAD
July 24, 2024
Vol. 6, No. 30

I am at the age where the diagnosis of pancreatic cancer is a looming fear, punctuated by the loss of my dear aunt Helen and two friends who have succumbed to the ravages of this vicious malignancy. There are several cutaneous manifestations of pancreatic diseases — icterus due to bile duct obstruction from any cause, hemorrhage in pancreatitis (Cullen’s sign around the umbilicus, Grey Turner sign on the flanks, Fox sign from retroperitoneal bleeding tracking to the thighs), cutaneous metastases (most famously the Sister Mary Joseph nodule), necrolytic migratory erythema (glucagonoma), and pancreatic panniculitis (PP). (1) Dermatologists are also aware that in addition to melanoma, the CDKN2A gene is one of the pancreatic cancer susceptibility genes. Depending on the family history of the disease, pathogenic germline CDKN2A variants have been identified in up to 3.3% of patients with pancreatic ductal carcinoma. (2) This commentary focuses on recent literature on PP. I will also mention evolving literature that potentially could have benefited my aunt and one of my friends.

PP (aka pancreatic fat necrosis) was first described in 1883 by Hans Chiari. Up to 3% of patients with all pancreatic disorders may present with PP. The disease is more common in men, often with an alcohol use disorder. (1,3) PP commonly presents in the seventh decade of life, but patients can be older if the etiology is pancreatic malignancy. PP characteristically appears as tender nodules on the lower extremities but may also be present on the thighs, hips, buttocks, breasts, upper extremities, scalp, and around various joints. Nodules may ulcerate accompanied by drainage of brown, oily secretions. PP may precede typical signs of pancreatitis or pancreatic tumor. (3)

PP is usually associated with acute and chronic pancreatitis, mainly secondary to cholelithiasis, alcohol abuse, drugs, or trauma. Less frequently, it is associated with pancreatic carcinoma, most often an acinar cell carcinoma, which only accounts for about 1% of all primary pancreatic neoplasms. It is less frequently associated with pancreatic neuroendocrine carcinoma and pancreatic ductal adenocarcinoma (PDAC), and rarely reported in the course of some other carcinomas, such as gastric or liver carcinoma. (4) Wallace et al. reported a case of PP and polyarthropathy in an 18-year-old man with an undifferentiated pancreatic pleomorphic sarcoma. (5) The triad of pancreatitis, PP, and polyarthritis defines the PPP syndrome. (6)

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The histological features of PP are mostly a lobular panniculitis with anucleate “ghost-like” adipocytes and necrosis. Segui et al. performed a retrospective review of 34 cases of PP, including 23 women and 11 men, aged 31 to 92 years. The most commonly associated pancreatic disease was acute pancreatitis (23 cases) with gallstones as its main triggering cause. Two patients had chronic pancreatitis, and 5 cases were associated with pancreatic cancer (3 acinar, 1 PDAC, 1 ampullary adenocarcinoma). One patient had a gastric carcinoma. In this study, cutaneous lesions disappeared within 2-4 weeks, with supportive care directed to the underlying disease. (4)

The pathogenesis of PP has not been fully elucidated. According to Zhu et al., “One possible mechanism is that pancreatic enzymes, including trypsin, lipase, and amylase, are released in large quantities into the blood leading to increased vascular permeability with consequent excess accumulation of free fatty acids, and ultimately fat necrosis and inflammation. It has been demonstrated that amylase and lipase by themselves are not capable of leading to panniculitis, while free fatty acids can induce systemic inflammatory responses related to adipose tissue by activating macrophages and protein kinase C (PKC)-NF-κB axis, increasing the release of proinflammatory factors such as interleukin-6 and tumor necrosis factor-α. Another possibility is that some patients may have inherent enzyme deficiencies that prevent individuals from degrading pancreatic enzymes, such as α−1 antitrypsin deficiency-associated panniculitis. In addition, the deposition of antigen-antibody immune complexes has also been proposed to participate in the pathogenesis.” (7)

The diagnosis of PP will be discovered and/or confirmed by biopsy, differentiating it from other panniculitides such as erythema nodosum (which does not ulcerate), erythema induratum, and α−1 antitrypsin deficiency. If there was no known history of pancreatic disease, imaging (MRI, CT scan) should be obtained in addition to serum lipase and amylase assays. Treatment is directed to the underlying pancreatic pathology; NSAIDs, steroids, and other immunosuppressive agents may not be effective. Pain management is appropriate. PP lesions may heal with hyperpigmented, atrophic scars. (3)

Although PDAC comprises only 3% of new cancer cases in the United States, the prediction that by 2030 it will become the second leading cause of cancer death reflects its high mortality. Currently, PDAC surveillance focuses on genetically predisposed individuals. Population-based screening for PDAC is not currently justified due to its relatively low incidence in the United States. Both my aunt and friend developed hard-to-control diabetes months before the diagnosis of pancreatic cancer was considered. Perhaps an earlier recognition of their pancreatic cancer would not have changed their outcome, but if there is any chance of a cure, the earlier the diagnosis is rendered, the better. According to Wood et al., “Although long-standing diabetes may play a causal role in pancreatic tumorigenesis, it appears that new-onset diabetes (NOD) is an effect rather than a cause of PDAC, and recent studies have focused on this symptom to define a high-risk group for screening. Approximately 1% or less of patients with NOD develop PDAC within 3 years. The incidence of PDAC in patients with NOD may increase to as high as 3% in white men after age 50 or range between 1.5% and 6% when a predictive model that considers age at onset, change in weight, and change in blood glucose (Enriching New-Onset Diabetes for Pancreatic Cancer or ENDPAC score) is used. A large NOD prospective cohort study consisting of subjects 50 years or older is under way to determine the 3-year incidence of PDAC and collect biospecimens as early detection initiative.” (8)

Point to Remember: The presence of “ghost cells” in the adipose tissue indicates pancreatic panniculitis. Once that diagnosis is rendered, a careful assessment of the nature of pancreatic disease, especially pancreatitis and pancreatic cancer, is crucial.

