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Pancreatic panniculitis in systemic lupus erythematosus and Crohn’s disease: rare event

ABSTRACT

Pancreatic panniculitis (PP) is a rare manifestation of pancreatic disease, involving subcutaneous adipose tissue. We report two cases of this entity: a 37-year-old female patient with systemic lupus erythematosus (SLE) and an elderly woman with Crohn’s disease. These are two chronic autoimmune inflammatory diseases that can be uncommonly related to acute pancreatitis and that culminates in PP. We also provide a brief review of the treatment, diagnosis and morphology of the lesions, as well as the pathophysiology of the disease. The importance of histopathological analysis of lesion biopsies is highlighted as an important diagnostic tool.

Key words:
fat necrosis; pancreatitis; Crohn disease; lupus erythematosus systemic

RESUMEN

La paniculitis pancreática (PP) es una manifestación rara de enfermedad pancreática que afecta el tejido graso subcutáneo. Reportamos dos casos de esa entidad: una paciente del sexo femenino, 37 años, con lupus eritematoso sistémico (LES), y una anciana con enfermedad de Crohn. Ambas manifestaciones son enfermedades crónicas autoinmunes raramente relacionadas con el cuadro de pancreatitis aguda y que culminaron en PP. También hicimos una breve revisión acerca de tratamiento, diagnóstico y morfología de las lesiones, así como fisiopatología de la enfermedad. Se resalta la importancia de la inmunohistoquímica y del análisis histopatológico de biopsias de la lesión como herramientas diagnósticas.

Palabras clave:
necrosis grasa; pancreatitis; enfermedad de Crohn; lupus eritematoso sistémico

RESUMO

A paniculite pancreática (PP) é uma manifestação rara de doença pancreática que acomete o tecido adiposo subcutâneo. Relatamos dois casos dessa entidade: uma paciente do sexo feminino, 37 anos, portadora de lúpus eritematoso sistêmico (LES) e uma idosa com doença de Crohn. Ambas manifestações são doenças inflamatórias crônicas autoimunes raramente relacionadas com o quadro de pancreatite aguda e que culminaram em PP. Também fizemos uma breve revisão sobre tratamento, diagnóstico e morfologia das lesões, bem como da fisiopatologia da doença. Destacamos a importância da imuno-histoquímica e da análise histopatológica de biópsias da lesão como ferramentas diagnósticas.

Unitermos:
necrose gordurosa; pancreatite; doença de Crohn; lúpus eritematoso sistêmico

INTRODUCTION

Pancreatic panniculitis (PP), described by Chiari, in 1883, consists of a rare cutaneous manifestation that, as the name indicates, is an inflammatory process of the subcutaneous tissue11 Neves Z, Segura U, Valente A, Pacheco MH, Malhado J. Paniculite: uma manifestação rara de pancreatite aguda. Portuguese J Gastroenterol. 2015; 22(3): 117-20.

2 Fernández-Sartorio C, Combalia A, Ferrando J, et al. Pancreatic panniculitis: a case series from a tertiary university hospital in Spain. Australas J Dermatol. 2018; 59(4): e269-72.
-33 Kalwaniya S, Choudhary P, Aswani Y, Jain S. Pancreatic panniculitis. Indian J Dermatol Venereol Leprol. 2015; 81(3): 282-3.. This cutaneous disorder is generally associated with benign pancreatic diseases, present in just 2%-3% of the cases, principally the acute and the chronic pancreatitis, although it is also found in malignant pancreatic neoplasms11 Neves Z, Segura U, Valente A, Pacheco MH, Malhado J. Paniculite: uma manifestação rara de pancreatite aguda. Portuguese J Gastroenterol. 2015; 22(3): 117-20., 33 Kalwaniya S, Choudhary P, Aswani Y, Jain S. Pancreatic panniculitis. Indian J Dermatol Venereol Leprol. 2015; 81(3): 282-3.

