A 46-year-old white woman was admitted to the Institute of Rheumatology (June 2017), because of a painful subcutaneous nodule on her face (right masseteric cheek) with erythema in overlying skin associated with fever, oral aphthous ulcers, arthralgia/arthritis, myalgia, dry eyes and mouth, Raynaud's phenomenon and generalized weakness. This condition started in 2002. From 2002 to 2017, she had biyearly flares of panniculitis. In 2017 flares recurred every month. Initially, the nodules spontaneously withdrew. Later, she received anti-inflammatory, local anti-edematous, and antibiotic therapy, as well as large or small doses of corticosteroids with no improvement. Also, she had multiple palpable subcutaneous masses on the surface on her body (lower trunk, arms and upper legs) since 2013. These tumours were symmetrical, painless, with a consistence suggestive of lipomas, but unlike the lipomas, they were not encapsulated.
Personal history revealed depression since 2008, high cholesterol and triglycerides since 2010, left adnexectomy and right salpingectomy in 2012 due to left tubo-ovarian abscess and bilateral pyosalpinx, radical hysterectomy in 2015 due to chronic salpingitis and oophoritis, and allergy to penicillin. There was no known tubercular contact or a family history of a similar disorder.
Clinical examinations revealed circumscribed mass in the right masseteric space, ovoid in shape, firm, tender with mild erythema in overlying skin, no fluctuation, with a dimple in the center, as well as bilateral, symmetric, soft, well-circumscribed round subcutaneous masses involving lower trunk, forearms and upper legs. These masses varied in size from 1 cm x 1 cm to 6 cm x 4 cm (Fig. 1a-b). Her body height was 172 cm, body weight was 69.3 kg and body mas index was 23.4 kg/m2. The percentage of fat was 34.9%, and fat mass was 24.2 kg (normal range 23–34%, vs 13.5–23.2 kg, respectively, Tanita analyzer). Complete blood cell count, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies (ANA), anti-neutrophilic cytoplasmic autoantibody, anticyclic citrullinated peptide, rheumatoid factor, anti Ro/SSA, anti La/SSB antibody, anticardiolipin antibody, anti-beta 2 glycoprotein-I antibody, cryoglobulins, immunoglobulin assay, protein electrophoresis, immunoelectrophoresis, IgG4, C1 inhibitor and C1q, circulating immune complexes, complement C3 and C4 levels, serum amylase, alpha 1-antitrypsin, angiotensin-converting enzyme, were all negative/normal. The renal functions and the electrolytes were also all normal. The urine was free of any sediments or protein. HLA B51 was negative. Hepatitis B and hepatitis C virus, HIV, Brucella abortus bovis test and dirofilaria repens test were negative. The chest radiograph and the abdominal ultrasonography were normal.
Salivary 99m Tc-pertechnetate scintigraphy showed decreased accumulation an excretory function in both parotid and submandibular glands. A salivary gland biopsy showed nonspecific sialoadenitis gradus 0. Lissamine green and Schirmerˈs test were negative. Capillaroscopy was normal. Dual-energy X-ray absorptiometry scanning showed osteopenia (T-score of total hip was − 1.0, and spine − 1.4). Ultrasound of the forearm showed subcutaneous masses of nonencapsulated adipose tissue with internal vascularity (Fig. 2a-b).
A skin biopsy (right masseteric cheek) showed intact and normal epidermis. The subcutaneous fat showed focal lobular lymphocytic infiltration around small blood vessels along with slightly widened interlobular septum with rare epithelioid granulomas (Fig. 3a). Granulomas were composed solely of epithelioid histiocytes, without necrosis or giant cells and rare granulomas were surrounded with lymphocytes (Fig. 3b). Focally, small areas of fat cell necrosis and foamy histiocytes (lipophagic panniculitis) were noted, unrelated to granulomas (Fig. 3c).
The endocrinology investigation revealed the following pathologic parameters: cholesterol 9.46, LDL-cholesterol 5.12 and triglycerides 2.23 mmol/l (normal range < 5.2 vs < 3.4 vs < 1.7 mmol/l, respectively), and autonomic neuropathy. She was absence of insulin resistance. Treatment for dyslipidemia was Rosuvastatin 20 mg/day, Esetimibe 10 mg/day, but with unsatisfactory values of total cholesterol and LDL-ch. All other endocrine parameters such as the thyroid hormones, catecholamines in 24 h urine, cortisol, adrenocorticotropic hormone, dehydroepiandrosterone sulfate, prolactin, human growth hormone, parathyroid hormone, neuron-specific enolase and chromogranin A were normal. The luteinizing hormone and follicle-stimulating hormone showed iatrogenic menopauses.
