Septal granulomatous panniculitis: comparison of the pathology of erythema nodosum migrans (migratory panniculitis) and chronic erythema nodosum

Fifty-eight cases of septal granulomatous panniculitis were reviewed; 14 cases were diagnosed as erythema nodosum migrans (migratory panniculitis) and 36 as chronic erythema nodosum on the basis of clinical and histopathologic features. Erythema nodosum migrans was characterized by markedly thickened and fibrotic septae, marked capillary proliferation (like granulation tissue), and massive granulomatous reaction (with giant cells) along the borders of the widened septa. Hemorrhage was rare, and phlebitis was not seen. Chronic erythema nodosum showed mild septal change, little fibrosis, and lymphohistiocytic perivascular inflammation with only focal granulomatous formation. Phlebitis and hemorrhage were common. The condition termed erythema nodosum migrans has many of the same clinical features as chronic erythema nodosum, and we think this term is preferable to migratory panniculitis. We believe that there are sufficient clinical and histopathologic features to justify considering erythema nodosum migrans as a unique clinicopathologic entity.     

33例脂膜炎与结核感染相关性分析

 目的 了解不同类型的脂膜炎患者与结核感染的相关性。方法 纳入2019年1月—2021年12月就诊于常德市第一人民医院33例脂膜炎患者的临床资料，对其临床特征、病理特征、与结核感染的相关性、治疗情况及随访情况进行分析。结果 ①33例脂膜炎患者中,结节性红斑24例，硬红斑9例，男女比例为1 ∶ 4.5，平均年龄46岁，平均病程10个月。②临床发病部位集中在四肢，均伴有疼痛。30例（90.91%)表现为红斑、结节、肿胀，其中1例硬红斑（3.03%）出现溃疡。6例(18.18%)出现发热、咳嗽、盗汗。2例硬红斑患者同时伴有或先后出现丘疹性坏死性结核疹，2例结节性红斑患者伴有全身多关节疼痛。③22例（66.67%,包括9例硬红斑、13例结节性红斑)伴结核分支杆菌潜伏感染（LTBI）。硬红斑患者结核感染阳性率高于结节性红斑患者（P＝0.020）。④皮损组织病理表现为间隔性脂膜炎11例、小叶性脂膜炎3例、混合性脂膜炎19例。与结核感染相关的22例脂膜炎患者病理下多可见上皮细胞肉芽肿、多核巨细胞以及干酪样坏死，其余11例均可见真皮层血管周围及脂肪间隔淋巴细胞浸润，且均未见上皮样肉芽肿及多核巨细胞。33例患者抗酸染色、PAS染色、直接免疫荧光均未见阳性表现。⑤22例与结核感染相关患者中，接受抗结核治疗15例，治愈率为68.18%，拒绝接受抗结核治疗患者7例，治愈率为14.29%。11例结核感染不相关患者采用免疫调节联合治疗，治愈率为100%。所有患者均未出现严重药物不良反应。结论 硬红斑患者的结核感染阳性率比结节性红斑患者高。在结核感染相关的脂膜炎患者中，接受抗结核治疗者治愈率比免疫调节联合治疗者高；对于未发现结核感染证据的结节性红斑，免疫调节治疗可能有效。结节性红斑患者的发病原因可能与结核感染相关。在结核高发地区，结节性红斑患者完善相关筛查极其重要。     

Diagnosis: erythema nodosum or not?

Erythema nodosum is the final common pathway to a myriad of insults and is thought to be a hypersensitivity reaction centered in the subcutis. To recognize the histological spectrum of erythema nodosum, one must be aware of the morphologic chronology of the disease (early, fully developed, late) and its clinical variants (erythema nodosum migrans). This article reviews the range of changes that can be seen in this prototype of a septal panniculitis and describes the diversity that may be accepted in the diagnosis. Differential diagnoses at each stage of disease development are discussed. The criteria elaborated should assist the pathologist in answering the clinician's query, "Erythema nodosum, or not?"     