4 Marcos P, Kieselova K, Cunha M. Pancreatic panniculitis. Am J Gastroenterol. 2017; 112(8): 1218.
-55 Requena L, Sánchez Yus E. Panniculitis. Part II. Mostly lobular panniculitis. J Am Acad Dermatol. 2001; 45(3): 325-61; quiz 362-4.. According to Zundler et al. (2017), PP is diagnosed in elderly patients, with mean age of 60 years; however, it can appear at any age due to the different etiologies of the disease, such as pancreatitis, neoplasms, graft rejection, fistulas, trauma, etc. Regarding gender, most cases of PP affect male individuals, perhaps for the highest incidence of chronic pancreatitis in men66 Zundler S, Strobel D, Manger B, Neurath MF, Wildner D. Pancreatic panniculitis and polyarthritis. Curr Rheumatol Rep. 2017; 19(10): 62., 77 Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016; 387: 1957-66..

Although its pathophysiology is still uncertain, it is believed that: 1. the increase in levels of circulating pancreatic enzymes (trypsin, amylase, elastase I and lipase), which triggers subcutaneous fat secondary saponification, is the probable mechanism; 2. in the earliest stages of PP, the endothelial damage provoked by pancreatic enzymes permits their migration to the subcutaneous tissue11 Neves Z, Segura U, Valente A, Pacheco MH, Malhado J. Paniculite: uma manifestação rara de pancreatite aguda. Portuguese J Gastroenterol. 2015; 22(3): 117-20., 33 Kalwaniya S, Choudhary P, Aswani Y, Jain S. Pancreatic panniculitis. Indian J Dermatol Venereol Leprol. 2015; 81(3): 282-3., 88 Laureano A, Mestre T, Ricardo L, Rodrigues AM, Cardoso J. Pancreatic panniculitis - a cutaneous manifestation of acute pancreatitis. J Dermatol Case Rep. 2014; 8(1): 35-7., 99 Johnson MA, Kannan DG, Balachandar TG, Jeswanth S, Rajendran S, Surendran R. Acute septal panniculitis. A cutaneous marker of a very early stage of pancreatic panniculitis indicating acute pancreatitis. JOP. 2005; 6(4): 334-8.; 3. trypsin plays a role in the increase of endothelial permeability and, therefore, would enable the movement of lipase from the intravascular space towards the interstitium11 Neves Z, Segura U, Valente A, Pacheco MH, Malhado J. Paniculite: uma manifestação rara de pancreatite aguda. Portuguese J Gastroenterol. 2015; 22(3): 117-20..

PP histology reveals a typical pattern of foci of liquefactive necrosis of the fat lobules, without presence of vasculitis, with anucleate adipocytes and cytoplasm with granular basophil material corresponding to calcium deposits (“ghost adipocytes”), resulting from saponification reactions. These dead adipocytes are grouped in the most central portion of the subcutaneous nodules, whereas in the periphery there is a polymorphonuclear infiltrate55 Requena L, Sánchez Yus E. Panniculitis. Part II. Mostly lobular panniculitis. J Am Acad Dermatol. 2001; 45(3): 325-61; quiz 362-4..

PP treatment is almost always based on the correction of pancreatitis, allowing reduction in the levels of pancreatic lipolytic enzymes in the bloodstream. Thus, a surgery is commonly required to correct the pancreatic anomaly for an efficient treatment, with the consequent disappearance of symptoms22 Fernández-Sartorio C, Combalia A, Ferrando J, et al. Pancreatic panniculitis: a case series from a tertiary university hospital in Spain. Australas J Dermatol. 2018; 59(4): e269-72., 55 Requena L, Sánchez Yus E. Panniculitis. Part II. Mostly lobular panniculitis. J Am Acad Dermatol. 2001; 45(3): 325-61; quiz 362-4., 1010 Lambiase P, Seery JP, Taylor-Robinson SD, Thompson JN, Hughes JM, Walters JR. Resolution of panniculitis after placement of pancreatic duct stent in chronic pancreatitis. Am J Gastroenterol. 1996; 91(9): 1835-7..

