Granulomatous vasculitis in Crohn's disease: a clinicopathologic correlate of two unusual cases

Cutaneous complications occur not uncommonly in patients with Crohn's disease (CD). Gastrointestinal CD often shows non‐caseating granulomas and a rare cutaneous finding in CD is a sterile granulomatous infiltrate not contiguous with the GI tract, termed extraintestinal CD (ECD). The clinical presentation of ECD is diverse. The most common histopathological presentation is a superficial and deep granulomatous infiltrate that often accompanies a mixed perivascular infiltrate. Here we report two patients with CD and skin lesions characterized on microscopy by granulomatous vasculitis. A 29‐year‐old female presented with papules and ulcerated nodules above the ankle. The biopsy showed dermal and superficial subcutaneous involvement by a vasocentric infiltrate of mononuclear and multinucleated histiocytes as well as mural fibrin deposition. A 35‐year‐old male presented with two tender indurated erythematous plaques with punched‐out centers on the lower leg. Histopathologically, a granulomatous vasculitis of small and medium‐sized vessels in the dermis and subcutis was evident. These two cases represent the rarely described phenomenon of cutaneous granulomatous vasculitis in CD. Previously reported examples of this entity are reviewed. Burns AM, Walsh N, Green PJ. Granulomatous vasculitis in Crohn's disease: a clinicopathologic correlate of two unusual cases.     

Mycobacteria other than Mycobacterium tuberculosis are not present in erythema induratum/nodular vasculitis: a case series and literature review of the clinical and histologic findings

Erythema induratum (EI)/nodular vasculitis (NV) is characterized by recurrent crops of tender oedematous nodules on the lower legs. A lobular panniculitis with granulomatous inflammation, vasculitis, focal necrosis and septal fibrosis is present. Mycobacterium tuberculosis DNA has been detected in some lesions by means of polymerase chain reaction (PCR). Ten cases of EI/NV were found. H&E slides were reviewed. PCR assays for M. tuberculosis and mycobacteria other than M. tuberculosis (MOTT) were performed. PCR did not reveal M. tuberculosis (0%) or MOTT (0%) DNA, with positive controls, indicating the reliability of the assays. Among the MOTT, cutaneous infections are most commonly caused by M. marinum. Subcutaneous tuberculoid granulomas may be seen with M. kansasii, M. marinum, M. scrofulaceum and M. avium complex. M. gordonae, M. szulgai and M. malmoense rarely cause cutaneous infections. M. simiae, M. gastri and M. asiaticum are probably not cutaneous pathogens. M. tuberculosis and MOTT DNA was not found in EI/NV. EI/NV has diverse aetiologies with varying pathogeneses leading to similar histologic changes. The cases analysed may not have had an infectious aetiology. However, in EI/NV, performance of PCR for MOTT as well as M. tuberculosis complex may still be beneficial, particularly in cases from immunocompromised hosts.     

Peripheral T-cell lymphoma with secondary epithelioid granulomatous cutaneous involvement: a clinicopathologic study of four cases

Epithelioid granuloma formation has rarely been observed in specific cutaneous lesions from T-cell lymphomas other than those of mycosis fungoides/Sézary syndrome (MF/SS). Three patients diagnosed with nodal and/or extranodal (tonsillar) non-Hodgkin's peripheral T-cell lymphoma (PTCL) and one patient with angioimmunoblastic T-cell lymphoma (AILD), developed specific cutaneous involvement showing prominent epithelioid cell and/or granulomatous inflammation. The original diagnostic lesions had no granulomatous features. In addition to a specific lymphomatous infiltrate, prominent dermal and/or subcutaneous granulomatous infiltrates were observed. Sarcoid-like granulomas were observed in two patients (one of them presented a granuloma annulare-like pattern in early lesions), granulomatous panniculitis was noted in one patient and in one patient with AILD, masses of epithelioid cells were noted. The clinicopathological features of cutaneous involvement by PTCL showing a florid epithelioid and/or granulomatous cell reaction are reviewed. Various histopathological patterns can be observed. The diagnostic difficulties of these cases are stressed.     

Nodules on the legs. A clinical, histological and immunohistological study of 82 patients representing different types of nodular panniculitis.

