Panniculitides of particular interest to the rheumatologist.

The panniculitides remain as one of the most challenging areas for clinicians, as they comprise a heterogeneous group of inflammatory diseases involving the subcutaneous fat with potentially-shared clinical and histopathological features. Clinically, most panniculitides present as red edematous nodules or plaques. Therefore, in addition to a detailed clinical history, a large scalpel biopsy of a recent-stage lesion with adequate representation of the subcutaneous tissue is essential to specific diagnosis and appropriate clinical management. Herein we review the panniculitides of particular interest to the rheumatologist.

Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome.

Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3's plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, promoting HLH and SPTCL. Our findings highlight HLH-SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH-SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.

Subcutaneous Panniculitis-Like T-cell Lymphoma in Dogs: Morphologic and Immunohistochemical Classification.

Canine nonepitheliotropic cutaneous T-cell lymphomas (NECTCL) are poorly characterized. In humans, a number of distinct subtypes of NECTCL have been recognized, including subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Five dogs with subcutaneous T-cell lymphomas histologically similar to SPTCL in humans are herein described. The mean age was 8.5 years (5.5 to 12 years). No breed or sex predilection was identified in this small cohort. Two dogs presented with an acute onset of multiple skin masses and 3 dogs had solitary masses with subsequent development of multiple smaller masses within 0.5 to 2 months post-diagnosis without treatment. Locations, when specified, included shoulder, neck, and ventral abdomen. Two dogs were euthanized following diagnosis and one dog treated with chemotherapy (CCNU) survived 7 months post-diagnosis. Histologically, all cases were characterized by proliferations of either small to intermediate or large sized, CD3-positive T cells that infiltrated the subcutis in a lace-like pattern and frequently rimmed adipocytes. No epitheliotropism was observed, neoplastic cells were often karyorrhectic, and there were regions of extensive necrosis. Heavy infiltrates of histiocytes with prominent phagocytosis masked the lymphoid neoplastic cell population in some sections. A clonal T-cell receptor gamma gene rearrangement was found in 4 of the 5 cases. While SPTCLs typically have a less aggressive clinical course in humans, their biological behavior in dogs remains to be determined. In summary, SPTCL may represent a distinct entity in dogs and needs to be accurately diagnosed to better determine clinical behavior.

Sclerosing mesenteritis and mesenteric panniculitis - clinical experience and radiological features.

BACKGROUND: Sclerosing mesenteritis (SM) is sometimes used as an umbrella-term for idiopathic inflammatory conditions in the mesentery. Mesenteric panniculitis (MP) is a radiological finding and its relation to clinical SM is not fully understood. The aims of this study were to determine whether any correlation could be found between the radiological findings and the clinical disease course. METHODS: Patients observed due to idiopathic inflammation of the mesentery were identified. If SM could be verified histologically or MP radiologically, the patients were included in this descriptive retro perspective study. RESULTS: Typical radiological changes were observed in 27 patients. A majority (23/27) of these patients had mild to moderate symptoms. This group with typical radiology was labelled MP. Four patients were included due to histologically verified disease but had uncharacteristic radiology involving multiple compartments of the abdomen. All four had marked systemic inflammation, fever and fluctuating radiologic findings. Three had severe disease with multiple hospitalisations and complications but responded promptly to corticosteroids. This group was denoted SM. CONCLUSIONS: We have identified two subgroups of patients; firstly, MP with stable and characteristic radiologic changes and secondly SM with atypical radiology and a more aggressive clinical course. We propose that the term SM should be reserved for this latter condition.

[Cutaneous panniculitis]. / Panniculites cutanées.

Panniculitis is an inflammation of the subcutaneous fat. Skin biopsy plays a critical role in the differential diagnosis of panniculitis. The most common approach to diagnosis relies on the differentiation between predominantly septal or lobular panniculitis, followed by the distinction between lesions with and without vasculitis. It is also very important to submit a part of the skin biopsy for microbiological analysis and for T-cell clonal expansion if T-cell lymphoma is suspected. Erythema nodosum, the most frequent septal panniculitis, has many causes and in its typical clinical presentation, does not require skin biopsy. In other panniculitis, diagnosis is based on the integration of the clinical and histological data, which renders a deep cutaneous biopsy necessary. Periarteritis nodosa, a septal panniculitis with vasculitis characterized by subcutaneous nodules and livedo racemosa, can be associated with systemic involvement. Nodular thrombophlebitis needs search for associated coagulopathy, Behçet's disease, periarteritis nodosa or Buerger's disease. Lobular panniculitis are classified according to the nature of cells present in the inflammatory infiltrate. If there is a lymphocytic infiltration, lupus panniculitis is difficult to differentiate from subcutaneous panniculitis-like T-cell lymphoma. If there are histiocytes, it can be a sarcoidosis, a cytophagic histiocytic panniculitis or, in newborn, a subcutaneous fat necrosis. Neutrophilic panniculitis needs careful clinic-pathologic correlation. Treatment of panniculitis can be challenging and is based on the histopathological findings. Frequently, the precise cause of panniculitis cannot be established from the outset, so it is important to follow-up patients and not hesitate to repeat the skin biopsy.