CASE REPORTS

Case 1

Brazilian female mixed-race 37-year-old patient, with a history of chronic kidney disease (CKD) for eight years, on peritoneal dialysis, was diagnosed with systemic lupus erythematosus (SLE) five years before. She denies tobacco use and alcohol consumption. Laboratory tests indicated a rise in amylase and lipase enzymes. The patient was hospitalized with abdominal pain, nausea, vomiting, and multiple painful nodules, of approximately 1-2 cm, with mild erythema in trunk and upper and lower limbs. Biopsies were carried out on the lesions of right arm and thigh. The initial hypotheses were PP (with fat necrosis), lupus panniculitis, poststeroid panniculitis, indurated erythema/nodular vasculitis, erythema nodosum and type 2 leprosy reaction. The final diagnosis was PP triggered by lupus pancreatitis (LP) (Figure 1).

FIGURE 1
Lobular panniculitis compatible with

Case 2

Brazilian 70-year-old female patient, with a 23-year history of Crohn’s disease treated with methotrexate 12.5 mg/day, and CKD treated conservatively. She was hospitalized with complaints of abdominal pain, nausea, vomiting, fever, with asymptomatic nodular lesions disseminated in the trunk and upper and lower limbs, but could not easily tell the time of onset. The lesions were biopsied, and the histopathological report described lobular panniculitis associated with areas of liquefactive necrosis and ghost adipocytes, compatible with PP. Computed tomography (CT) of abdomen and pelvis was performed and revealed jejunal and ileal loops, besides ascending colon with adjacent fat densification. Enlarged pancreas with parenchymal densification was compatible with acute pancreatitis. Subcutaneous nodules of soft-tissue density were also observed in areas of thorax and abdomen (Figure 2).

FIGURE 2
A) lobular panniculitis with inflammatory infiltrate, extensive necrosis, cell debris and saponification with ghost adipocytes, compatible with PP (HE, 40×); B) and C) patient with asymptomatic nodular lesions, sometimes erythematous, disseminated over trunk and upper and lower limbs; D) CT presenting enlarged pancreas, with parenchyma densification and pancreatic fat. Nodules with soft-tissue density in the subcutaneous tissue

DISCUSSION

In case 1, we present a young patient who denies history of use of alcohol, tobacco and other recreational drugs; besides, the presence of choledocholithiasis was discarded, what excluded the two major causes of the disease acute manifestation (80%)1111 de Azevedo ABC, Brito FA, Santos FPST, Ferreira GA, de Carvalho MAP. Lúpus eritematoso sistêmico e pancreatite aguda: relato de dois casos. Rev Bras Reumatol. 2003; 43(3): 194-8.. Although the incidence of acute pancreatitis in individuals with CKD undergoing dialysis is higher than that in the general population, we concluded that the patient had a LP, a rare presentation of SLE, which, in its turn, is a chronic multisystemic autoimmune disease1111 de Azevedo ABC, Brito FA, Santos FPST, Ferreira GA, de Carvalho MAP. Lúpus eritematoso sistêmico e pancreatite aguda: relato de dois casos. Rev Bras Reumatol. 2003; 43(3): 194-8.

12 Barbara M, Tsen A, Rosenkranz L. Acute pancreatitis in chronic dialysis patients. Pancreas. 2018; 47(8): 946-51.
-1313 Alibegovic E, Kurtcehajic A, Hasukic I, Hujdurovic A, Fejzic JA, Kurtcehajic D. Silence pancreatitis in systemic lupus erythematosus. Intractable Rare Dis Res. 2017; 6(2): 141-4..