Panniculitis

The classification of inflammatory disorders of the subcutaneous tissue has mystified dermatologists for decades. Overlapping clinical and histologic features, and a lack of specific treatments have added to the confusion. This article initially classifies the various panniculititides by their primary histopathologic pattern: (1) septal panniculitis without vasculitis, (2) septal panniculitis with vasculitis, (3) lobular panniculitis without vasculitis, and (4) lobular panniculitis with vasculitis. Subsequently, we describe the key clinical findings in the most important forms of panniculitis. We begin with the most common form of panniculitis, erythema nodosum. Indeed, in many patients suspected of having panniculitis, a worthwhile question to consider initially might be, "Is this, or is this not, erythema nodosum?" before engaging in an elaborate (and expensive) exercise in differential diagnosis.     

Exploring the combination of SSKI and topical heparin in a case of erythema nodosum migrans

Erythema nodosum migrans (subacute nodular migratory panniculitis) is an uncommon type of panniculitis characterized by migrating subcutaneous nodules or plaque on the lower extremity. There are a very few cases of Erythema nodosum migrans reported and thus its appropriate treatment modality is not defined. We describe a case of a 30‐year‐old male with idiopathic erythema nodosum migrans which was manifest centrifugally spreading, slightly morpheaform erythematous plaque on the lower left leg. The patient was diagnosed initially and treated as a case of furunculosis with poor clinical response. The skin biopsy showed features consistent with subacute nodular panniculitis. Saturated Solution of Potassium Iodide along with topical Heparin successfully treated the patient, when the conventional treatment modalities failed. In a morpheaform centrifugally expanded plaque, erythema nodosum migrans should be kept in mind in the differential diagnosis, especially in the lower extremities in cases of unknown etiology.     

Erythema induratum (nodular vasculitis) associated with Crohn's disease: a rare type of metastatic Crohn's disease

We herein report a patient with erythema induratum/nodular vasculitis (EI/NV) associated with Crohn's disease (CD), which is considered to be a rare type of metastatic CD. A 54-year-old woman, who had a history of CD, presented with erythematous nodules on her legs. The histopathological features of the skin biopsy revealed a granulomatous, mixed septal and lobular panniculitis, which was characterized by many discrete epithelioid cell granulomas (necrobiotic/necrotizing-type and sarcoidal type), necrosis of the adipocytes, and granulomatous phlebitis in the muscular wall of a subcutaneous vein. A review of the pertinent literature and the presented case suggested the following: (1) panniculitis associated with CD may be either an erythema nodosum type or an EI/NV type; (2) so far, the reported cases of metastatic CD or granulomatous vasculitis in CD rarely presented with granulomatous panniculitis without dermal involvement, and most cases showed histopathological features that were similar to or indistinguishable from those of EI/NV; and (3) the finding of granulomatous vasculitis (especially the presence of discrete epithelioid cell granulomas involving the veins or venules) may be a characteristic feature of EI/NV associated with CD, in contrast to the finding of acute vasculitis, which is typically present in patients with EI/NV due to causative factors other than CD.     

ERYTHEMA NODOSUM VERSUS NODULAR VASCULITIS

Background. Erythema nodosum (en ) is usually considered to be a septal panniculitis, and nodular vasculitis (nv ) a lobular panniculitis. We tested the usefulness of this histologic classification in clarifying a frequent clinical dilemma: en versus nv . Methods. Over 3 years 109 patients with panniculitis were included in this study. After a history and a physical examination, a clinical diagnosis was made according to well-established criteria. Results. From the study of 88 patients, we concluded that in the clinically typical cases, the clinico-pathologic agreement was 93% and 94% for en and nv respectively, whereas it diminished to 79%, 72%, and 67% in the cases clinically diagnosed as en migrans, atypical en , and atypical nv , respectively. Moreover, septal and lobular panniculitis were always two clear-cut, different, opposite patterns of hypodermal inflammation to these conditions. Conclusions. In the absence of a known pathogenetic mechanism, the histopathology remains the most objective discriminating marker between en and nv , mainly in the clinically atypical and doubtful cases.     