Cold-Associated Perniosis of the Thighs ("Equestrian-Type" Chilblain): A Reappraisal Based on a Clinicopathologic and Immunohistochemical Study of 6 Cases.

Cold-associated perniosis of the thighs ("equestrian cold panniculitis") is an unusual and still enigmatic entity. The authors retrieved 6 cases for a re-evaluation of their clinicopathologic features and for an immunohistochemical assessment with antibodies anti-CD3, anti-CD20, and anti-CD123. All patients were women, aged 17-45 years. One of them had elevated antinuclear antibody titers. Available anamnestic data confirmed the triggering role of prolonged/intermittent exposure to cold (not necessarily for equestrian activities). The lesions affected the thighs, with a preferential, although not exclusive involvement of the upper lateral surface. The histopathological pattern was perivascular, superficial, and deep, extending toward the superficial fat lobules, with lymphocytic vasculitis and mucin deposition; clumps of CD123 cells were found in 4 of 6 cases. Cold-associated perniosis of the thighs cannot be considered as a panniculitis. The histopathological features considerably overlap with perniosis at other sites of the body and with chilblain lupus erythematosus.

Histological Classification and Differential Diagnosis of Nonepisodic Angioedema With Eosinophilia: A Clinicopathologic Study of 12 Cases With Literature Review.

Nonepisodic angioedema with eosinophilia (NEAE) is a rare condition characterized with monoepisodic angioedema, a nonfebrile state, eosinophilia, normal serum IgM levels, and lack of internal organ involvement. The histology of this disease is not yet well known. The purpose of this study was to characterize the histopathologic features of NEAE. Twelve cases of clinically confirmed NEAE were retrieved from 6 institutions, and these cases were reviewed regarding the clinical data and histopathology, particularly regarding granulomatous lesions. The authors demonstrated that the histology of NEAE can be classified into 3 patterns that of eosinophilic granulomatous panniculitis (7/12 cases), eosinophilic dermatitis without granuloma formation (3/12 cases), and invisible dermatosis (2/12 cases). Six of the 7 granulomatous cases showed the characteristic eosinophilic granulomatous lesions containing individual necrotic adipocytes with membranous fat changes, which could be a differential clue to the diagnosis of NEAE. Review of the previously reported cases (n = 37) revealed that the histological classification could be adaptable to these reported cases. The authors should recognize the histological variation of NEAE and distinguish it from the histological mimickers, including eosinophilic granulomatosis with polyangiitis, erythema nodosum, hypereosinophilic syndrome, and episodic angioedema with eosinophilia.

Lymphocytic panniculitis: an algorithmic approach to lymphocytes in subcutaneous tissue.

The diagnosis of panniculitis is a relatively rare occurrence for many practising pathologists. The smaller subset of lymphocyte-predominant panniculitis is further complicated by the diagnostic consideration of T cell lymphoma involving the subcutaneous tissue, mimicking inflammatory causes of panniculitis. Accurate classification of the panniculitis is crucial to direct clinical management as treatment options may vary from non-medical therapy to immunosuppressive agents to aggressive chemotherapy. Many diseases show significant overlap in clinical and histological features, making the process of determining a specific diagnosis very challenging. However, with an adequate biopsy including skin and deep subcutaneous tissue, a collaborative effort between clinician and pathologist can often lead to a specific diagnosis. This review provides an algorithmic approach to the diagnosis of lymphocyte-predominant panniculitis, including entities of septal-predominant pattern panniculitis (erythema nodosum, deep necrobiosis lipoidica, morphea profunda and sclerosing panniculitis) and lobular-predominant pattern panniculitis (lupus erythematous panniculitis/lupus profundus, subcutaneous panniculitis-like T cell lymphoma, cutaneous γ-δ T cell lymphoma, Borrelia infection and cold panniculitis).