Eighty-two cases of nodular panniculitis of the legs were examined clinically, histologically and immunohistologically. Clinically the cases could be divided into four groups: typical erythema nodosum (ENty) (35 cases), erythema nodosum migrans (ENmi) (11 cases), erythema induratum (EI) (11 cases) and the remaining 25 cases not consistent with the others as "non-definite panniculitis" (NDP). The main histological categories were septal panniculitis and lobular panniculitis, the former including erythema nodosum, both typical and migrans, the latter EI and NDP. Lobular panniculitis was divided into three subgroups in which the most prominent histological features were epithelioid cell granuloma, vasculitis and palissading granuloma, respectively. Immunoglobulins in the vessel walls were found in 5 of the 46 cases of erythema nodosum, in 19 of the 36 EI and NDP cases and, in the histological groups in 4 of the 43 cases of septal panniculitis and in 19 of the 35 cases of lobular panniculitis, respectively. Fibrin was found in the walls of the papillary capillaries and deep dermal vessels in the majority of cases of lobular panniculitis. In EI and NDP the follow-up time was 40 months, on average. Twenty-two patients were treated with antituberculous drugs, 15 became symptomless, as did 5 of the 12 patients who were not treated at all.     

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.     

Cutaneous manifestations of Crohn's disease

Crohn's disease is a chronic inflammatory bowel disease which may have distinctive mucocutaneous manifestations. Included in this group are perianal, peristomal, and perifistular ulceration, as well as granulomatous cutaneous inflammation separate from gastrointestinal tract openings (metastatic Crohn's disease). In the oral cavity, both ulcerations and granulomatous nodules may occur. Malabsorption of nutrients may lead to several changes, including an acrodermatitis enteropathica-like syndrome secondary to zinc deficiency. Patients with Crohn's disease may also have pyoderma gangrenosum, erythema nodosum, cutaneous vasculitis, and other less specific changes.     

Delayed reaction after an octopus bite showing a giant cell-rich granulomatous dermatitis/panniculitis

Adequate clinical data and a sufficient workup, in addition to the histopathological findings, are frequently required to make a correct diagnosis of granulomatous dermatitis/panniculitis. These lesions with an unexpected etiology may include delayed hypersensitivity granulomatous reactions to various factors, such as metals or marine animal injuries. A 50-year-old male presented with multiple subcutaneous nodules on his right forearm 1 month following an octopus bite at his right wrist. After the disappearance of these lesions, which responded well to low-dose oral prednisone, another type of skin lesion characterized by small, numerous papules reappeared on his right forearm. Histopathologically, a specimen from a subcutaneous nodule showed mostly lobular granulomatous panniculitis, which showed an extensive diffuse infiltrate composed of numerous multinucleated giant cells and epithelioid cells intermingling with lymphocytes and eosinophils. A specimen from a papule that subsequently developed disclosed a diffuse granulomatous dermatitis composed of similar cells and also showed granuloma annulare-like features. This case is considered to be a delayed reaction after an octopus bite showing an unusual giant cell-rich granulomatous dermatitis/panniculitis. Octopus bites should therefore be included among the marine animal injuries, which cause a delayed-type reaction with granulomatous dermatitis/panniculitis.     

Annular lesions of cutaneous sarcoidosis with granulomatous vasculitis

Sarcoidosis is known to be involved in diseases with vasculitis as sarcoid vasculitis. However, vasculitis in cutaneous sarcoidal lesions is extremely rare. Here we describe a case of sarcoidosis with multiple annular skin lesions with granulomatous vasculitis. A 62‐year‐old female was diagnosed with sarcoidosis by chest‐abdominal computed tomographic examination and laboratory tests. The skin lesions had appeared on her lower limbs 2 years before. Physical examination showed multiple infiltrated annular eruptions on the lower extremities. A skin biopsy of an area of erythema showed multiple non‐caseating epithelioid cell granulomas in the dermis and subcutaneous fat and granulomatous vasculitis with fibrinoid degeneration in the subcutaneous fat. There are two types of vasculitis in sarcoidosis: leukocytoclastic and granulomatous vasculitis. Ulcers and livedo were more common in granulomatous vasculitis than in leukocytoclastic vasculitis. The present case had unique annular skin lesions of sarcoidosis with granulomatous vasculitis.     

