INTRODUCTION

Necrobiosis lipoidica (NL) is a rare, chronic, granulomatous connective tissue disease of unknown etiology commonly associated with adult diabetes mellitus. It is reported in approx. 0.3% of diabetic people and commonly develops in the lower extremities, and appears three times more often in young adult women than in men [1–3]. NL was originally described by Oppenheim under the heading of dermatitis lipoidica atrophicans diabetica, and later by Urbach as NL diabeticorum. Later on, many kinds of literature have been published about NL diabeticorum in non-diabetic patients. Currently, a wider term, necrobiosis lipoidica, covers all cases with identical lesions unrelated to the presence or absence of diabetes [2,4,5]. Typically, the presentation is characterized by yellow-brown plaques on the shin with scleroderma and a telangiectatic form. Generally, the diagnosis is made by clinicopathological correlation, because the classical appearance is not always seen [6]. The histopathological features of NL lesions are nearly analogous to those of granuloma annulare but without mucin deposition. Palisading granuloma encompasses the entire reticular dermis and sometimes the panniculus, with areas of degenerated collagen surrounded by histiocytes as well as other inflammatory cells, including lymphocytes, giant cells, and plasma cells [7,8].

Although the etiopathogenesis of NL is not well established, immune-mediated vascular changes are the most widely accepted theory for driving the condition. Common theories implicate immune complex deposition or microangiopathic changes as a cause of vascular injuries and subsequent collagen degeneration. Also, immunoglobulin-like IgM, IgA, C3 and fibrinogen deposition in blood vessel walls were recorded. Others, such as abnormal collagen fibrils, impaired neutrophil functions, metabolic changes, and tumor necrosis-alpha, are contributory factors [9–12].

The diagnosis of NL is challenging and is missed in most cases because it is quite rare in our population, and there is no literature evaluating the disease in the Iraqi scenario. This interesting article increased awareness of this rare disease and studied twelve patients to determine the distinctive clinical and histological features of NL.

MATERIALS AND METHODS

This is a descriptive case series study in which all patients with NL seen at a private clinic (KES) and Baghdad Teaching Hospital, Baghdad, Iraq, during the period from January 2014 to December 2023 were recognized and recorded. All individuals with Fitzpatrick skin types III and IV were included. Full demographic features and clinical history taking and examination were conducted, including age at the time of NL diagnosis, sex, duration of illness, and site, as well as morphological features, sizes, shapes, colors, and associated atrophy, ulceration or dilated vessels at the surface of the lesion.

A thorough history of non-specific features such as fatigue, fever, and weight loss with an appropriate physical examination was taken. Any associated comorbidities of all participants with NL like diabetes mellitus, rheumatoid arthritis, thyroid dysfunction, inflammatory bowel disease, celiac disease and hyperlipidemias were investigated and reported. Continuous follow-up for eligible persons with necrobiosis lipoidica was done to assess the appearance of systemic diseases from their diagnosis up to December 2023. The initial clinical differential diagnoses extended from cutaneous sarcoidosis, tinea corporis, granuloma annulare, cutaneous vasculitis, and myxedema. Cutaneous biopsies of the border of the lesion and histopathological assessment were performed with a review of the clinicopathological correlation.

RESULTS

Thirteen patients were evaluated, with their ages ranging from 27 to 50 years, with a mean of 35.7 years, with 11 (84.6%) females and 2 (15.4%) males, giving a ratio of 5:1. The mean duration of the disease was 3.3 (2–5) years. All patients were asymptomatic, apart from slight discomfort. The sites were mostly on the legs, apart from three (23.1%) patients on a hand and one (7.7%) case on the face. The rash in 8 (61.5%) subjects was bilateral on both legs, but 5 (38.5%) patients had one-site involvement, 3 (23.1%) on the legs and 2 (15.4%) on the hand and face (Table 1). The rash consisted of erythematous-xanthomatous to violaceous and brown plaques or patches, but unexpectedly, two (15.4%) cases showed pigmented lesions. The morphology of the lesions was atrophic, annular or irregular plaques and/or patches with indurate borders ranging in size from 2 to 8 cm in diameter and ranging from 1 to 7 lesions for each individual case (Figs. 1 – 3). There were associations with dilated vessels and ulceration of the surface in 5 (38.5%) and 2 (15.4%) patients, respectively. Diabetes mellitus was recorded in three (23.1%) participants (Table 2).

	Figure 1: (a) Thirty-five-year-old female with necrobiosis lipoidica on both shins. (b) NL on one leg. (c) Thirty-year-old male patient showing NL on the dorsal aspect of the hand only. (d) NL of both anterior shins.
	Figure 2: A 27-year-old male patient showing pigmented necrobiosis lipoidica on both legs: (a) left and (b) right.
	Figure 3: (a-c) A forty-eight-year-old female showing NL on the face and hand.

	Table 1: The frequency of clinical manifestations of necrobiosis lipoidica (n=13).
	Table 2: The clinical demographics of the 13 patients presenting with necrobiosis lipoidica.