Canine sterile nodular panniculitis: a retrospective study of 39 dogs.

BACKGROUND: Canine sterile nodular panniculitis (SNP) is an inflammatory disease of the panniculus that is typically managed with immunomodulatory or immunosuppressive treatments. It has been reported to be a cutaneous marker of an underlying systemic disease. HYPOTHESIS/OBJECTIVES: To assess the presence or absence of concurrent systemic diseases associated with canine SNP and to document breed predispositions. ANIMALS: Thirty nine dogs presented to a veterinary teaching hospital from 1990 to 2012 which met inclusion criteria. METHODS: Inclusion in this retrospective study required a diagnosis of SNP via histopathological analysis and negative special stains for infectious organisms. Breed distributions of affected dogs were compared to all other dogs examined at this hospital during the study period. Correlations between the histological pattern of panniculitis and the histological presence of dermatitis, clinical presentation of lesions, dog breed and therapeutic outcomes were assessed. RESULTS: Australian shepherd dogs, Brittany spaniels, Dalmatians, Pomeranians and Chihuahuas were significantly over-represented, but correlations between inflammatory patterns of panniculitis and other histological and clinical factors were not identified. Based on the information available in medical records, 32 dogs (82.1%) had no concurrent systemic diseases identified. Four dogs had concurrent polyarthritis, which may be related to SNP through unknown mechanisms. CONCLUSIONS/CLINICAL IMPORTANCE: This study identified several novel breed predilections for SNP; it failed to find any clear correlations with associated systemic diseases other than polyarthritis. The histological inflammatory pattern of SNP does not predict therapeutic outcome.

The classification and diagnosis of cutaneous lupus erythematosus.

Lupus erythematosus (LE) is an inflammatory connective tissue disease of generalized autoimmunity characterized by pathogenic autoantibodies and immune complexes, attributed to loss of immune tolerance. Cutaneous involvement, which appears in the majority of patients with the disease, can present as LE-specific or LE-nonspecific manifestations. The LE-nonspecific manifestations include e.g. vascular skin changes and may be associated with systemic organ manifestations or other autoimmune diseases. In contrast, the LE-specific manifestations encompass the various subtypes of cutaneous lupus erythematosus (CLE), which are classified as separate entities without or with less severe systemic organ involvement. In the "Duesseldorf Classification", CLE is subdivided into four different categories: acute CLE (ACLE), subacute CLE (SCLE), chronic CLE (CCLE), and intermittent CLE (ICLE). Differentiation between these subtypes is based on clinical features and average duration of the cutaneous lesions, but can also consider histological changes of skin biopsy specimens and laboratory abnormalities. In addition, direct immunofluorescence and photoprovocation may be applied to confirm the diagnosis in specific cases. Further investigations should be considered dependent on the clinical symptoms of the CLE patient and the results of the laboratory tests. A revised scoring system, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI) has recently been validated to assess disease activity and damage in CLE. In this review, we focus on the classification of CLE and the diagnostic procedures to identify and confirm the different subtypes of the disease.

Panniculitides, an algorithmic approach.

The issue of inflammatory diseases of subcutis and its mimicries is generally considered a difficult field of dermatopathology. Yet, in my experience, with appropriate biopsies and good clinicopathological correlation, a specific diagnosis of panniculitides can usually be made. Thereby, knowledge about some basic anatomic and pathological issues is essential. Anatomy differentiates within the panniculus between the fatty lobules separated by fibrous septa. Pathologically, inflammation of panniculus is defined and recognized by an inflammatory process which leads to tissue damage and necrosis. Several types of fat necrosis are observed: xanthomatized macrophages in lipophagic necrosis; granular fat necrosis and fat micropseudocysts in liquefactive fat necrosis; mummified adipocytes in "hyalinizing" fat necrosis with/without saponification and/or calcification; and lipomembranous membranes in membranous fat necrosis. In an algorithmic approach the recognition of an inflammatory process recognized by features as elaborated above is best followed in three steps: recognition of pattern, second of subpattern, and finally of presence and composition of inflammatory cells. Pattern differentiates a mostly septal or mostly lobular distribution at scanning magnification. In the subpattern category one looks for the presence or absence of vasculitis, and, if this is the case, the size and the nature of the involved blood vessel: arterioles and small arteries or veins; capillaries or postcapillary venules. The third step will be to identify the nature of the cells present in the inflammatory infiltrate and, finally, to look for additional histopathologic features that allow for a specific final diagnosis in the language of clinical dermatology of disease involving the subcutaneous fat.