Perianal Crohn's disease

A 13-year-old girl with a history of 4 months of perianal skin lesions is described. Physical examination revealed three 0.5 I 1-cm red, swollen, fleshy, skin tags extending from the perianal area to the perineum (Fig. 1). The patient reported intermittent fever, diarrhea, and abdominal pain, and her body weight was below the third percentile for her age. Laboratory studies showed an erythrocyte sedimentation rate of 101 mm/h; hematocrit of 26%; white blood cell count of 9800/mm3; serum iron of 15 mg/L (normal value (NV), 60-160 mg/L); ferritin of 43.4 microg/L (NV, 12-150 microg/L); transferrin of 203 mg/100 mL (NV, 200-400 mg/100 mL); transferrin saturation of 6% (NV, 20-50%); hypoalbuminemia; negative purified protein derivative (PPD), cytomegalovirus (CMV), human immunodeficiency virus (HIV), venereal disease research laboratory (VDRL), and antinuclear antibody tests; and Toxoplasma titers of 1/16, Van de Kamer 1.67 g/day. A barium examination revealed marked irregularity of the descending colon, and a colonoscopy showed uneven areas of mucosal edema and pseudopolyps in the transverse and descending colon, associated with irregular thickening and stenosis. Histopathologically, large intestine and skin lesions consisted of noncaseating epithelioid and giant cell granulomas (Fig. 2). Cultures for acid-fast bacilli and fungi were negative, and under polarized light no foreign bodies were seen. Treatment with metronidazole (250 mg three times a day), prednisone (0.5 mg/kg/day), and acetylsalicylic acid (75 mg/kg/day) was moderately effective. Vitamin, folic acid, and iron supplements were also added.     

Metastatic Crohn's disease of the umbilicus

We report a case of metastatic Crohn's disease of the umbilicus which responded to topical corticosteroid treatment, Crohn's disease is a granulomatous disease of the bowel which may a fleet other organs. The skin is commonly involved¹, and the cutaneous manifestations may be non-specific, e.g. pyoderma gangrenosum or erythema nodosum² or specific with epilhelioid granulomas and multinucleated giant cells in the skin. Specific skin lesions may be contiguous with the bowel at sites including the perineum, mouth and adjacent to fistulae, or separated from it by normal skin from the bowel, a rare condition which has been termed ‘metastatic’ Crohn's disease.³     

Subungual hyperkeratosis due to sarcoidosis

A 30-year-old Japanese woman presented to our clinic for evaluation and treatment of subungual hyperkeratotic lesions of the toenails. Five years previously the bilateral parotid glands and hilar lymph nodes became enlarged, and tender subcutaneous nodules developed in the lower extremities. Transbronchial lung biopsies showed epithelioid granulomas and systemic sarcoidosis was diagnosed. A skin biopsy showed nonspecific septal panniculitis, a finding compatible with erythema nodosum. Since then the patient had experienced intermittent episodes of low grade fever, general malaise, dyspnea, diarrhea, and superficial lymphadenopathy, and systemic steroid was administered when the disease was aggravated. The initial erythema nodosum subsided in a couple of months and was replaced by a large number of slightly scaly, erythematous papules and nodules in the lower extremities and in the face. The biopsy specimens of these lesions showed noncaseating epithelioid granulomas in the dermls. These cutaneous lesions waxed and waned along with the systemic symptoms. The patient had never had uveitis or lupus pernio. A few months previously new erythematous papules and nodules had developed in the face and in the lower extremities. Hyperkeratotic verrucous lesions also developed at the hyponychium and beneath the distal portion of the nail plates in all the toenails (Fig. 1a). The proximal and lateral nail folds and the nail plates appeared normal. Repeated potassium hydroxide stain and culture of the subungual hyperkeratotic materials were negative for fungus. Roentgenogram of the toe phalanges was normal. Interestingly, none of the fingernails were affected. A biopsy specimen of the nail bed showed orthokeratotic hyperkeratosis and acanthosis of the epidermis, but no papillomatosis or vacuolated keratinocytes (not shown). There were discrete epithelioid granulomas in the superficial dermis (Fig. 2). Systemic steroid, 30 mg/day, was administered because the patient's lung parenchymal lesions were aggravated. The subungual hyperkeratosis rapidly improved after administrating steroid for 2 weeks (Fig. 1b).     

