Kaposi sarcoma misdiagnosed as granuloma annulare: A case of mistaken identity.

The microscopic features of patch stage Kaposi sarcoma (KS) and interstitial granuloma annulare (GA) may be difficult to differentiate, because both may exhibit a subtle "busy" dermis due to infiltration of spindled cells between collagen bundles. The clinical distinction is particularly challenging in human immunodeficiency virus (HIV)-affected individuals, as the incidence of GA appears to be greater in the HIV-infected population. KS is the most common neoplasm in this population. Despite the significant decrease in the incidence of KS since the advent of highly active antiretroviral therapy (HAART), KS tends to occur with late onset and indolent progression in patients with preserved immune function and minimal viral load. We present a 47-year-old homosexual HIV-positive man, under virologic and immunologic control on long-term HAART therapy, with a 5-year history of progressive red-brown patches and plaques on the legs, feet, hands, and trunk. Prior skin biopsy specimens were interpreted as interstitial GA. Histopathology on new skin biopsy specimens along with review specimens supported the diagnosis of plaque and patch stages of KS, respectively, supported by immunohistochemical expression of human herpes virus-8 (HHV-8). This case underscores the importance of maintaining a high suspicion for KS in progressive, treatment-recalcitrant skin lesions, particularly in HIV-infected individuals.

The interstitial variant of granuloma annulare: Clinicopathologic study of 69 cases with a comparison with conventional granuloma annulare.

BACKGROUND: The full-blown lesion of granuloma annulare (GA) is characterized by necrobiotic granulomas with palisading of histiocytes and stromal mucin deposition. Cases in which the granulomatous features are not fully developed have been described as the "interstitial" variant; however, there is no good definition regarding their criteria for diagnosis. METHODS: We conducted a retrospective study of 97 cases of GA. RESULTS: Cases of interstitial GA (69) were paucicellular with scant to no mucin, with only a few scattered mononuclear cells but lacking well-formed granulomas with multinucleated giant cells. Immunohistochemical study showed that the cells in conventional cases of GA stained strongly positive for CD68 and CD163, whereas the small mononuclear cells in interstitial GA were strongly positive only for CD163. CONCLUSIONS: Interstitial GA differs from the classical GA in several respects, including morphology and immunophenotype. Use of antibodies to CD163 may be helpful for distinguishing the interstitial variant from other conditions. Recognition of the interstitial variant is of importance to explain the presence of lesions that clinically are suspicious for GA but histologically do not resemble the conventional form of the disease.

Keratoacanthomatous Changes: Unifying the Histologic Spectrum of Actinic Granuloma.

Actinic granuloma (AG) manifests as annular plaques on sun-damaged skin. There remains no universal consensus on the nosology, etiology, or clinicopathologic criteria of AG as a distinct entity. Broadly, AG is characterized by granulomatous inflammation, multinucleated giant cells, elastophagocytosis, and the absence of mucin and necrobiosis. It is not uncommon, however, to encounter overlapping histological features of other granulomas, such as granuloma annulare and necrobiosis lipoidica, confounding the diagnosis of this controversial entity. Herein, we describe 2 cases of AG with features of granuloma annulare and necrobiosis lipoidica, supporting the concept of AG as a histologic spectrum. These 2 cases displayed dilated follicular infundibula and pseudoepitheliomatous hyperplasia analogous to changes in keratoacanthomas. These unique epithelial changes, in tandem with characteristic elastin alterations and clinical findings, are helpful and unifying features that permit accurate diagnosis of this controversial entity.

Intraorbital granuloma annulare in an elderly patient.

Classically, granuloma annulare (GA) is a cutaneous disorder localized to the dorsum of the hands and/or feet in children and young adults. Very rarely it can present on the face and rarer still on periorbital structures such as the eyelid and orbital rim. Diagnosis hinges on clinical presentation and histological features, such as palisading granulomas with central destruction of collagen, presence of mucin and lymphohistiocytic infiltration. The etiology of this condition remains unknown, but may involve a delayed-type hypersensitivity reaction, malignancy and/or infection. Herein is the first reported case of an intraorbital GA in an 86-year-old male patient who presented with right eye proptosis.

Immunohistochemical Features of MMP-9 and pSTAT1 in Granuloma Annulare and Sarcoidosis: A Comparative Study of 62 Cases.