Panniculitis in children.

This paper will give a comprehensive view of the most frequent panniculitides seen in childhood, with emphasis on the types exclusively found in infancy, and for all other types of panniculitides also found in adults. Aim of this paper is also to analyze the clinical differences between panniculitis in childhood and in adulthood, and to give reliable histopathologic criteria for a specific diagnosis. A review of the literature is here integrated by authors' personal contribution. Panniculitides in children is a heterogeneous group of diseases, as well as in adult life, characterized by inflammation of the subcutaneous fat. Only very few types of panniculitis are exclusively found in childhood, such as Sclerema neonatorum and subcutaneous fat necrosis of the newborn, while the vast majority of the other types may be found both in paediatric age and in adults. Furthermore, this paper will consider in detail panniculitis according to their frequency, such as Erythema nodosum, Lupus panniculitis, Cold panniculitis, panniculitis in Behçet disease, and poststeroid panniculitis. It will also describe rare forms of panniculitis, such as Eosinophilic panniculitis (a pathological entity debated by many authors), Subcutaneous panniculitis T-cell lymphoma, and the different forms of the so call "Lipophagic panniculitis", encompassing respectively the febrile relapsing panniculitis of Weber-Christian disease and the non-relapsing form of Rothmann-Makai disease. For each type of panniculitis considered concise information will be given about epidemiology, etiology, clinical findings, laboratory data, prognosis and therapy, while histopathologic findings will be described in detail.

Subcutaneous panniculitis-like T-cell lymphoma.

Subcutaneous panniculitis like T-cell lymphoma derived from α/ß T-cells (SPTCL-AB) belongs to the group of primary cutaneous T-cell lymphoma, and it represents less than the 1% of all primary cutaneous T-cell lymphomas. It affects patients in the 4th decade of life (median age of 36 years) with a female preference (male/female ratio 0.5) with 19% of patients being 20 years or younger. It can be sometime complicated by a hemophagocytic syndrome, and patients without hemophagocytic syndrome had a significantly better survival (5-year OS: 91% vs. 46%). Histopathologically, SPTCL-AB is characterized by a lobular lymphocytic panniculitis. Tumor cells distribute between individual adipose lobules, proliferating and forming "rim" and "capping" images, conferring a lace-like appearance at scanning magnification. This is not an entirely disease-specific feature, and can also be seen in other lobular lymphocytic panniculitis, either of inflammatory and neoplastic origin. Tumor cells are phenotypically CD45RO+, ßF1+ (a monoclonal antibody able to identify the alpha/beta chain of TCR), CD3+, CD4-, CD8+, and express cytotoxic granules (TIA-1, granzyme and perforin), whereas they show variable deletion of T-cell restricted antigens like CD2, CD5 and CD7. The majority of cases show a monoclonal rearrangement for TCR beta and gamma genes and do not show genomic integration of EBV. The present review will focus on histopathologic, immunophenotypical and molecolare data useful to overcome to a specific diagnosis of SPTCL-AB and to differentiate SPTCL-AB from other lymphomas of T-cell or NK/T cell origin and with benign panniculitidis sharing with SPTCL-AB a predominant lobular lymphocytic pattern of involvement of subcutaneous tissue.

Infectious panniculitides: an update.

Very few areas in the realm of diagnostic dermatopathology may be so challenging both for the dermatologist and the histopathologist as are those related to panniculitis, because of their frequent overlapping microscopical patterns and uncertain etiology. Classically, a dicotomic taxonomy key has been proposed according the prevalent involvement of subcutaneous septa or lobules of the inflammation, presence or absence of vasculitis and type of vessel involved, but exceptions to this approach do occur and overlapping forms are sometimes encountered. Infectious panniculitides have also been traditionally approached according to this schema, and their microscopic diagnosis may be even more complex when the causative agent is unknown and underrepresented in the specimen. Many types of pathogens are capable to evoke protean clinical manifestations, which range from organism-specific to aspecific pictures. For this reason a tissue biopsy is always mandatory to ascertain the type of lesion and differentiate an infectious process from its many other mimickers essentially represented by reactive-based panniculitides. Recognition of morphologic changes which characterize distinct infections in the subcutis often needs a complete clinical history, physical examination and laboratory studies, especially when few microorganisms if any are found. This review will be focussed on the pathophysiology of the adipose tissue in relation to immunity and mechanisms of host reaction. The most frequent infectious panniculitides will then be discussed with special reference to their microscopic pictures, to provide clues to their specific diagnosis and the use of immunohistochemistry and molecular biology techniques as ancillary techniques.