LP in an uncommon association, with prevalence lower than 4.2% of the SLE cases1414 Wang Q, Shen M, Leng X, Zeng X, Zhang F, Qian J. Prevalence, severity, and clinical features of acute and chronic pancreatitis in patients with systemic lupus erythematosus. Rheumatol Int. 2016; 36(10): 1413-9., 1515 Gayam V, Mandal AK, Khalid M, et al. A rare case of systemic lupus erythematosus with gastric ulcer and acute pancreatitis: a case report and literature review. Gastroenterol Res. 2018; 11(4): 321-5.. Although physiopathology is still uncertain, it is likely related to the immune complex deposition within the walls of pancreatic vessels, leading to vasculitis and, finally, pancreatitis1111 de Azevedo ABC, Brito FA, Santos FPST, Ferreira GA, de Carvalho MAP. Lúpus eritematoso sistêmico e pancreatite aguda: relato de dois casos. Rev Bras Reumatol. 2003; 43(3): 194-8., 1313 Alibegovic E, Kurtcehajic A, Hasukic I, Hujdurovic A, Fejzic JA, Kurtcehajic D. Silence pancreatitis in systemic lupus erythematosus. Intractable Rare Dis Res. 2017; 6(2): 141-4., 1515 Gayam V, Mandal AK, Khalid M, et al. A rare case of systemic lupus erythematosus with gastric ulcer and acute pancreatitis: a case report and literature review. Gastroenterol Res. 2018; 11(4): 321-5.. It is characterized by abdominal pain (in more than 90% of the cases), nausea, vomiting (65%-75% of the cases) and fever (50%); however, the patient was not feverish1313 Alibegovic E, Kurtcehajic A, Hasukic I, Hujdurovic A, Fejzic JA, Kurtcehajic D. Silence pancreatitis in systemic lupus erythematosus. Intractable Rare Dis Res. 2017; 6(2): 141-4., 1616 Li Z, Xu D, Wang Z, et al. Gastrointestinal system involvement in systemic lupus erythematosus. Lupus. 2017; 26(11): 1127-38..

The PL diagnosis is confirmed if the individual presents: elevated serum levels of pancreatic enzymes, evidence in imaging tests, exclusion of toxic metabolic causes and mechanical obstruction of the pancreatic duct1313 Alibegovic E, Kurtcehajic A, Hasukic I, Hujdurovic A, Fejzic JA, Kurtcehajic D. Silence pancreatitis in systemic lupus erythematosus. Intractable Rare Dis Res. 2017; 6(2): 141-4., 1616 Li Z, Xu D, Wang Z, et al. Gastrointestinal system involvement in systemic lupus erythematosus. Lupus. 2017; 26(11): 1127-38.. The patient met all the described criteria. It is worth highlighting that in case 1 the patient presented panniculitis associated with SLE, and not with LP. PP in patients with SLE is an extremely rare event, with less than 10 cases reported in the literature1717 Goyal A, Jain M, Rehberg K, Goodman W, Gertner E. Pancreatic panniculitis in active systemic lupus erythematosus. J Cutan Pathol. 2019; 46(9): 688-90.

18 Simons-Ling N, Schachner L, Penneys N, Gorman H, Zillereulo G, Strauss J. Childhood systemic lupus erythematosus. Association with pancreatitis, subcutaneous fat necrosis, and calcinosis cutis. Arch Dermatol. 1983; 119(6): 491-4.
-1919 Feuer J, Spiera H, Phelps RG, Shim H. Panniculitis of pancreatic disease masquerading as systemic lupus erythematosus panniculitis. J Rheumatol. 1995; 22(11): 2170-2..

In case 2, we have a patient without history of alcohol consumption or biliary lithiasis, but with Crohn’s disease for more than 20 years. As well as SLE, Crohn’s disease is an autoimmune inflammatory disease with severe intestinal damage, although it may also present extraintestinal manifestations, being a very uncommon cause of acute pancreatitis too88 Laureano A, Mestre T, Ricardo L, Rodrigues AM, Cardoso J. Pancreatic panniculitis - a cutaneous manifestation of acute pancreatitis. J Dermatol Case Rep. 2014; 8(1): 35-7., 1414 Wang Q, Shen M, Leng X, Zeng X, Zhang F, Qian J. Prevalence, severity, and clinical features of acute and chronic pancreatitis in patients with systemic lupus erythematosus. Rheumatol Int. 2016; 36(10): 1413-9.. The leading causes of acute pancreatitis in patients with Crohn’s disease are gallstones and certain medications used in the treatment of Crohn’s disease2020 Jasdanwala S, Babyatsky M. Crohn's disease and acute pancreatitis. A review of literature. JOP. 2015; 16(2): 136-42.. Thus, we point towards a possible drug association, given that the presence of gallstones was excluded.