Skin lesions in human yersiniosis

Various types of skin manifestations of human yersiniosis were examined with routine histological and immunohistological methods. The biopsy material consisted of sixteen cases of erythema nodosum, eight cases of erythema multiforme, and one case of erythema figuratum. The principal histopathological changes in erythema nodosum were septal or diffuse, mild panniculitis and in seven cases also necrotizing vasculitis in small, medium-sized or large arteries. Perivascular lymphocytic infiltration without vasculitis was the most prominent feature in erythema figuratum. By using a polyvalent conjugate, immunoglobulins in vessel walls in the dermis were found in two cases of EM. The rapid course of the skin eruptions and the frequency of necrotizing vasculitis in arteries fit the changes seen in an experimental Arthus reaction, in which necrotizing vasculitis is followed by lymphocytic inflammation consistent with a delayed type of reaction.     

Panniculitis: clinical overlap and the significance of biopsy findings

Background: Panniculitides are well-recognized clinicopathologic entities but the non-specificity of their clinical and pathological features often troubles the diagnostician.
Methods: This study retrospectively evaluates the clinical overlaps and the significance of histological findings among various panniculitides.
Results: The clinical evaluation in 55 panniculitides cases suggested the diagnosis of typical erythema nodosum (EN) in 26 cases, atypical EN in 17 cases, atypical nodular vasculitis (NV) in two cases, soft tissue infection in five cases and five cases remained unclassified. Skin biopsy evaluation provided definite panniculitis diagnosis in 53 cases including EN (28 cases), leukocytoclastic vasculitis (seven cases), NV (four cases), superficial thrombophlebitis (ST) (two cases), eosinophillic panniculitis (EP) (three cases), infection-related panniculitis (five cases), and one case each of erythema nodosum leprosum (ENL), lupus panniculitis (LP), pancreatic fat necrosis and acne conglobata with two cases remaining unclassified. Histologically, 'predominantly septal' and 'mixed panniculitis' were the chief inflammatory patterns in EN cases, while mixed panniculitis was seen in most LCV cases and predominantly lobular and mixed panniculitis in NV cases.
Conclusions: Biopsy evaluation of a panniculitis lesion is usually significant, and the application of a combination of histologic features rather than of a single biopsy finding or an inflammatory pattern is helpful in the diagnosis of panniculitis.     

Neutrophilic panniculitis

Neutrophilic (lobular) panniculitis (NP) is a very rare condition that belongs to the group of neutrophilic dermatoses. We report the case of a patient with NP and review the relevant literature. NP appears as a subcutaneous nodular eruption. Histology shows a lobular neutrophilic infiltrate. NP must be differentiated from other types of panniculitis, and also from the subcutaneous septal involvement that may occur in some cases of Sweet's syndrome and from erythema nodosum. NP is significantly associated with myelodysplasia. It is highly sensitive to oral steroid therapy.     

Normal subcutaneous fat, necrosis of adipocytes and classification of the panniculitides

The panniculitides represent a group of heterogeneous inflammatory diseases that involve the subcutaneous fat. The specific diagnosis of these diseases requires histopathologic study because different panniculitides usually show the same clinical appearance, which consists of erythematous nodules on the lower extremities. However, the histopathologic study of panniculitis is difficult because of an inadequate clinicopathologic correlation and the changing evolutive nature of the lesions. In addition, large scalpel incisional biopsies are required. From histopathologic point of view, all panniculitides are somewhat mixed because the inflammatory infiltrate involves both the septa and lobules. However, nearly always the differential diagnosis between a mostly septal and a mostly lobular panniculitis is straightforward at scanning magnification on the basis of the structures more intensely involved by the inflammatory infiltrate. Mostly septal panniculitides with vasculitis are actually more vasculitis than panniculitis and include superficial thrombophlebitis and cutaneous polyarteritis nodosa. Mostly septal panniculitides with no vasculitis include erythema nodosum, necrobiosis lipoidica, deep morphea, subcutaneous granuloma annulare, rheumatoid nodule, and necrobiotic xanthogranuloma. Mostly lobular panniculitis with vasculitis is only represented by erythema induratum of Bazin. In contrast, mostly lobular panniculitides without vasculitis comprise a large series of disparate disorders, including sclerosing panniculitis, calciphylaxis, sclerema neonatorum, subcutaneous fat necrosis of the newborn, poststeroid panniculitis, lupus erythematosus profundus, pancreatic panniculitis, alpha(1)-antitrypsin deficiency panniculitis, subcutaneous Sweet syndrome, infective panniculitis, factitial panniculitis, lipodystrophy, traumatic panniculitis, subcutaneous sarcoidosis, and sclerosing postirradiation panniculitis. Finally, some cutaneous lymphomas may simulate panniculitis, both from clinical and histopathologic points of view and, for that reason, they will be included in this review, although they are not inflammatory processes, but authentic lymphocytic neoplasms involving subcutaneous tissue.     

