Diagnostic Dilemma: Pancreatic Panniculitis

Department Editor: Tania Phillips, MD, FRCPC Overall Learning Objective: The physician or podiatrist participant will develop a rational approach to the evaluation and treatment of a variety of uncommon wounds and will have an increased awareness of the differential diagnosis of cutaneous wounds and the systemic diseases associated with these wounds. Submissions: To submit a case for consideration in Diagnostic Dilemmas, e-mail or write to: Executive Editor, WOUNDS, 83 General Warren Blvd., Suite 100, Malvern, PA 19355, eklumpp@hmpcommunications.com Completion Time: The estimated time to completion for this activity is 1 hour. Target Audience: This CME/CPME activity is intended for dermatologists, surgeons, podiatrists, internists, and other physicians who treat wounds. At the conclusion of this activity, the participant should be able to: 1) Generate a differential diagnosis when panniculitis is suspected 2) Describe and discuss illnesses that are associated with pancreatic panniculitis 3) Describe and discuss the management of a patient with pancreatic panniculitis. Disclosure: All faculty participating in Continuing Medical Education programs sponsored by HMP Communications are expected to disclose to the program audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Federman, McNiff, and Kirsner disclose that they have no financial conflicts relevant to the content of this activity. Accreditation: HMP Communications is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine. Designation: HMP Communications designates this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association. Each physician should claim only those hours he/she spent in the educational activity. HMP Communications designates this continuing medical activity for .1 CEUs available to participating podiatrists. Method of Participation: Participants must read the article and take, submit, and pass the post-test by April 15, 2005. Participants must completely fill out the answer and evaluation form, answer at least 70 percent of the questions correctly, and mail or fax the answer/evaluation forms to: Trish Levy, CME Director, HMP Communications, Suite 100, 83 General Warren Blvd., Malvern, PA 19355 Fax (610) 560-0501 This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Release date: April 15, 2004 Expiration date: April 15, 2005 Presentation A 67-year-old man was admitted to the hospital after complaining of painful lower-extremity ulcers and two days of fever. One month prior to admission, he developed a raised, red, nodular lesion on his right lateral foot and over the next few weeks developed multiple other similar lesions on his lower extremities and forearms, as well as painful bilateral lower-extremity swelling. He was recently treated with a course of antibiotics for presumed cellulitis of his lower extremities at another facility without improvement. During that time, he complained of diffuse abdominal pain and a 20-pound weight loss. A computerized tomography (CT) scan was obtained and revealed a pancreatic mass; a subsequent biopsy performed during upper endoscopy with ultrasound guidance was reportedly negative for malignancy. His past medical history was significant for a remote history of alcohol abuse, hypertension, and peripheral vascular disease. His surgical history included a left femoral-popliteal lower-extremity bypass procedure six years before presentation and repair of a cerebral aneurysm 11 years prior to presentation. His medications included felodipine and aspirin, and he denied any known medication allergies. He denied illicit drug use but admitted to heavy alcohol consumption in the past, though he stated that he recently drank 1 to 2 cans of beer daily. He smoked one pack of cigarettes per day and had a 40-pack year smoking history. Physical Examination Physical examination revealed a cachectic, elderly, slightly confused man in no apparent distress. He had temporal wasting and bilateral knee contractures. He was afebrile, had a blood pressure of 152/72mmHg, a pulse of 58 beats/minute, a respiratory rate of 20 per minute, and a room air oxygen saturation of 96 percent by pulse oximetry. His neck, cardiac, and chest examinations were normal. Although no midline abdominal mass was appreciated, his liver was measured to be 14cm. There were multiple, nontender, deep-pink, nonblanching nodules measuring 1 to 7cm distributed bilaterally and symmetrically over the trunk and proximal extremities. No suppuration or ulceration was noted. Also noted was a purple-red retiform purpura with retiform central black eschars over the knees and right heel (Figures 1A and B). There was trace bilateral pedal edema. His dorsalis pedis pulses were not palpable but were present by Doppler. Investigations Admission laboratory analysis was significant for a serum sodium of 130mmol/L, aspartate aminotransferase (AST) of 289 U/L (normal 10–445U/L), alanine aminotransferase (ALT) 202 U/L (normal 7–52U/L), alkaline phosphatase 215 U/L (normal 30–115U/L), and a total bilirubin 1.4 mg/dL. His amylase was 3278 U/L (normal 20–105U/L), and lipase 3497 