Cutaneous granulomatous vasculitis: its relationship to systemic disease

Microscopic and medical review of twenty-six patients with skin biopsy specimens that showed granulomatous vasculitis demonstrated vascular histiocytic granulomas with fibrinoid destruction of blood vessels in the dermis and panniculus. Cultures of the biopsy specimens were nonspecific. The skin lesions varied from erythema to papulonodular and vesicular eruptions; they were usually on the extremities but also involved the trunk. Eight patients had systemic lymphoproliferative diseases: three, lymphoma; two, angioimmunoblastic lymphadenopathy; two, preleukemia; and one, chronic granulocytic leukemia. Five of these eight patients died within 2 years after the onset of skin lesions. The four patients with systemic vasculitis died within 1 year after the onset of skin lesions. Five patients with arthritis, four with gastrointestinal disease, three with systemic sarcoidosis or sarcoidlike disease, and one with tuberculosis had a more favorable prognosis. The histologic pattern of cutaneous nonlymphomatoid granulomatous vasculitis is associated with significant systemic disease, especially lymphoproliferative disorders. Patients with lymphoproliferative disorders or systemic vasculitis have a much poorer prognosis than those with inflammatory or infectious granulomatous disease.     

Palisading neutrophilic granulomatous dermatitis in a Japanese patient with Wegener's granulomatosis

Wegener's granulomatosis (WG) is an etiologically obscure entity with multiple systemic manifestations. Recently, cytoplasmic anti-neutrophil cytoplasmic antibody (C-ANCA) has become recognized as a valuable adjunct in the diagnosis of this disorder. WG typically involves the upper airway, lungs, and kidneys, but any other organ can be involved, including the skin. We encountered a unique case in which a 27-year-old Japanese man with WG presented with various typical cutaneous manifestations. Purpuric skin lesions and erythematous rash on the lower extremities progressively involved and changed into a necrotizing ulceration on his toe. Additionally, several nodules developed on the extensor surfaces of his elbows. His serum C-ANCA level increased remarkably. Leukocytoclastic vasculitis, the most common histopathological finding in WG patients, was detected in a purpuric lesion on his hand. A biopsy of a nodule on his elbow revealed palisading epithelioid histiocyte granulomas with features of leukocytoclastic vasculitis. The distinctive pattern of papules has been referred to as "palisading neutrophilic granulomatous dermatitis". An open lung biopsy confirmed WG with focal necrotizing granuloma. A renal biopsy demonstrated necrotizing vasculitis and crescentic glomerulonephritis. He showed a good response to oral corticosteroids and cyclophospamide with total remission of symptoms. We believe that a careful balance between the clinical manifestations and the histopathological evidence allows for timely treatment of WG, which may prevent serious morbidity or death. Although uncommon, WG can present with various types of accompanying cutaneous lesions. Therefore, clinicians should keep this diagnosis in mind when presented with these manifestations.     

Eosinophilic panniculitis: a clinicopathologic study

Study of 18 patients with biopsy diagnoses of eosinophilic panniculitis revealed diverse patterns of systemic disease, including Wells' syndrome, vasculitis, atopy, and erythema nodosum as well as localized panniculitis. Significant associated diseases included psychiatric illness, 6 (drug dependency, 4); atopy, 5 (asthma, 3); malignancies, 5; immune complex vasculitis, 4; thyroid disease, 2; Wells' eosinophilic cellulitis, 2; glomerulonephritis and sarcoidosis, 1 each. The skin lesions varied from urticarial papules and plaques to purpura, pustules, and ulcerative lesions but always included a nodular subcutaneous component, frequently as a presenting complaint. Eosinophilic panniculitis is a non-specific finding that can signify localized disease, such as an insect bite or injection lipophagic granuloma in a drug-dependent patient, or systemic lymphoma or immune reactive disease. Eosinophilic panniculitis in erythema nodosum is perhaps its most confusing presentation.     

Erythema nodosum and erythema induratum (nodular vasculitis): diagnosis and management

Erythema nodosum is the most common type of panniculitis; it may be due to a variety of underlying infectious or otherwise antigenic stimuli. The pathogenesis remains to be elucidated, but both neutrophilic inflammation and granulomatous inflammation are implicated. Beyond treating underlying triggers, therapeutic options consist mainly of nonsteroidal anti‐inflammatory drugs, symptomatic care, potassium iodide, and colchicine. Erythema induratum (nodular vasculitis) is a related but distinctly different clinicopathologic reaction pattern of the subcutaneous fat. It is classically caused by an antigenic stimulus from Mycobacterium tuberculosis but may be associated with several other underlying disorders. After appropriate antimicrobial treatment in tuberculous cases, therapy for erythema induratum is similar to options for erythema nodosum.     