Acute Crohn’s colitis with lobular panniculitis – metastatic Crohn’s?

One of the common lesions in Crohn's colitis is erythema nodosum, a septal panniculitis that may appear before diagnosis or in conjunction with flare up. We report a case of Crohn's colitis where the presenting sign was neutrophilic lobular panniculitis with few granulomas. The possibility that this case represents a forme fruste of metastatic Crohn's is suggested. As skin biopsies are not usually performed by gastroenterologists in erythema nodosum-like skin lesions in Crohn's patients it may well be that the incidence of lobular panniculitis is higher than reported in the literature.     

Erythema nodosum-like lesions in Behçet''s syndrome: a histopathologic study of 30 cases

Thirty patients who fulfilled the criteria for complete and incomplete types of Behçet's syndrome were studied to determine the histopathologic changes of erythema nodosum-like lesions. Lymphocytic vasculitis was observed in 12 (40%) of the cases, but it was only focal in areas of severe lymphocytic inflammation and only mild in degree. No diffuse vasculitis was seen. It is our opinion that the observed lymphocytic vasculitis is only secondary to moderate or severe lymphocytic inflammation. Twelve cases (40%) revealed septal panniculitis, 10 cases (33%) demonstrated lobular panniculitis with moderate to marked inflammation and fat cell necrosis, and 8 cases (27%) showed mild and nonspecific inflammation in the panniculus. Therefore, there is a spectrum of histopathologic changes of erythema nodosum-like lesions in Behçet's syndrome, similar to that of erythema nodosum secondary to other systemic disorders.     

与结核相关的脂膜炎研究进展

【摘要】 脂膜炎病因繁多而复杂,感染为重要病因之一,在欧美等结核低发区,以链球菌感染最为常见,但在结核高发地区如我国,结核杆菌感染是脂膜炎的重要因素,以Bazin硬红斑和结节性红斑最为常见。Bazin硬红斑与结核关系最为密切,常表现为下肢屈侧结节、斑块,可出现溃疡,病理表现为小叶性脂膜炎。结节性红斑可作为结核的早期症状出现,可作为结核的预测指标,常表现为双下肢伸侧红斑、结节,极少破溃,间隔性脂膜炎是其病理特征。Bazin硬红斑和结节性红斑的抗结核治疗常可取得理想效果。因此,明确结核分支杆菌与脂膜炎的关系,在脂膜炎的治疗及预后方面,尤其在结核高发地区有着重要意义。     

Acute infectious id panniculitis/panniculitic bacterid: a distinctive form of neutrophilic lobular panniculitis

Background: Lobular panniculitis encompasses lupus profundus, atypical lymphocytic lobular panniculitis, erythema induratum and subcutaneous Sweet’s syndrome, while septal panniculitis includes erythema nodosum and fibrosing dermal processes of burn out necrobiosis lipoidica and morphea profundus. Panniculitis may represent a sign of systemic disease and/or a modified immune response to hematogenously disseminated antigen. Methods: We describe 10 cases of sterile neutrophilic dominant lobular panniculitis that represented an id reaction to non‐tuberculous stimuli. Results: Four males and six females had sudden tender non‐ulcerated lower extremity nodules with preceding non‐tuberculous infectious triggers. Three also had upper extremity lesions. Biopsies showed dominant neutrophilic infiltrate with subcutaneous microabscesses (7), extravascular granulomatous infiltrates (5), thrombotic microangiopathy (5) and necrotizing vasculitis (5). Stains evaluating microbial pathogens were negative. Lesions resolved with antibiotic treatment and/or abscess drainage; no case recurred. Medical histories included atopic diathesis (4), primary antiphospholipid antibody syndrome (1), ulcerative colitis (1) and acute lymphocytic leukemia (1). Serologies showed polyclonal hypergammaglobulinemia, cold agglutinins and cryofibrinogens. Conclusions: We propose the term acute infectious id panniculitis for cases of neutrophilic lobular panniculitis triggered by non‐tuberculous infectious stimuli. This course may be self‐limited. Microvascular cofactors and/or procoagulant states may be pathogenetically important. Recognizing this entity may circumvent the need for an exhaustive evaluation for other causes of neutrophilic lobular panniculitis.     