U/L (normal 11–82 U/L) were markedly elevated. The serum calcium was 7.4mg/dL, and serum albumin was 2.0g/dL. A complete blood count revealed a white blood cell count of 24.5K/cmm, hemoglobin of 9.2g/dL, hematocrit of 27.2 percent, and platelet count of 534K/cmm. The sedimentation rate was greater than 140mm/hr. Urinalysis, renal function, serum potassium, and other electrolytes were unremarkable. Chest radiographs were unremarkable. A CT scan of the abdomen revealed heterogeneity of the pancreatic head and neck with large, coarse calcifications within the pancreatic head and uncinate process. A hypodensity and infiltrative changes were noted to surround the superior mesenteric vein and were associated with mass effect and extended into the mesentery. A lobulated and heterogenous mass-like material was noted within the mesenteric root and midline mesentery. A bilobed mass with necrosis measuring 7.7 by 2.5cm was noted in the anterior mesentery. A similar mass measuring 6.8 by 3.1cm was noted along the right colon. No ascites was noted. The liver and spleen were unremarkable. An excisional biopsy of a lesion on the upper chest demonstrated necrosis of the fat surrounded by a palisade of neutrophils and histiocytes. Necrotic lipocytes with thick cell membranes formed characteristic ghost cells. Calcification of the fat was present (Figures 2–4). Diagnosis The clinical history of abdominal pain, markedly elevated serum amylase and lipase levels, abnormal CT scan of the pancreas, histologic findings typical of pancreatic panniculitis, and compatible skin lesions led to the diagnosis of pancreatic panniculitis. The patient’s pancreatic disease was felt to be either due to pancreatitis or pancreatic malignancy. Discussion Panniculitis is an inflammatory reaction of adipose tissue and can primarily involve the fat lobules or the septa between lobules. Several forms of panniculitis exist and are listed in Table 1. The most commonly encountered form of panniculitis is erythema nodosum. This reactive septal panniculitis usually presents with tender, deep-seated, contusion-like plaques on the shins with palpable cutaneous and subcutaneous nodules. The lesions are self-limited and resolve completely. Often there are associated arthralgias, malaise, fever, chills, and leukocytosis. On biopsy, initially neutrophils are seen at the edges of the septa; this is followed by a proliferation of small vessels and fibroblasts. Later, granulomatous inflammation and fibrosis are seen.[1] It is important for clinicians to recognize that although erythema nodosum may be idiopathic, it is more often associated with another condition, such as infection (streptococci, yersinia, chlamydia, salmonella, tuberculosis, histoplasmosis, coccidiomycosis, psittacosis, leprosy), medications (oral contraceptives, sulfonamides), sarcoidosis, Behçet’s disease, malignancies (leukemia, lymphoma), and inflammatory bowel disease.[2] Erythema induratum, also known as nodular vasculitis, is a less common entity that often presents with chronic, recurrent, tender, subcutaneous nodules or plaques on the lower extremities. Unlike erythema nodosum, this entity has more of a predilection for calf involvement than the shin area, may ulcerate, and may heal with scarring. Erythema induratum has been associated with tuberculosis, and a thorough history, physical examination, and appropriate testing (purified protein derivative, chest radiograph) should be employed to rule out tuberculous infection. Biopsy of these lesions reveals evidence of a lobular granulomatous panniculitis with varying degrees of necrosis, vasculitis, and tuberculoid granulomas.[3] Using polymerase chain reaction (PCR) amplification, mycobacterium tuberculosis DNA can be found in these lesions.[4] Lupus profundus, also known as lupus panniculitis, is seen in patients with systemic lupus erythematosus and typically presents with multiple, tender, painful nodules on the face, upper arms, breasts, or buttocks. Usually, the overlying skin is normal, though lesions may ulcerate. A characteristic atrophy of the subcutaneous tissue may be a late finding when lesions resolve. On histopathology, a dense lobular infiltrate of lymphocytes, plasma cells, and histiocytes associated with fat necrosis are found. Alpha1-antitrypsin deficiency is an under-recognized disease caused by decreased hepatic production of a proteinase inhibitor that inhibits both trypsin and other serine proteinases, such as elastase. In addition to cirrhosis and/or emphysema, afflicted patients may have evidence of panniculitis manifested by recurrent, tender, erythematous, subcutaneous, ulcerating nodules on the trunk and proximal extremities.[5] Weber-Christian disease, also known as idiopathic lobular panniculitis or relapsing febrile nodular panniculitis, is characterized by tender skin nodules often associated with constitutional symptoms, such as fever, arthralgia, and myalgias. While more common in women, especially between the ages of 30 and 60, this disease has been seen in all ages, even in infancy.