Cytophagic histiocytic panniculitis in a 74-year-old man.

Cytophagic histiocytic panniculitis is a chronic histiocytic disease of the subcutaneous adipose tissue characterised by lobular panniculitis with histiocytes containing blood cell fragments. It is also associated with marked systemic features such as fever, pancytopenia, hepatosplenomegaly, liver abnormalities and coagulopathy. We report a case of cytophagic histiocytic panniculitis in a 74-year-old man successfully treated using combination therapy with prednisolone and cyclosporine A.

Xanthogranulomatous panniculitis of the head of an aquarium-maintained California moray.

An aquarium-maintained male California moray Gymnothorax mordax had a symmetrical enlargement of the soft tissues of the head dorsal to the cranium for 2 years prior to its death. This individual was anesthetized for radiographic and ultrasonographic examination of the lesion, and blood was collected for plasma biochemical analytes and lipid profiles. Radiographs and ultrasound of the lesion demonstrated a symmetrical and homogeneous soft tissue density that was consistent with adipose tissue. Plasma cholesterol and triglyceride values appeared elevated; therefore, the animal's diet was amended to decrease fat consumption. Triglyceride values decreased after dietary changes were made; however, values for cholesterol, high-density lipoproteins, and low-density lipoproteins fluctuated but remained largely unchanged. Histopathological assessment of the lesion revealed localized xanthogranulomatous inflammation of hypodermal adipose tissue. The etiology of the lesion in this animal was never determined. This paper describes the first documented case of localized xanthogranulomatous panniculitis in a California moray and demonstrates the need for additional research on specific dietary requirements, species-specific physiological differences, and lesions involving the adipose tissue of morays in comparison with other teleost species.

Anatomy and histology of normal subcutaneous fat, necrosis of adipocytes, and classification of the panniculitides.

The panniculitides comprise a group of heterogeneous inflammatory diseases that involve the subcutaneous fat. Histopathologic study is required for the specific diagnosis of these disorders, because different panniculitides usually show the same clinical appearance, which consists of erythematous nodules on the lower extremities. The histopathologic study of panniculitis is difficult, however, because of an inadequate clinicopathologic correlation and the changing evolutive nature of the lesions. Some cutaneous lymphomas may simulate panniculitis, both from clinical and histopathologic points of view, and for that reason are included in this article despite the fact that they are not inflammatory processes but authentic lymphocytic neoplasms involving subcutaneous tissue.

Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases.

In the WHO classification, subcutaneous panniculitis-like T-cell lymphoma (SPTL) is defined as a distinct type of T-cell lymphoma with an aggressive clinical behavior. Recent studies suggest that distinction should be made between SPTL with an alpha/beta T-cell phenotype (SPTL-AB) and SPTL with a gammadelta T-cell phenotype (SPTL-GD), but studies are limited. To better define their clinicopathologic features, immunophenotype, treatment, and survival, 63 SPTL-ABs and 20 SPTL-GDs were studied at a workshop of the EORTC Cutaneous Lymphoma Group. SPTL-ABs were generally confined to the subcutis, had a CD4-, CD8+, CD56-, betaF1+ phenotype, were uncommonly associated with a hemophagocytic syndrome (HPS; 17%), and had a favorable prognosis (5-year overall survival [OS]: 82%). SPTL-AB patients without HPS had a significantly better survival than patients with HPS (5-year OS: 91% vs 46%; P<.001). SPTL-GDs often showed (epi)dermal involvement and/or ulceration, a CD4-, CD8-, CD56+/-, betaF1- T-cell phenotype, and poor prognosis (5-year OS: 11%), irrespective of the presence of HPS or type of treatment. These results indicate that SPTL-AB and SPTL-GD are distinct entities, and justify that the term SPTL should further be used only for SPTL-AB. SPTL-ABs without associated HPS have an excellent prognosis, and multiagent chemotherapy as first choice of treatment should be questioned.

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.