We established the diagnosis of PWCD and BMSNA, after other types of panniculitis and multiple lipomas were excluded (Table 1, Table 2). Treatment options was prednisone 20 mg/day. Angiolipomas were treated conservatively, because patient had no other complaints related to the excess fat tissue.
Table 1
Classification of panniculitis and conditions associated with panniculitis
Type of panniculitis
|
I. Lobular panniculitis
|
1. Pfeifer-Weber-Christian disease (Idiopathic relapsing febrile lobular non-suppurative panniculitis)
2. Panniculitis in systemic connective tissue diseases: (Systemic lupus erythematosus, Rheumatoid arthritis, Vasculitis, Myositis, Systemic sclerosis, Eosinophilic fasciitis, Eosinophilia-myalgia syndrome)
3. Complement deficiency
4. Lipodystrophic panniculitis
5. Enzymatic panniculitis: (pancreatitis, pancreatic carcinoma, alpha-1-antitrypsin deficiency)
6. Factitial panniculitis
7. Cytophagic histiocytic panniculitis
8. Post-steroid panniculitis (withdrawal of glucocorticoids)
9. Hodgkin’s lymphoma and leukemia
10. Rothmann-Makai syndrome (Lipogranulomatosis subcutaneous)
|
II. Septal panniculitis
|
1. Erythema nodosum
2. Subacute nodular migratory panniculitis (Vilanova disease)
|
III. Mixed panniculitis
|
1. Lupus profundus panniculitis
2. Erythema nodosum-like lesions in Behcet's syndrome
|
IV. Panniculitis with vasculitis
|
1. Vasculitis of small blood vessels
2. Medium-size vessel vasculitis (small arteries or arterioles)
3. Polyarteritis nodosa
4. Erythema induratum (nodular vasculitis)
|
Table 2
Rare syndromes associated with lipomas
Syndrome
|
Components
|
Familial angiolipomatosis
|
Family history of similar lesions, autosomal-recessive or autosomal-dominant fashion
|
Benign symmetric lipomatosis (Madelung's disease, Launois-Bensaude's syndrome)
|
Diffuse or circumscribed symmetrical accumulation of adipose tissue, primarily around the neck, back, shoulders and upper trunk
|
Neurofibromatosis type I
|
Café au lait macules, cutaneous/subcutaneous neurofibromas, axillary or groin freckling, optic pathway glioma, nodules, bony dysplasia
|
Cellular angiolipoma
|
Histologic are composed almost entirerly of small vessels (> 95% of the lesion)
|
Spindle cell-lipoma
|
Subcutaneous nodule in the head and neck region, composed of mature adipocyte and bland spindle cells
|
Angiomyxolipomas
|
Contains mature adipose tissue, extensive myxoid stroma nad numerous blood vessels
|
Lipomatosis syndrome in patients infected with HIV
|
Lipomas, peripheral lipodystrophy, central adiposity, dyslipidemia, inulin resistence
|
Bannayan-Zonana syndrome
|
Multiple lipomas, hemangiomas, macrocephaly
|
Cowden disease
|
Lipomas, hemangiomas, goiter, various skin and mucosal lesions (including intraoral papillomas, acral keratoses, facial trichilemomas), colorectal hamartomatous polyps, gastric polyps with hyperplastic features
|
Fröhlich syndrome
|
Multiple lipomas, sexual infantilism, obesity
|
Proteus syndrome
|
Pelvic lipomatosis, fibroplasia of hands and feet, skeletal hypertrophy, bony exostoses, scoliosis, pigmented skin lesions
|
Due to poor control of main disease and rapid angiolipoma growth on forearms (approximately 10 × 10 mm to 25 × 17 mm) corticosteroids were discontinued after two month of use. The patient underwent surgical excision. Tumor measured 25 × 15 × 10 mm in size. It was encapsulated yellow adipose tissue with a smooth surface at the intersection with red areas corresponding to blood vessels (Fig. 4a). Microscopically, tumour were composed of the lobules of mature adipose tissue with focally grouped, branching capillaries (Fig. 4b). Hyaline thrombi were found in capillaries (Fig. 4c).
After surgical excision patient was treated with cyclosporine A (CyA), 6 mg/kg/day for 12 months. As she was with no disease activity reported and no new tumour growth CyA dose was reduced to 2.5 mg/kg/day. Eight months after the dose reduction, patient was readmitted due to one-month history of abdominal discomfort, weight loss, nausea, and vomiting, accompanied by arthritis, fever, and oral aphthous ulcers. Appendectomy was performed. Apendix was 45 mm long, 6 mm in diameter, turbid serose and wall thickening surrounded with many adhesions. Due to pronounced peritoneal adhesiones, the mesoappendix was difficult to see but seemed to be unchanged. The histopathological analysis revealed acute phlegmonous appendicitis. The dose of CyA was increased to 6 mg/kg/day. Patient is currently disease-free with no new growth of angiolipomas.