Background: Granuloma annulare (GA) and sarcoidosis are granulomatous inflammatory diseases that share similarities. Objective: To identify the histological and immunohistochemical (IHC) features of GA and sarcoidosis. Methods: A retrospective review of 36 patients with GA and 26 with sarcoidosis was performed. Results from hematoxylin and eosin (H&E) staining and IHC staining of MMP-9 and pSTAT1 within the skin lesions of GA and sarcoidosis were analyzed, and random forest was applied for developing a predictive model. Results: Significantly greater expressions of MMP-9 (especially in elastic fibers, EFs, P < 0.0001) and pSTAT1 (P = 0.0003) were observed in lesion samples of GA versus sarcoidosis patients. In GA patients, MMP-9 was significantly upregulated in the interstitial type (P = 0.0222), while staining of pSTAT1 was positively correlated with the area of mucinous collagen in palisading GA (R = 0.5356, P = 0.0484). In sarcoidosis patients, MMP-9 (R = -0.7127, P = 0.0009) and pSTAT1 (R = -0.5604, P = 0.0067) were found to show stronger expressions in lesions with less lymphocyte infiltration. The predictive model demonstrated an AUC of 0.9675. Conclusion: These results indicate that MMP-9 and pSTAT1 might exert roles in granulomatous inflammation in different modes, and the presence of more robust MMP-9 staining in EFs appears to be more suggestive of GA.

Granuloma annulare-like eruption associated with B-cell chronic lymphocytic leukemia.

BACKGROUND: Cutaneous granulomatous inflammation can occur in patients with T-cell lymphoma and Hodgkin disease. We describe the unusual microscopic pattern of a granuloma annulare (GA)-like eruption co-existing with B-cell chronic lymphocytic leukemia (B-CLL). METHODS: We reviewed the histopathology and immunophenotype of skin biopsies from two patients with B-CLL and cutaneous lesions resembling GA. RESULTS: Both patients had symptomatic cutaneous lesions clinically resembling GA; one had lesions refractory to standard dermatologic therapy. Histopathology showed GA-like palisaded histiocytic infiltration, with subtle collections of lymphocytes interspersed among the granulomatous inflammation. Immunohistochemistry showed strong expression of CD20 and CD79a, with aberrant CD5 co-expression, confirming cutaneous involvement by B-CLL. CONCLUSIONS: Co-existence of a GA-like infiltrate and cutaneous B-CLL raises the possibility that granulomatous inflammation occurs as a secondary response to dermal infiltration by leukemic cells. Because histopathologic findings can be subtle, knowledge of this association is essential to avoid overlooking the diagnosis. Regardless of whether histopathology reflects a reactive or primary phenomenon, documentation of cutaneous involvement by B-CLL may serve as a rationale for specific treatment of the underlying B-CLL in patients with skin lesions unresponsive to dermatologic therapy and for whom there is no other justification for leukemia-targeted therapy.

Granuloma annulare of the penis: a uncommon location for an usual disease.

The subcutaneous clinical variant of granuloma annulare (GA) is rare and tends to present more frequently in children, in locations unusual for conventional GA. Involvement of the penis is exceptional and has been rarely reported. Most cases are located in the shaft of the penis and tend to persist without spontaneous remission. Diagnosis is done only after biopsy, and surgical resection of the lesions is not unusual. We report a new case of subcutaneous GA of the penis in a 13-year-old boy with lesions persistent for the past year. Surgical excision of one of them allowed the correct diagnosis. No further treatment was done, and the condition has not remitted 1 year later. We stress the importance of clinical recognition of unusual presentations of GA to avoid overtreatment of lesions that do not need an aggressive approach.

Collagen-elastic tissue changes and vascular involvement in granuloma annulare: a review of 35 cases.

BACKGROUND: The pathogenesis of granuloma annulare (GA) is unclear. Collagen fiber degeneration is commonly reported, and there are several conflicting studies on elastic fiber and vascular changes associated with GA. In this study, we aimed to evaluate histopathologic characteristics, collagen and elastic tissue changes and vascular changes in GA. METHODS: Clinical records of 35 GA patients were examined alongside serial sections of 38 biopsy specimens from these patients. New sections of biopsy tissue were stained with hematoxylin and eosin, Verhoeff-van Gieson or Alcian blue and then evaluated. RESULTS: Four different histopathologic patterns were observed: interstitial (57.9%), palisadic granulomatous (26.3%), sarcoidal granulomatous (5.3%) and mixed (10.5%). Dermal mucin deposition was determined in 84.2% of specimens. Solar elastosis was observed in only seven specimens, and elastophagocytosis was observed in only two specimens. Collagen and elastic tissue damages were consistent findings in all biopsy specimens. Fibrin thrombi and vasculitic changes were not found in any of the specimens from this patient group. CONCLUSIONS: Elastic and collagen fiber damage are the main accompanying features of GA, which may develop from delayed-type hypersensitivity. Vasculitis does not appear to be a major causative process. Sun exposure also seems to have no major effect on the formation of GA but can be one of the stimulants or predisposing factors.