Our expert’s viewpoint

David A. Wetter, MD, FAAD
Professor of Dermatology
Mayo Clinic
Rochester, Minnesota

During my residency training at Mayo Clinic, my dermatology mentors continually stressed the importance of “clinicopathological correlation” when assessing patients. This mantra is particularly important when striving to provide an accurate diagnosis for a patient presenting with panniculitis, given the clinical and histopathological complexities of (and similarities between) the various subtypes of panniculitis. A recent Mayo Clinic study proposed an updated clinical classification of panniculitides based upon ulceration, location, and number of lesions to allow clinicians to narrow their differential diagnosis of panniculitis at the bedside. (9) Although there were only 3 patients with pancreatic panniculitis in the study (of 207 total patients with panniculitis), 2 of the patients had ulceration while all 3 patients had bilateral lesions involving the lower body (with one patient also having involvement of the upper body) with a median number of 4 lesions per patient. (9) A retrospective Mayo Clinic study in the mid-1990s of 11 patients with pancreatic panniculitis spearheaded by one of our emeritus professors of dermatology, W.P. Daniel Su, MD (a world expert on panniculitis and one of the aforementioned mentors who emphasized the paramount role of clinicopathologic correlation), found that 6 of 11 patients had an associated pancreatic carcinoma; 6 patients had arthritic symptoms; and 10 of 11 patients had involvement of the lower extremities. (10) Clinical features that were observed in patients with pancreatic panniculitis due to underlying pancreatic carcinoma (compared to other causes) included “more skin nodules, lesions not on the legs, and extensive spontaneous ulceration.” (10) Hopefully through the careful consideration of clinical features (such as the presence of ulceration and the distribution of lesions) and histopathological features (such as the presence of “ghost cells”), clinicians can more easily diagnose pancreatic panniculitis and the presence of an associated pancreatic disorder (including malignancy).

1. Kunovsky L, Dite P, Brezinova E, Sedlakova L, Trna J, Jabandziev P. Skin manifestations of pancreatic diseases. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2022 Dec;166(4):353-358. doi: 10.5507/bp.2022.035. Epub 2022 Jul 22. PMID: 35938387.

2. Kimura H, Klein AP, Hruban RH, Roberts NJ. The Role of Inherited Pathogenic CDKN2A Variants in Susceptibility to Pancreatic Cancer. Pancreas. 2021 Sep 1;50(8):1123-1130. doi: 10.1097/MPA.0000000000001888. PMID: 34714275; PMCID: PMC8562885.

3. Kabir KF, Lotfollahzadeh S. Pancreatic Panniculitis. 2023 Jun 3. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 37276285.

4. Seguí M, Rodríguez-Jiménez P, Fraga J, Navas J, Ríos JJ, Revilla D, Santos-Briz Á, Lluch JJ, Fernández Figueras MT, Luque M, Llamas Velasco M. Pancreatic panniculitis revisited: A series of 34 patients. J Cutan Pathol. 2023 Nov;50(11):983-990. doi: 10.1111/cup.14515. Epub 2023 Aug 21. PMID: 37605438.

5. Wallace CE, Heath C, Visconti M, Auster B. Pancreatic panniculitis and polyarthropathy due to undifferentiated pleomorphic sarcoma. JAAD Case Rep. 2022 Oct 27;30:94-96. doi: 10.1016/j.jdcr.2022.10.012. PMID: 36425661; PMCID: PMC9678784.

6. Devineni GS, Zackariah NM, Surendran S, Eapen M. Pancreatitis, panniculitis and polyarthritis (PPP) syndrome. BMJ Case Rep. 2023 Sep 26;16(9):e254732. doi: 10.1136/bcr-2023-254732. PMID: 37751979; PMCID: PMC10533739.

7. Zhu WF, Fang S, Qiao JJ. Pancreatic panniculitis as the first presentation of pancreatic ductal adenocarcinoma. Hepatobiliary Pancreat Dis Int. 2023 Aug 22:S1499-3872(23)00135-2. doi: 10.1016/j.hbpd.2023.08.016. Epub ahead of print. PMID: 37640576.

8. Wood LD, Canto MI, Jaffee EM, Simeone DM. Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment. Gastroenterology. 2022 Aug;163(2):386-402.e1. doi: 10.1053/j.gastro.2022.03.056. Epub 2022 Apr 7. PMID: 35398344; PMCID: PMC9516440.

9. Anand NC, Takaichi M, Johnson EF, Wetter DA, Davis MDP, Alavi A. Suggestions for a New Clinical Classification Approach to Panniculitis Based on a Mayo Clinic Experience of 207 Cases. Am J Clin Dermatol. 2022 Sep;23(5):739-746. Epub 2022 Jul 18. PMID: 35849324.

10. Dahl PR, Su WPD, Cullimore KC, Dicken CH. Pancreatic Panniculitis. J Am Acad Dermatol 1995;33:413-7. PMID: 7657863.

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