Pancreatic panniculitis caused by pancreatic acinar cell carcinoma: A case report and literature review

Pancreatic acinar cell carcinoma (PACC) is a rare type of pancreatic tumor with a dismal prognosis, which accounts for <2% of all exocrine pancreatic malignancies.1 Due to its low incidence, PACC is frequently misdiagnosed or diagnosed at the advanced stage, leading to a low surgical resection rate and poor patient survival. In addition to its nonspecific symptoms such as abdominal pain, weight loss, and jaundice that can also be observed in other pancreatic neoplasms, PACC also presents with skin manifestations in the form of pancreatic panniculitis (PP). PP refers to inflammation involving the subcutaneous fat tissues secondary to pancreatic inflammation or neoplasms.2 It is characterized by tender, erythematous subcutaneous nodules distributed over the lower extremities, upper extremities, and trunk.3 PP can also be found in cases of acute or chronic pancreatitis and pancreatic pseudocysts. Here we report a rare case of PACC complicated by PP and conducted a literature review for published cases, aiming to raise clinical awareness and provide diagnostic clues for this fatal disease. A 59-year-old female was admitted to our hospital on July 1, 2022, complaining of painful, erythematous, scattered nodules for one month that had been worsening despite initial treatment with topical corticosteroids and oral nonsteroidal anti-inflammatory drugs (NSAIDs). The lesions first appeared on both lower extremities before spreading upwards to her thighs, buttocks, and upper limbs. The largest lesion measured 10 cm in diameter (Figure 1). She also reported fatigue and bilateral leg edema but without arthralgia, abdominal pain, or fever, though she had unintentional weight loss of 8 kg during the past 2 weeks. On physical examination, she had multiple tender, erythematous subcutaneous nodules distributed over her lower back, legs, and arms. A skin biopsy of the lesion of the right calf revealed diffuse lymphohistiocytic infiltration in the subcutaneous fat lobules and septa, with visible fat necrosis and ghost cells, which was consistent with the diagnosis of PP (Figure 2). Serum laboratory tests showed an elevated high-sensitivity C-reactive protein (hsCRP) of 97.40 mg/L and lipase of 11 158 U/L, and the level of cancer antigen 19–9 (CA19–9) was within the normal range. Contrast-enhanced computed tomography (CT) showed a mixed solid–cystic mass lesion in the tail of the pancreas and tumor thrombus in the portal vein and its branches (Figure 3). Positron emission tomography computed tomography (PET-CT) showed a hypermetabolic pancreas with a cystic mass in the tail (standardized uptake value maximum [SUVmax] 4.3) and hypermetabolic thrombus in the portal vein (SUVmax 4.4). Ultrasound-guided biopsy of the pancreatic mass confirmed the diagnosis of PACC (Figure 4). Surgery was not considered the primary treatment due to the presence of tumor thrombosis in the portal vein. During hospitalization, the patient showed a strong inclination toward further treatment. Unfortunately, she only received palliative care and passed away 6 months after discharge without any chemotherapy or targeted therapy. PP is a rare complication that occurs in 2%–3% of patients with pancreatic disease. It was first reported by Chiari in 1883 who first identified subcutaneous fat necrosis and inflammation associated with underlying pancreatic pathology.4 Since then, PP has been reported in hundreds of cases of pancreatitis and pancreatic cancer worldwide. The diagnosis of PP depends primarily on skin biopsy, with over 90% of biopsy samples demonstrating characteristic findings of fat necrosis with ghost cells, saponification, calcification, and infiltration of neutrophils and lymphocytes.5 Interestingly, fat necrosis is not limited to the skin and can involve fat tissues throughout the body as confirmed by autopsy. This suggests that PP represents a cutaneous manifestation of a systemic processs.6 Advanced stage at diagnosis is common in PACC due to its nonspecific symptoms. We then conducted a literature search in the PubMed, Web of Science, CNKI, and SinoMed databases to identify all reported cases of pancreatic neoplasms, especially PACC associated with PP, published from 1970 to March 1, 2023. The search terms were "(pancreatic neoplasms OR pancreatic carcinoma) AND (panniculitis OR subcutaneous fat necrosis)." Finally, a total of 62 English-language reports and 7 Chinese reports were identified, comprising 78 patients. Clinical data extracted from each case included demographics, symptoms and signs, site and features of the skin lesions, histopathological features of both the pancreatic tumor and skin biopsy samples, serum markers, surgical intervention, follow-up, and patient survival. Among these 79 cases (including our case) (Table 1), PP affected males more than females at a ratio of 1.7:1, with a median age of 63.5 years at diagnosis. The majority (97.5%) of patients presented with multiple tender erythematous nodules, typically on the lower limbs (56.4% also involved the upper limbs or trunk). The nodules were usually 5 cm or less in diameter and associated with focal pain. Although skin manifestations preceded other symptoms in 60.7% of cases, accurate diagnosis of PP was sometimes missed or delayed due to misdiagnosis such as infections, vasculitis, or atypical panniculitis. PP tends to recur despite temporary improvement, warranting close surveillance and screening for pancreatic malignancy, especially in those with persistently elevated lipase level. Although current studies do not specify exact follow-up intervals, we recommend outpatient follow-up to be conducted every 3 months within the first year after disease onset due to the poor prognosis of PACC. An immediate clinical visit is required if there is a deterioration in condition, such as the emergence of new-onset nodules or symptoms. Beyond cutaneous findings, patients frequently reported abdominal pain (25.3%), weight loss (22.8%), fever (16.5%), and jaundice (1.3%). Arthritis occurred in 27.8% of the cases, which was less frequent than those in previous reports (54%–88%) of