INI1 and GLUT-1 expression in epithelioid sarcoma and its cutaneous neoplastic and nonneoplastic mimics.

The morphological features of epithelioid sarcoma may closely mimic those of epithelial neoplasms, such as squamous cell carcinoma, mesenchymal tumors, such as benign fibrous histiocytoma, and nonneoplastic lesions, such as granuloma annulare. Immunohistochemistry, particularly for epithelial markers and CD34, thus plays a valuable role in the differential diagnosis of epithelioid sarcoma. However, some epithelioid sarcomas may show very focal or even absent expression of such markers and may be difficult to distinguish from various morphological mimics. There is therefore continued interest in the development of new immunohistochemical markers of epithelioid sarcoma. Recently, loss of expression of INI1, a tumor suppressor gene/protein, and expression of GLUT-1, a glucose transporter protein, have been described in epithelioid sarcoma. We examined the utility of immunohistochemistry for INI1 and GLUT-1 in the diagnosis of epithelioid sarcoma and various cutaneous mimics. Twenty-four cases of epithelioid sarcoma, 13 cases of granuloma annulare, 10 cases of rheumatoid nodule, 19 cases of cutaneous squamous cell carcinoma, 7 cases of atypical fibroxanthoma, 9 cases of benign fibrous histiocytoma (dermatofibroma), and 3 cases of nodular fasciitis were immunostained for GLUT-1 and INI1 using commercially available antibodies, heat-induced epitope retrieval, and the Dako Envision detection system. Total or near-total loss of normal constitutive expression of INI1 protein was noted in more than 85% of epithelioid sarcomas, with 19 of 24 cases (79%) showing complete loss of INI1 expression. In contrast, all other cases studied showed uniformly retained expression of INI1. GLUT-1 was positive in 40%-50% of epithelioid sarcomas, all cases of granuloma annulare and rheumatoid nodules, 67% of benign fibrous histiocytomas, and in all squamous cell carcinomas. In contrast, atypical fibroxanthomas and cases of nodular fasciitis were consistently GLUT-1 negative. We conclude that immunohistochemistry for INI1 expression should be included as part of the routine immunohistochemical panel for the diagnosis of epithelioid sarcoma, along with established markers such as wide-spectrum cytokeratins, cytokeratin 5/6, p63, and CD34. In this clinical context, loss of INI1 expression seems to be an entirely specific marker of epithelioid sarcoma and this finding may be of great value in distinguishing CD34-negative epithelioid sarcoma from squamous cell carcinoma and in the distinction of rare cytokeratin-negative epithelioid sarcomas from necrobiotic processes, nodular fasciitis, and benign fibrous histiocytomas. In contrast, there does not seem to be a role for GLUT-1 immunohistochemistry in this differential diagnosis.

Colocalization of C4d deposits/CD68+ macrophages in rheumatoid nodule and granuloma annulare: immunohistochemical evidence of a complement-mediated mechanism in fibrinoid necrosis.

Rheumatoid nodule (RN) represents a palisading granuloma with central fibrinoid necrosis, which is not only a classical manifestation of rheumatoid arthritis (RA) and part of the American College of Rheumatology (ACR)-criteria, but also is its diagnostic hallmark. The pathogenesis of RN is still not fully understood. At present, only data on serum analyses indicating a complement-mediated pathogenesis in the development of RA are available. Equivalent examinations for RN have not yet been performed. Granuloma annulare (GA) represents another type of palisading granuloma. A special subtype of GA, subcutaneous GA (SGA), is an important differential diagnosis to RN. Therefore, our aim was to examine RN and SGA regarding the complement deposition (C4d) by immunohistochemical means. All RN and GA were stained by hematoxylin/eosin and different special stains. In addition, all specimens were stained immunohistochemically with antibodies against CD68. Five GA and five RN were analyzed immunohistochemically with antibodies against C4d and CD68, and evaluated using single- and doublestaining immunohistochemistry. All RN and GA displayed depositions of C4d within their central necroses and between the surrounding palisading macrophages. Most importantly, C4d/CD68 double staining was visible in the palisading macrophages next to the necroses, while macrophages in the periphery were negative for C4d but positive for CD68. The main difference between RN and GA was a quantitative phenomenon with less positively reacting macrophages in a more incomplete palisade in GA. The positive reactions of all central necroses to C4d and colocalization of CD68 and C4d suggest that a complement-mediated mechanism may be operative in the formation of fibrinoid necrosis. This mechanism may be involved in any form of "fibrinoid necrosis", since no different patterns of C4d/CD68 expression could be observed in GA. This may explain why RG/GA are not distinguishable morphologically.