[6] Lesions typically are erythematous, edematous, subcutaneous nodules and are often seen to occur symmetrically in the thighs and lower legs, though they may be seen in the upper extremities, breasts, buttocks, trunk, and face. Fat necrosis of individual lesions may eventuate in a hyperpigmented atrophic scar. Though this form of panniculitis is classically thought of as a lobular panniculitis, septal as well as lobular involvement may occur. Affected patients may have an elevated erythrocyte sedimentation rate, anemia, leukocytosis or leukopenia, thrombocytopenia, and hypocomplementemia.[7] The usual course of patients with this malady is one of frequent remissions and exacerbations with eventual permanent remission after several years. Rarely, however, Weber-Christian disease can be a severe systemic illness, which can be fatal due to panniculitis involving the heart, liver, lungs, or kidneys.[7] Pancreatic disease has been associated with lobular panniculitis. As early as 1883, pancreatic disease was found to be associated with subcutaneous fat necrosis.[8] Several pancreatic diseases have been found to occur in association with pancreatic panniculitis, such as acute or chronic pancreatitis, pancreatic pseudocyst, pancreatic islet cell tumors, ductal adenocarcinoma, and acinar-cell carcinoma.[9] While some have postulated that this syndrome has an immunologic cause,[10] it is widely thought that circulating lipase and amylase released from the diseased pancreas causes these lesions via enzymatic destruction of fat. To support this hypothesis, Dhawan, et al.,[11] demonstrated intracellular staining of adipocytes with a monoclonal antibody against pancreatic lipase in this condition. Pancreatic panniculitis is usually seen in the lower legs and may be either painful or painless. There are no clinical differences in the character of the subcutaneous nodules between the cases seen with pancreatic malignancy and those seen with benign pancreatic disease. When associated with pancreatic malignancy, acinar-cell carcinoma, an uncommon tumor, appears to be a much more common cause than ductal adenocarcinoma.[12] These tumors usually present with distant metastases from an occult malignancy.[13] Treatment Treatment of pancreatic panniculitis is mainly directed at treating the underlying pancreatic disease (e.g., bowel rest and nutritional support for alcohol-induced pancreatitis, surgery for gallstone pancreatitis, resection for operable pancreatic cancer, etc.). Chemotherapy or radiation therapy can be considered for inoperable pancreatic cancer in an effort to reduce serum lipase and decrease the development of painful subcutaneous lesions.[9] Patient Management The patient was admitted to the medical service, and intravenous amoxicillin/sulbactam was started. His necrotic eschars were debrided and treated with topical silver sulfadiazine. An upper endoscopy revealed changes consistent with acute and chronic esophogitis. Multiple biopsies of the esophagus, stomach, and small intestine were negative for malignancy. His hospital course was complicated by recurrent fevers and respiratory decompensation with the development of the adult respiratory distress syndrome (ARDS). He was felt to be too ill to undergo CT-guided biopsy of his pancreas. He complained of persistent pain in his lower extremities, and morphine was administered intravenously. He continued to deteriorate and expired on the 25th hospital day. At autopsy, the peritoneal cavity contained 300ccs of a serous fluid. The pancreas appeared edematous and showed extensive areas of fat necrosis and calcifications, which extended to the adjacent adipose tissue forming multiple adhesions involving the pancreas, duodenum, and transverse colon mesentery. Microscopic examination of the pancreas and adjacent tissue revealed extensive fat necrosis with marked calcium deposits. These changes were felt to be due to acute and chronic pancreatitis. Pancreatic Panniculitis Answer and Evaluation Form Please print clearly: Name Degree Position/Title Organization/Institute Department Mailing Address for Certificate (H or W): City State Zip Code Email Address Social Security Number Phone (area code) Fax (area code) Answers (Refer to questions below.) Circle one letter for each answer: 1. A B C D E 2. A B C D E 3. A B C D E 4. A B C D E 5. A B C D E F Evaluation (circle one) Excellent (4) Good (3) Satisfactory (2) Poor (1) Accuracy and timeliness of content: 4 3 2 1 Relevance to your daily practice: 4 3 2 1 Impact on your professional effectiveness: 4 3 2 1 Relevance of the content to the learning objectives: 4 3 2 1 Effectiveness of the teaching/learning methods: 4 3 2 1 This activity avoided commercial bias or influence YES NO Now that you have read this article, can you: 1) Generate a differential diagnosis when panniculitis is suspected? YES NO 2) Describe and discuss illnesses that are associated with pancreatic panniculitis? YES NO 3) Describe and discuss the management of a patient with pancreatic panniculitis? YES NO What questions do you still have?_______________________________________ How will you use what you have learned from this activity?_____________________ All tests must be received by 4/15/05.