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.     

Nodular vasculitis associated with lung adenocarcinoma

Nodular vasculitis is an uncommon type of panniculitis. It was firstly associated to the infection by Mycobacterium tuberculosis and named erythema induratum of Bazin, however nowadays it has been associated with several other underlying disorders and it is better described as nodular vasculitis. Concerning its relationship with malignant conditions, there is only one reported case, in association with metastatic colon adenocarcinoma. We report a case of nodular vasculitis as the first manifestation of lung adenocarcinoma. To the best of our knowledge, this is the first reported association of both diseases.     

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.     

Cutaneous vasculitis update: neutrophilic muscular vessel and eosinophilic, granulomatous, and lymphocytic vasculitis syndromes

Most biopsies of cutaneous vasculitis will exhibit a small vessel neutrophilic vasculitis [leukocytoclastic vasculitis (LCV)] that is associated with immune complexes on direct immunofluorescence examination or, less commonly, antineutrophilic cytoplasmic antibodies (ANCA) by indirect immunofluorescence testing. Is in uncommon for skin biopsy to reveal solely a neutrophilic arteritis signifying the presence of cutaneous polyarteritis nodosa or, if accompanied by significant lobular panniculitis, nodular vasculitis/erythema induratum. In other cases, cutaneous vascular damage (fibrinoid necrosis, muscular vessel wall disruption, or endarteritis obliterans) will be mediated by a nonneutrophilic inflammatory infiltrate. Eosinophilic vasculitis can be a primary (idiopathic) process that overlaps with hypereosinophilic syndrome, or it can be a secondary vasculitis associated with connective tissue disease or parasite infestation. Authentic cutaneous granulomatous vasculitis (versus vasculitis with extravascular granulomas) can represent a cutaneous manifestation of giant cell arteritis, an eruption secondary to systemic disease such as Crohn's disease or sarcoidosis, or a localized disorder, often a post-herpes zoster (HZ) phenomenon. Lymphocytic vasculitis is a histologic reaction pattern that correlates with broad clinical differential diagnosis, which includes connective tissue disease - mostly systemic lupus erythematosus (SLE), endothelial infection by Rickettsia and viruses, idiopathic lichenoid dermatoses such as perniosis or ulcerative necrotic Mucha-Habermann disease, and angiocentric cutaneous T-cell lymphomas. Skin biopsy extending into the subcutis, identifying the dominant inflammatory cell and caliber of vessels affected, extravascular histologic clues such as presence of lichenoid dermatitis or panniculitis, and correlation with clinical data allows for accurate diagnosis of these uncommon vasculitic entities.     

Granulomatous rosacea: unusual presentation as solitary plaque

A 45-year-old male presented with a 6 month history of an enlarging smooth, erythematous plaque over the central part of his face. Mild erythema of both eyes was present. Sarcoidosis, Hansen disease, lupus vulgaris, cutaneous leishmaniasis, pseudolymphoma, foreign body granuloma, granuloma faciale, discoid lupus erythematosus, and granulomatous rosacea were considered in the differential diagnosis. CBC, urinalysis, renal function tests, liver function tests, serum electrolytes, and blood sugar were all normal. Chest X-ray and ECG revealed no abnormality. Serology for syphilis and HIV, and mantoux test were negative. Slit-skin smear, tissue smear and culture for AFB and fungi were negative. Skin biopsy revealed multiple non-caseating epitheloid granulomas around the pilosebaceous unit suggestive of granulomatous rosacea. Granulomatous rosacea, a rare entity comprising only about 10 percent of cases of rosacea can mimic many granulomatous conditions both clinically and histologically making the diagnosis an enigma. It usually presents as yellowish brown-red discrete papules on the face; non-caseating epithelioid granulomas are seen on histology examination. We herein report the case because it presented in atypical fashion, as a solitary indurated plaque on the nose, likely representing Morbihan's disease or solid persistent facial edema of rosacea (rosacea lymphedema).