Collagen synthesis in granuloma annulare.

Previous research has demonstrated active collagen synthesis in granuloma annulare (GA), a mainly degenerative disease of the skin. The present investigation is aimed to characterize details of the collagen synthesis and its regulation. Northern and in situ hybridization techniques and immunohistochemical methods are used to identify type I and type III collagen synthesis, regulation-associated polypeptides TGF-beta, Il-1 alpha, and Il-1 beta and an extracellular matrix protein tenascin, as well as lymphohistiocytic cells present in GA lesions. High mRNA levels of both pro-alpha 1 (I) and pro-alpha 1 (III) collagens were detected in GA lesions. In situ hybridization with cDNA probes revealed active fibroblasts with signals for both type I and III collagen mRNA around GA lesions. Some TGF-beta expression was found within the areas of inflammatory cells. Immunohistochemically, most of the mononuclear/lymphatic cells were CD3+ T cells. The helper/inducer phenotype (CD4+) was common among them, but there were no T-suppressor (CD8) cells. CD1+ cells were few in number, as were cells with activation or proliferation markers (CD26, CD30, and Ki67 antigens). Il-1 alpha- and Il-1 beta-positive lymphocytes/monocytes as well as interleukin-2 receptor containing cells were detected around the lesions, i.e., in the same areas as collagen-synthesizing fibroblasts. Another possible association with the regulation of collagen synthesis was the finding of an accumulation of tenascin, a growth-promoting extracellular matrix protein, in the surroundings of the GA lesions. We suggest that the firmly established and seemingly well-regulated type I and type III collagen synthesis presents a reparative phenomenon in the cutaneous lesions of GA.

Enhanced expression of human metalloelastase (MMP-12) in cutaneous granulomas and macrophage migration.

Accumulation of inflammatory cells such as macrophages may lead to degeneration of connective tissue matrix in various skin diseases. Macrophage metalloelastase, is a matrix metalloproteinase (MMP-12) capable of degrading elastin as well as various basement membrane components. To investigate the role of human macrophage metalloelastase in skin, we assessed by in situ hybridization and immunohistochemistry 66 specimens representing skin diseases characterized either by changes in elastic fibers or by pronounced infiltrations of extravasating and migrating macrophages. CD68 immunostaining was performed to identify the human macrophage metalloelastase-positive cells and Weigert's Resorcin-Fuchsin staining to reveal the status of elastic fibers. We found abundant expression of human macrophage metalloelastase mRNA in macrophages in areas devoid of normal elastic fibers in granulomatous skin diseases sarcoidosis, necrobiosis lipoidica diabeticorum, and granuloma annulare. Positive cells for human macrophage metalloelastase protein could be detected in the same regions as well as positive immunostaining for urokinase plasminogen activator. Of the other matrix metalloproteinases capable of degrading elastin, 92 kDa gelatinase colocalized with human macrophage metalloelastase, while 72 kDa gelatinase was produced by surrounding fibroblast-like cells. Furthermore, human macrophage metalloelastase was expressed by macrophages in areas with disrupted basement membrane, as assessed by type IV collagen staining, in pityriasis lichenoides and dermatitis herpetiformis. Specimens of anetoderma, acrodermatitis chronica atrophicans and pseudoxanthoma elasticum showed no signal for human macrophage metalloelastase. Matrilysin was not detected in any of the samples investigated. Our study suggests that human macrophage metalloelastase may contribute to elastin degradation occurring in granulomatous skin diseases and may aid macrophage migration through the epidermal and vascular basement membranes in inflammatory disorders.

The oligosaccharidic component of the glycoconjugates in lichen planus, granuloma annulare, seborrheic keratosis and plamoplantar keratoderma: lectin histochemical study.