The PP lesions occur mainly in lower limbs, less frequently in abdomen, upper limbs, trunk, breasts, buttocks and scalp11 Neves Z, Segura U, Valente A, Pacheco MH, Malhado J. Paniculite: uma manifestação rara de pancreatite aguda. Portuguese J Gastroenterol. 2015; 22(3): 117-20., 88 Laureano A, Mestre T, Ricardo L, Rodrigues AM, Cardoso J. Pancreatic panniculitis - a cutaneous manifestation of acute pancreatitis. J Dermatol Case Rep. 2014; 8(1): 35-7.. These lesions present as tender plaques and edematous and erythematous nodules, which measure 1-2 cm in diameter99 Johnson MA, Kannan DG, Balachandar TG, Jeswanth S, Rajendran S, Surendran R. Acute septal panniculitis. A cutaneous marker of a very early stage of pancreatic panniculitis indicating acute pancreatitis. JOP. 2005; 6(4): 334-8.. In milder cases, the nodule can be single and resolve without the presence of ulcerations, as soon as the pancreatic inflammation recedes. Moreover, these nodules may evolve into necrotic abscesses with spontaneous ulceration, presence of exudate of an oily brown material due to liquefactive fat necrosis55 Requena L, Sánchez Yus E. Panniculitis. Part II. Mostly lobular panniculitis. J Am Acad Dermatol. 2001; 45(3): 325-61; quiz 362-4., 99 Johnson MA, Kannan DG, Balachandar TG, Jeswanth S, Rajendran S, Surendran R. Acute septal panniculitis. A cutaneous marker of a very early stage of pancreatic panniculitis indicating acute pancreatitis. JOP. 2005; 6(4): 334-8..

Panniculitis can be traditionally divided into septal, lobular and mixed (septal and lobular), what permits a better individual diagnosis of the disease. This classification, however, is only useful when panniculitis is histologically fully developed, as during its progression, it keeps altering itself. Studies propose that, despite PP is predominantly of the lobular type, it begins in a septal form, with a lymphoplasmatic infiltrate in the septa that involve fatty lobules and blood vessels2121 Reed RJ, Clark WH, Mihm MC. Disorders of the panniculus adiposus. Hum Pathol. 1973; 4(2): 219-29., 2222 de Souza FHM, Siqueira EBD, Mesquita L, Fabricio LZ, Tuon FF. Paniculite pancreática como a primeira manifestação de doença visceral: relato de caso. An Bras Dermatol. 2011; 86(4): 125-8.. Consequently, as it evolves, the lesions, in a more advanced stage, take the lobular form, with predominantly granulomatous infiltrate, composed mainly of histiocytes, hemosiderin deposits and giant polynucleated cells. Later, this picture becomes a fibrosis2121 Reed RJ, Clark WH, Mihm MC. Disorders of the panniculus adiposus. Hum Pathol. 1973; 4(2): 219-29., 2323 García-Romero D, Vanaclocha F. Pancreatic panniculitis. Dermatol Clin. 2008; 26(4): 465-70.. In both studied cases, there is evidence of “advanced” process, due to hemorrhage, infiltrate of histiocytes and neutrophils, associated with areas of enzymatic necrosis, and with ghost adipocytes.

CONCLUSION

We presented unique and well-illustrated cases of PP, triggered by SLE and Crohn’s disease. We highlight the importance of the histopathological correlation of cutaneous lesions with the clinical picture to confirm the diagnostic hypothesis.