The histopathology of the lesions showed a normal epidermis, but it was sometimes atrophic with an intact basal layer. Increased melanin deposition was seen in the basal layer in pigmented lesions. The dermis showed a palisaded and interstitial granulomatous reaction. The granulomas were organized in a layered manner called layered tiers of granulomatous (“wedding cake” or “sandwich” appearance) inflammation and were admixed with areas of collagen degeneration parallel to the skin surface involving the entire dermis. In many sections, the inflammation extended into the subcutaneous fat layer. In addition, there were increased dilated blood vessels, both in the superficial and deep dermis with greatly thickened walls and prominent swollen endothelial cells. The inflammatory granulomatous reaction consisted of histiocytes, lymphocytes, and plasma cells (Fig. 4).

Figure 4: (a) Histopathological findings in a patient with necrobiosis lipoidica of the leg showing a layered granulomatous reaction extending into the panniculus (H&E; 10x); (b) interstitial inflammatory reaction (H&E; 10x); (c) layered granuloma with thickened dilated vessel (H&E; 40x); (d) greatly thickened walls of capillaries with swelling of endothelial cells (H&E; 40x).

DISCUSSION

Necrobiosis lipoidica is a rare idiopathic chronic cutaneous disease that has a significant morbidity for the patient, and it is frequently refractory to management. Typically, NL presents as red, brown-yellow, atrophic plaques most often recognized on the leg [6]. It is mandatory and of clinical importance to differentiate NL from other granulomatous inflammatory skin diseases. The current research shows the complete and varied clinical presentations of different cases that have been grown over the decade.

The age of the participating individuals indicated that NL mostly affects adult women, with a mean of 35.7 years and a sex ratio of 5:1 (female preponderance). Ongoing studies from other countries showed similar conclusions of NL, as it occurs during the third or fourth decades of life, and was considerably more frequent in women (89%) [13–16]. A study on Indian patients with NL showed a mild difference, where the mean of age was 51 years with a male-to-female ratio of 2:3 [8].

Interestingly, NL in the current report appeared asymptomatic, with chronic lesions and difficult to treat, with a mean duration of the disease of 3.3 (2–5) years, and the most common site affected on the legs in 84.6%, apart from 23.1% of the patients involving the hand, and one interesting lesion that involved the face; this could be considered an original case report of NL presented in this work. The lesions were bilateral in 61.5% of the cases. Other reviewed articles approved and suggested that the shins were the most common and well-recognized affected site in chronic NL, but the lesions existed unilaterally in 60% of the patients [8,17].

The presenting rash consisted typically of erythematous-xanthomatous to violaceous and brown plaques or patches, but surprisingly, 15.4% of the cases showed pigmented lesions, which were not reported in prior research. This might be related to their type IV Fitzpatrick skin color, in addition to the chronic usage of different remedies, or might be an abnormal daily habit of washing (lifa) causing skin friction, which increases the pigmentation of the rash. The clinical features of the lesion in the present study were atrophic, annular or irregular plaques and/or patches, sometimes with indurated borders ranging in size from 2 to 8 cm in diameter and ranging from 1 to 7 lesions in each case. These morphologic variations and their association with dilated vessels, as reported in 38.5% of the subjects and ulceration in 15.4%, may contribute to the longer disease duration (2–5 years) and probably longer cumulative management by topical or intralesional corticosteroids. Furthermore, preceding studies displayed similar findings as well as the formation of an ulcer, infections, and rarely, the development of squamous cell carcinoma, suggesting the cause is mainly the chronicity of the lesion along with frequent trauma, which induced atrophy or ulceration and might develop a focus of mutation [2,17].

The occurrence of diabetes mellitus was recorded in three (23.1%) participants. One patient was associated with uncontrolled blood sugar, and it is thought to be highly associated with NL. Numerous previous studies have described a relationship between NL and diabetes mellitus with the wide spectrum of the prevalence of diabetes at the time of diagnosis of NL, ranging from 11% to 65%, which may play a significant role in the etiology of NL; this is proposed as one of the multiple pathogenic characters of the disease [18,19]. Unlike the current report, NL is also reported and presented with autoimmune thyroiditis, coeliac disease, obesity, and dyslipidemia [20,21].

Regarding the histopathology of the lesions and microscopic descriptions of the present study, they were approved by many previous kinds of literature [2,6]. It showed a normal epidermis but sometimes was atrophic with an intact basal layer; increased melanin deposition was seen in the basal layer in pigmented lesions. The dermis showed a palisaded and interstitial granulomatous reaction and were admixed with areas of collagen degeneration parallel to the skin surface involving the entire dermis. In many sections, the inflammation extended into the subcutaneous fat layer. In addition, there were increased dilated blood vessels both in the superficial and deep dermis with greatly thickened walls with prominent swollen endothelial cells. The inflammatory granulomatous reaction consisted of histiocytes, lymphocytes, and plasma cells.

As for differential diagnoses, NL may be confused with other granulomatous diseases like granuloma annulare through the absence of the mucin deposition in the center of the palisading granulomas, the presence of plasma cells, with perivascular fibrin deposition, and the inflammation extending into the subcutaneous fat layer. Sarcoidosis is another closely similar cutaneous granulomatous disease, but it differs from NL by the absence of necrobiosis, no lymphoplasmacytic infiltrate, and no telangiectasia [8,22–24].

CONCLUSION

Over many years, thirteen patients with necrobiosis lipoidica have been described, mostly females, with typical clinical and histopathological pictures. Diabetes mellitus is often found in conjunction with NL in 23.1% of the participants. Histopathology is an appropriate test in confirming the diagnosis. By this work, we aim to raise awareness and suspicion regarding this rare chronic aspect of necrobiosis lipoidica.

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