Histopathology of erythema nodosum

The histopathology of erythema nodosum is discussed with reference to the literature and of 19 cases of our clinic. There is a significant vascular involvement especially of the subcutaneous tissue. The veins and arteries are equally affected. The histological picture consists not only of an acute inflammatory process in the subcutaneous tissue, but also of inflammatory cells which area see to a lesser extent in the dermis. In many cases the typical small granulomatous foci of MIESCHER which are considered to be pathognomonic for erythema nodosum do not develop. In the cases which we examined we were not always able to tell from the histological picture how long the erythema nodosum had been present. Multinucleated giant cells which are often found in the septal connective tissue are seen even in relatively acute cases.     

Panniculitis. Part I. Mostly septal panniculitis.

The panniculitides represent a group of heterogeneous inflammatory diseases that involve the subcutaneous fat. The specific diagnosis of these diseases requires histopathologic study because different panniculitides usually show the same clinical appearance, which consists of subcutaneous erythematous nodules on the lower extremities. However, the histopathologic study of panniculitis is difficult because of an inadequate clinicopathologic correlation, and the changing evolutionary nature of the lesions means that biopsy specimens are often taken from late-stage lesions, which results in nonspecific histopathologic findings. In addition, large-scalpel incisional biopsies are required. However, we believe that by obtaining appropriate biopsy specimens and with adequate clinicopathologic correlation, a specific diagnosis may be rendered in most cases of panniculitis. It must be accepted that all panniculitides are somewhat mixed because the inflammatory infiltrate involves both the septa and lobules; however, in general the differential diagnosis between a mostly septal and a mostly lobular panniculitis is straightforward at scanning magnification. Mostly septal panniculitides with vasculitis include leukocytoclastic vasculitis involving the small blood vessels of the septa; superficial thrombophlebitis resulting from inflammation and subsequent thrombosis of large veins of the septa; and cutaneous polyarteritis nodosa, which is a vasculitis involving arteries and arterioles of the septa of subcutaneous fat with few or no systemic manifestations. Often septal panniculitides with no vasculitis are the consequence of dermal inflammatory processes extending to the subcutaneous fat, such as necrobiosis lipoidica, scleroderma, subcutaneous granuloma annulare, rheumatoid nodule, and necrobiotic xanthogranuloma. However, in other cases, the inflammatory process is primarily located in the fibrous septa of the subcutis with or without involvement of the overlying dermis. The most frequently seen septal panniculitis is erythema nodosum, which, in fully developed lesions, is characterized histopathologically by Miescher's radial granulomas in the septa.     

Erythema nodosum

Erythema nodosum is the most frequent clinico-pathological variant of the panniculitides. The disorder is a cutaneous reaction consisting of inflammatory, tender, nodular lesions, usually located on the anterior aspects of the lower extremities. The process may be associated with a wide variety of diseases, being infections, sarcoidosis, rheumatologic diseases, inflammatory bowel diseases, medications, autoimmune disorders, pregnancy, and malignancies the most common associated conditions. The typical eruption consists of a sudden onset of symmetrical, tender, erythematous, warm nodules and raised plaques usually located on the shins, ankles and knees. Often the lesions are bilaterally distributed. At first, the nodules show a bright red color, but within a few days they become livid red or purplish, and finally they exhibit a yellow or greenish appearance taking on the look of a deep bruise. Ulceration is never seen and the nodules heal without atrophy or scarring. Some clinical variants of erythema nodosum have been described under different names, including erythema nodosum migrans, subacute nodular migratory panniculitis, and chronic erythema nodosum, but probably they are just clinical variants which may all be included within the spectrum of erythema nodosum. Histopathologically, erythema nodosum is the stereotypical example of a mostly septal panniculitis with no vasculitis. The septa of subcutaneous fat are always thickened and variously infiltrated by inflammatory cells that extend to the periseptal areas of the fat lobules. The composition of the inflammatory infiltrate in the septa varies with age of the lesion. In early lesions edema, hemorrhage, and neutrophils are responsible for the septal thickening, whereas fibrosis, periseptal granulation tissue, lymphocytes, and multinucleated giant cells are the main findings in late stage lesions of erythema nodosum. A histopathologic hallmark of erythema nodosum is the presence of the so-called Miescher's radial granulomas, which consist of small, well-defined nodular aggregations of small histiocytes arranged radially around a central cleft of variable shape. Treatment of erythema nodosum should be directed to the underlying associated condition, if identified. Usually, nodules of erythema nodosum regress spontaneously within a few weeks, and bed rest is often sufficient treatment. Aspirin, nonsteroidal anti-inflammatory drugs, such as oxyphenbutazone, indomethacin or naproxen, and potassium iodide may be helpful drugs to enhance analgesia and resolution. Systemic corticosteroids are rarely indicated in erythema nodosum and before these drugs are administered an underlying infection should be ruled out.     