REFERENCES

  • 1
    Neves Z, Segura U, Valente A, Pacheco MH, Malhado J. Paniculite: uma manifestação rara de pancreatite aguda. Portuguese J Gastroenterol. 2015; 22(3): 117-20.
  • 2
    Fernández-Sartorio C, Combalia A, Ferrando J, et al. Pancreatic panniculitis: a case series from a tertiary university hospital in Spain. Australas J Dermatol. 2018; 59(4): e269-72.
  • 3
    Kalwaniya S, Choudhary P, Aswani Y, Jain S. Pancreatic panniculitis. Indian J Dermatol Venereol Leprol. 2015; 81(3): 282-3.
  • 4
    Marcos P, Kieselova K, Cunha M. Pancreatic panniculitis. Am J Gastroenterol. 2017; 112(8): 1218.
  • 5
    Requena L, Sánchez Yus E. Panniculitis. Part II. Mostly lobular panniculitis. J Am Acad Dermatol. 2001; 45(3): 325-61; quiz 362-4.
  • 6
    Zundler S, Strobel D, Manger B, Neurath MF, Wildner D. Pancreatic panniculitis and polyarthritis. Curr Rheumatol Rep. 2017; 19(10): 62.
  • 7
    Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016; 387: 1957-66.
  • 8
    Laureano A, Mestre T, Ricardo L, Rodrigues AM, Cardoso J. Pancreatic panniculitis - a cutaneous manifestation of acute pancreatitis. J Dermatol Case Rep. 2014; 8(1): 35-7.
  • 9
    Johnson MA, Kannan DG, Balachandar TG, Jeswanth S, Rajendran S, Surendran R. Acute septal panniculitis. A cutaneous marker of a very early stage of pancreatic panniculitis indicating acute pancreatitis. JOP. 2005; 6(4): 334-8.
  • 10
    Lambiase P, Seery JP, Taylor-Robinson SD, Thompson JN, Hughes JM, Walters JR. Resolution of panniculitis after placement of pancreatic duct stent in chronic pancreatitis. Am J Gastroenterol. 1996; 91(9): 1835-7.
  • 11
    de Azevedo ABC, Brito FA, Santos FPST, Ferreira GA, de Carvalho MAP. Lúpus eritematoso sistêmico e pancreatite aguda: relato de dois casos. Rev Bras Reumatol. 2003; 43(3): 194-8.
  • 12
    Barbara M, Tsen A, Rosenkranz L. Acute pancreatitis in chronic dialysis patients. Pancreas. 2018; 47(8): 946-51.
  • 13
    Alibegovic E, Kurtcehajic A, Hasukic I, Hujdurovic A, Fejzic JA, Kurtcehajic D. Silence pancreatitis in systemic lupus erythematosus. Intractable Rare Dis Res. 2017; 6(2): 141-4.
  • 14
    Wang Q, Shen M, Leng X, Zeng X, Zhang F, Qian J. Prevalence, severity, and clinical features of acute and chronic pancreatitis in patients with systemic lupus erythematosus. Rheumatol Int. 2016; 36(10): 1413-9.
  • 15
    Gayam V, Mandal AK, Khalid M, et al. A rare case of systemic lupus erythematosus with gastric ulcer and acute pancreatitis: a case report and literature review. Gastroenterol Res. 2018; 11(4): 321-5.
  • 16
    Li Z, Xu D, Wang Z, et al. Gastrointestinal system involvement in systemic lupus erythematosus. Lupus. 2017; 26(11): 1127-38.
  • 17
    Goyal A, Jain M, Rehberg K, Goodman W, Gertner E. Pancreatic panniculitis in active systemic lupus erythematosus. J Cutan Pathol. 2019; 46(9): 688-90.
  • 18
    Simons-Ling N, Schachner L, Penneys N, Gorman H, Zillereulo G, Strauss J. Childhood systemic lupus erythematosus. Association with pancreatitis, subcutaneous fat necrosis, and calcinosis cutis. Arch Dermatol. 1983; 119(6): 491-4.
  • 19
    Feuer J, Spiera H, Phelps RG, Shim H. Panniculitis of pancreatic disease masquerading as systemic lupus erythematosus panniculitis. J Rheumatol. 1995; 22(11): 2170-2.
  • 20
    Jasdanwala S, Babyatsky M. Crohn's disease and acute pancreatitis. A review of literature. JOP. 2015; 16(2): 136-42.
  • 21
    Reed RJ, Clark WH, Mihm MC. Disorders of the panniculus adiposus. Hum Pathol. 1973; 4(2): 219-29.
  • 22
    de Souza FHM, Siqueira EBD, Mesquita L, Fabricio LZ, Tuon FF. Paniculite pancreática como a primeira manifestação de doença visceral: relato de caso. An Bras Dermatol. 2011; 86(4): 125-8.
  • 23
    García-Romero D, Vanaclocha F. Pancreatic panniculitis. Dermatol Clin. 2008; 26(4): 465-70.

Publication Dates

  • Publication in this collection
    23 Apr 2021
  • Date of issue
    2021

History

  • Received
    31 Mar 2020
  • Reviewed
    05 Apr 2020
  • Accepted
    05 Apr 2020
  • Published
    20 Mar 2021
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