Membranous fat necrosis: a non-specific histological finding

ARTICLE

In 1973, the term Membranous Lipodystrophy (ML) was used by Nasu et al. [1] to refer to a disease characterized by the appearance of membranous pseudocystic structures in the adipose tissue of long bones and several organs, associated with sudanophilic leukodystrophy of the brain. Later, in 1983 Machinami [2] used the term Membranous Lipodystrophy-like (MLl) to describe pseudocystic lesions in the adipose tissue of the legs of patients affected with ischaemic problems but who did not present with associated bone or neurological alterations. Further on, Poppiti et al. [3] proposed the name Membranous Fat necrosis (MFN) to refer to a process with the same features as MLl but whose etiopathogenesis did not seem to be linked to vascular alterations.

Membranous-cystic lesions have been reported in association with multiple processes, such as ischaemic arterial changes [2, 4], connective tissue disease [5-9], diabetes mellitus [8, 10], traumatic events [3, 9, 11, 12], infection due to atypical mycobacteria [12] multiple myeloma [13], erythema nodosum-like of Behcet's syndrome [14] morphea [9], as well as in patients with venous insufficiency or a past history of thrombophlebitis who had clinical and histological features of sclerosing panniculitis or lipodermatosclerosis [6, 8, 15, 16]. Primary idiopathic types of ML have also been described [17].

In this article we report two patients who presented with similar skin lesions and histological findings as those reported for MFN.

Case reports

Case 1. A 37-year-old man had surgery for a Clark level IV melanoma with a Breslow depth greater than 3 mm on his right leg. Two and a half years later he presented with a skin metastasis that was also removed surgically. He subsequently received complementary treatment with subcutaneous interferon alpha and interleukin 2, that were inoculated either into the thighs or arms. After 6 months on this regimen, a painless nodular lesion was noted on the left thigh; it was covered by normal skin and had a semisoft consistency. Two months after removal of this lesion, a new nodular lesion of similar clinical characteristics appeared under the scar tissue of the first lesion. Central sectioning of both lesions with a scalpel revealed a yellowish gelatinous content inside.

Case 2. A 49-year-old woman with no relevant medical history presented with recurrent outbreaks of nodular lesions and erythematous plaques that appeared on the anterior and posterior sides of her legs. The lesions were warm and painful. They were uni-or bilateral and sometimes ulcerated; they healed in 3-4 months, leaving hyperpigmented depressed scars. Some nodular lesions appeared over previous scars. Prior to the appearance of these lesions, the patient had suffered trauma to the antero-inferior region of her right leg. She had not suffered from varicose veins nor had a history of thrombophlebitis. All the blood tests, including amylasemia and alpha-antitrypsin, were normal.

Materials and methods

Skin biopsies were fixed in 10% formalin and processed on an automatic processor. Sections from paraffin blocks were stained with hematoxilin-eosin, periodic acid-Schiff (PAS) and diastase-PAS, Sudan black B, Sudan III, phosphotungstic acid-hematoxilin, Alcian blue, Giemsa and Masson Trichrome.

Histopathological findings

In case 1, a pseudocystic cavity was found in the hypodermis; with a festooned pseudomembrane edge sending off small pseudopapillary projections towards the inside of the cavity, it was formed by eosinophilic and anuclear material. Bundles of collagen had condensed around it, resembling a conjunctival pseudocapsule. On one of the lateral edges of the cavity there was a lymphohistiocytic infiltrate and, on the other, adipose micro- and macrocysts with a discrete inflammatory reaction around them (Fig. 1). Staining with Perls' potassium ferrocyanide showed deposits of haemosiderin in the vicinity of the pseudomembranous wall. The festooned membrane delimiting the cystic cavity was formed by a PAS positive diastase-resistant material (Fig. 2) and in the macrocysts a PAS positive festooned or ragged membrane had begun to appear. Sudan black, Sudan III and Giemsa were also positive and the positive phosphotungstic acid-hematoxilin reaction revealed that the membranous structure had two layers. Staining with Masson trichrome and Alcian blue gave negative results.

The histological and staining characteristics of the second nodular lesion removed from this patient were similar.