Histopathologic spectrum of erythema nodosum

Erythema nodosum (EN) is the most common panniculitis and histologically represents the prototype of a septal panniculitis. However, the histologic findings can be quite variable. We describe four patients with EN who each underwent two consecutive biopsies. In each case, the first biopsy showed histopathologic features that fall outside the usual spectrum of disease. Two cases showed predominantly neutrophilic infiltrates with focal suppuration as well as vasculitis of medium-sized arteries. The areas of suppuration were more extensive in the first case prompting special stains for microorganisms that were all negative. The third case demonstrated a lobular panniculitis with a predominantly lymphohistiocytic infiltrate. Special stains were negative in this case as well. The fourth case revealed vasculitis of a medium sized artery, small vessel vasculitis, and a mixed septal and lobular panniculitis with a polyclonal population of atypical lymphocytes. In all patients, the clinical course and the subsequent biopsy were classic for EN. We conclude that lobular neutrophilic panniculitis with suppuration, small vessel vasculitis, and even medium vessel arteritis may rarely occur in EN. There are few clues in these unusual cases that allow for a specific diagnosis from the start, and often, a second biopsy is required.     

Erythema nodosum

Erythema nodosum is the most frequent clinicopathologic variant of panniculitis. The process is a cutaneous reaction that may be associated with a wide variety of disorders, including infections, sarcoidosis, rheumatologic diseases, inflammatory bowel diseases, medications, autoimmune disorders, pregnancy, and malignancies. Erythema nodosum typically manifest by the sudden onset of symmetrical, tender, erythematous, warm nodules and raised plaques usually located on the lower limbs. Often the lesions are bilaterally distributed. At first, the nodules show a bright red color, but within a few days they become livid red or purplish and, finally, they exhibit a yellow or greenish appearance, taking on the look of a deep bruise. Ulceration is never seen, and the nodules heal without atrophy or scarring. Histopathologically, erythema nodosum is the stereotypical example of a mostly septal panniculitis with no vasculitis. The septa of subcutaneous fat are always thickened and variously infiltrated by inflammatory cells that extend to the periseptal areas of the fat lobules. The composition of the inflammatory infiltrate in the septa varies with age of the lesion. In early lesions edema, hemorrhage, and neutrophils are responsible for the septal thickening, whereas fibrosis, periseptal granulation tissue, lymphocytes, and multinucleated giant cells are the main findings in late stage lesions of erythema nodosum. A histopathologic hallmark of erythema nodosum is the presence of the so-called Miescher's radial granulomas, which consist of small, well-defined nodular aggregations of small histiocytes arranged radially around a central cleft of variable shape. Treatment of erythema nodosum should be directed to the underlying associated condition, if identified. Usually, nodules of erythema nodosum regress spontaneously within a few weeks, and bed rest is often sufficient treatment. Aspirin, nonsteroidal antiinflammatory drugs, such as oxyphenbutazone, indomethacin or naproxen, and potassium iodide may be helpful drugs to enhance analgesia and resolution. Systemic corticosteroids are rarely indicated in erythema nodosum and before these drugs are administered an underlying infection should be ruled out.