patients with PP and underlying pancreatitis.7 Elevated lipase of synovial fluid and disseminated fat necrosis in 35% of cases suggest a shared pathophysiological mechanism underlying the joint and cutaneous manifestations,7 which requires further study. To make an accurate diagnosis, skin biopsy is necessary, which typically shows infiltration of focal histiocytes, neutrophils, and lymphocytes, including characteristic ghost cells formed from coagulation necrosis. Focal lobular fat necrosis and saponification may also be seen, but there is no evidence of vasculitis. Pancreatic tumor is one of the predominant etiologies of PP, which is located mainly in the tail (48.2% [27/56]) and head (35.7% [20/56]) of the pancreas. PACC was the most common pathologic type, which was identified in 54.5% (36/66) of cases. Though as a rare exocrine malignancy comprising <1% of pancreatic tumors, PACC was found in over half the cases, suggesting unique pathobiological features that may predispose to panniculitis. Pancreatic ductal adenocarcinoma (PDAC) was found in 15.2% (10/66) of cases. As the most common pancreatic exocrine tumor, its low frequency of developing panniculitis suggests that PDAC less commonly induces the inflammation, necrosis, and pancreatin release required to trigger skin manifestations and fat necrosis. Except for PACC and PDAC, 12.1% (8/66) of cases resulted from pancreatic endocrine tumors, which typically lack lipase secretion but may display acinar differentiation in some cases enabling pancreatin release. Additional 18.2% of cases were linked to rare neoplasms such as solid pseudopapillary neoplasm and intraductal papillary mucinous neoplasm. Two cases arose from ectopic pancreatic tissue in the duodenum or pancreas-type hepatocellular lesions.8, 9 Panniculitis also occurred with ampullary carcinoma infiltrating the pancreas (n = 1)10 and gastric carcinoma infiltrating the pancreas (n = 1),11 suggesting that local organ involvement and inflammation may induce pancreatitis and pancreatin release. Elevated lipase in most cases supports the proposed pathophysiology of increased circulating pancreatin due to pancreatic pathology, which raises vascular permeability and hydrolyzes fat into fatty acids and glycerol, culminating in fat necrosis and panniculitis.12 However, normal lipase level in one case suggests that other mechanisms or inadequate pancreatin degradation may also play a role in the disease.13 Skin predilection of the limbs remains unexplained, but may indicate site-specific factors. Our observation during the hospitalization revealed that the patient had developed panniculitis in the areas of friction and compression, showing that the emergence of panniculitis could be linked to physical elements such as pressure and trauma. PACC is highly malignant, and most patients have already developed tumor metastases at diagnosis. The overall poor prognosis of 4.75 months in pancreatic malignancy-related PP may reflect the advanced stage of disease at diagnosis.14 As a systemic skin manifestation of PACC, treatment targeting the primary tumor may improve PP. Moreover, surgical resection of the primary tumor or metastasectomy resulted in panniculitis resolution in some cases.6, 15-17 Palliative chemotherapy, radiotherapy, or octreotide provided symptomatic relief and postponed disease progression with panniculitis improvement,15, 18 highlighting the relationship between panniculitis and tumor relapse. Platinum-based chemotherapy was chosen for pancreatic cancer with a somatic BRCA2 mutation, with reports of improved progression-free survival and panniculitis remission under maintenance therapy with olaparib.19 Transarterial chemoembolization of liver metastases also alleviated panniculitis in some cases. Analgesia, especially narcotics, was required for the treatment of intolerable pain in some cases,14 but not yet needed in our patient. However, topical steroids provided little benefit. Panniculitis recurrence or emergence sometimes precedes clinical evidence of disease progression, highlighting its potential as an indicator of treatment efficacy or marker for close monitoring.20 Improved panniculitis may predict better outcome or guide therapeutic decision-making, as the underlying pathology inciting local and systemic inflammation is targeted.11 Further studies are needed to determine whether resolution of skin lesions conclusively signifies disease control or longer survival. Our patient was found to have advanced PACC at the presence of PP. Regarding the differential diagnosis of skin lesions before pancreatic etiologies were confirmed, potential pathologies to consider include skin infection, allergy, nodular erythema, subcutaneous panniculitis-like T-cell lymphoma, and cutaneous metastases of malignancies. Therefore, skin biopsy is crucial for a confirmed diagnosis. Upon confirmation of PP, a variety of pancreatic diseases including acute or chronic pancreatitis, pancreatic pseudocyst, congenital pancreatic divisum, and vascular pancreatic fistula, should be considered. Although these conditions can easily be ruled out in our case, it is essential to consider these when initially evaluating patients with PP before obtaining definitive pathologic results. In conclusion, PP may occur in various pancreatic pathologies. It is also a rare complication that can provide critical clues that results in an early diagnosis of pancreatic carcinoma. Characterized by "ghost cells" and saponification, calcification, and infiltration of neutrophils and lymphocytes on histology, panniculitis tends to parallel disease activity with emergence or recurrence signaling potential progression. PACC is the predominant cause of PP, while elevated lipase in most cases supports pancreatin-mediated fat necrosis as the mechanism. Supportive treatment provides symptomatic relief, but resolution relies upon targeting the primary disease such as surgery, chemotherapy, or octreotide. This report highlights the need for clinicians to recognize panniculitis as a sign of underlying pancreatic disease that warrants further investigation. This work was supported by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-022).