In case 2 we performed two biopsies. The first corresponded to an ulcerated nodular lesion of three months duration. Histopathologically, we observed an ulcer covered by a thick crust with a necrobiotic background and manifestations indicating intense fibrosis and neoangiogenesis. The hypodermis showed a granulomatous panniculitis with fat necrosis and the presence of numerous micro- and macrocysts with both lipophagic and haemorrhagic component (Fig. 3). Staining with Perls' Prussian blue revealed the presence of multiple haemosiderin deposits and staining with PAS and PAS-diastase showed the existence of PAS positive intracytoplasmic deposits in the cells bordering the macrocysts, most of which were of macrophage lineage. Examination under polarized light did not reveal the presence of birefringent particles.

The second biopsy was of a nodular lesion of semisoft consistency located on the medial side of the patient's leg that had been present for one month. The papillary dermis showed abundant capillaries with a prominent endothelium, wall thickening and a certain degree of fibroblast proliferation. In the middle dermis there was a large oval cavity whose wall was formed by a membranous structure. This pseudomembrane consisted of material with similar morphological and staining characteristics to those observed in Case 1. Fibrosis, vascular proliferation and haemorrhagic zones were observed under the pseudocyst. No inflammatory infiltrates were observed at the edges of the pseudocyst.

Discussion

The two patients discussed here showed nodular lesions on their lower limbs, with histopathological findings consistent with MFN. In the first patient, the etiopathogenic mechanisms involved seemed to be traumatic, while in the second the membranous-cystic changes appeared in the setting of lesions compatible with sclerosing panniculitis [15].

The term MLl was used by Machinami [2] in 1983 to describe pseudocystic lesions located in the adipose tissues of patients with ischaemic necrosis of the legs due to arteriosclerotic damage and one year later in patients with obliterating thromboangeitis and progressive systemic sclerosis [4]. This author considered that MLl could be the result of different types of chronic circulatory alterations, causing ischaemic injury to the adipose tissue. Later, Poppiti et al. [3] reported a patient who showed MLl lesions on the trunk whose etiopathogenesis - according to the histological findings - seemed to be related to traumatic factors; to name this process, they proposed the term MFN and considered it to be a special form of necrosis of the adipose tissue consisting of the development of pseudocystic cavities surrounded by a serpiginous membranous structure showing the same staining characteristics of ceroid.

Ceroid was the term introduced by Lillie et al. [18] to describe a brownish pigment stored in the liver of rats maintained on a diet poor in fat and proteins. Ceroid displays a brownish gold autofluorescence in paraffin-embedded sections and has a light yellowish hue in frozen sections: it has also special staining characteristics since it is stained by lipid-specific dyes, both in frozen and in paraffin-embedded sections. It is PAS positive diastase-resistant and also stains blue with Giemsa and with methylene blue and basic fuscin. It is negative for Prussian blue [19].

In their review of 8 cases of traumatic panniculitis, Dorado Bris et al. [11] observed cystic formations similar to those reported in MFN. Traumatic panniculitis does not display specific histological features and evaluation of a whole set of data is necessary to make this diagnosis [11, 20].

The observations of Poppiti [3] and Dorado Bris [11], together with our first case, suggest that traumatic factors may play a role in the pathogenesis of some cases of MFN. We believe that in our first case trauma, caused by the subcutaneous injections of interferon and interleukin, played an important role in the development of MFN. In addition, interferon and/or interleukin might also have a direct effect on adipocytes.

In case 2, MFN lesions appeared in a woman who had had trauma to her right leg. However the lesions were bilateral and appeared in successive outbreaks. Clinical and histological findings were compatible with sclerosing panniculitis (lipodermatosclerosis) [15, 21, 22].

Chronic lipodermatosclerosis is a manifestation of venous insufficiency. The acute phase is characterized by the presence of hot and painful nodular lesions or erythematous plaques, on the legs of afebrile healthy patients [22]. In some cases, as in our own patient, the condition may appear with no clinical evidence of venous disease [21]. Negative Doppler ultrasoound studies do not rule out this diagnosis [15].

In summary, several factors seem to play a role in adipocyte membrane breakage in MFN resulting in the formation of micro- and macrocysts through the coalescence of contiguious adipocytes. The release of unsaturated fatty acids, and phagocytosis by macrophages, would give rise to the ceroid-like material that forms the festooned membrane delimiting the cystic cavities. MFN can be a late and uncommon stage of fat necrosis and in its etiology it is necessary to assess vascular aggression as well as traumatic, infectious and autoimmune factors. Therefore it must be considered a non-specific histological finding whose appearance is associated with multiple processes. This diagnosis can be established on the basis of conventional histological studies, although only specific dyes will allow confirmation that the festooned membrane is formed by a material that presents with the same staining characteristics as ceroid.

Article accepted on 10/7/01

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