It is well known that cell surface glycoconjugates play an important role in cell proliferation, adhesion and differentiation. The aim of this investigation was to define the changes of the glycoconjugate saccharidic moieties in the epidermis and derma of patients affected by several skin pathologies such as seborrheic keratosis, lichen planus, granuloma annulare and palmoplantaris keratoderma. Bioptical specimens from skin lesions as well as from normal skin were fixed in Carnoy's fluid and routinely processed. The sections were treated with HRP-lectins (PNA, DBA, SBA, WGA, ConA, LTA and UEAI). Cytochemical controls were performed for specificity of lectin-sugar reaction. Some sections were pre-treated with neuraminidase prior to staining with HRP lectins. In comparison with normal human skin, epidermal lectin binding pattern in the considered diseases showed considerable qualitative and quantitative variations. In general, in all the considered pathologies, a lack and/or a decrease in lectin binding at the epidermal layers was observed; among the various diseases, differences in cellular localisation of the sugar residues were also noted. In such respect, an exception was represented by seborrheic keratosis, where the cells of the basal layer showed PNA reactivity, which was absent in the basal layer of the normal skin. Although seborrheic keratosis and lichen planus have been studied by others authors, our findings are not in total accordance concerning lectin binding; this is probably due to the different fixatives employed. Our findings seem to reveal significant changes in keratinocyte glycoconjugate oligosaccharides in the previously mentioned diseases, providing clues to their pathogenesis.

Expression of IFNgamma, coexpression of TNFalpha and matrix metalloproteinases and apoptosis of T lymphocytes and macrophages in granuloma annulare.

Granuloma annulare, a prototype noninfectious granulomatous dermatitis, is morphologically characterized by a necrobiotic core surrounded by a cellular infiltrate. Because of many morphological similarities to tuberculosis, granuloma annulare has been suggested to represent a delayed-type hypersensitivity (Th1) reaction in the course of which inflammatory cells elicit matrix degradation. In the present study we (1) investigated the expression of interferon-gamma as the most important Th1-associated cytokine, (2) sought in situ evidence for the coexpression of the proinflammatory cytokine tumor necrosis factor-alpha and cytokine-regulated matrix metalloproteinases 2 (gelatinase A) and 9 (gelatinase B), and (3) sought to determine whether shrunken cells seen within necrobiotic areas of granuloma annulare are apoptotic cells. In situ hybridization combined with immunofluorescence showed that large numbers of infiltrating CD3+ lymphocytes express interferon-gamma. Application of catalyzed signal amplification in immunodetection revealed that the vast majority of CD3+ lymphocytes and CD68+ macrophages contained tumor necrosis factor-alpha. Immunohistochemistry demonstrated that macrophages producing tumor necrosis factor-alpha coexpress matrix metalloproteinases 2 and 9. In situ end-labeling combined with immunofluorescence detected few apoptotic T cells in perivascular regions and numerous apoptotic macrophages within necrobiotic areas. These results suggest that in granuloma annulare interferon-gamma+ Th-1 lymphocytes may cause a delayed-type hypersensitivity reaction whereby macrophages are differentiated to aggressive effector cells expressing tumor necrosis factor-alpha and matrix metalloproteinases. In parallel, activation-induced apoptosis in lymphocytes and macrophages may serve to restrict the destructive potential of the inflammatory cells.

[Immunohistologic determination of extracellular matrix components in granuloma annulare]. / Imunohistologické stanovenie zloziek extracelulárnej matrix u granuloma anulare.

BACKGROUND: The histological diagnosis of granuloma annulare is based on assessment of a palisade-like granuloma and necrobiosis. The authors attempt to make a more accurate diagnosis of the disease based on immunohistological assessment of components of the extracellular matrix. METHODS AND RESULTS: In a group of 15 patients with granuloma annulare the authors assessed, using the immunoperoxidase method, collagens type I, III and V and fibronectin. An increased amount of collagens type III and V was found within the palisade-like granuloma and its neighbourhood resp. In the area of the necrobiosis the findings of the mentioned collagens depended on the degree of necrobiotic changes (12 of 15 patients). An increased occurrence of collagen type I was only indicated in the vicinity of granulomas or within the palisade-like granuloma in 7 of 15 patients. Larger amounts of fibronectin were found in the area of the necrobiosis and in the area of the granulomatous palisade-like infiltrate resp. (12 of 15 patients). CONCLUSIONS: In the author's opinion the higher incidence of collagens types III and V in the neighbourhood of the palisade-like granulomatous infiltrate and its size resp, as well as the finding of fibronectin in the area of necrobiosis and the granulomatous infiltrate justify the use of immunohistological assessment of the above constituents of the extracellular matrix as a supplementary examination in the diagnosis of the above disease.

Histological and immunohistochemical study of granuloma annulare and subcutaneous granuloma annulare in children.

BACKGROUND: The aim of this study was to investigate the histological and immunohistochemical features of granuloma annulare (GA) in comparison to deep granuloma annulare (DGA) and granulomatous dermatoses (GDs). METHODS: Our material comprised 13 GA, 8 DGA and 1 atypical granuloma annulare (AGA) in a child with primary immunodeficiency, 10 cases of nonspecific GDs and 1 case of sarcoidosis with cutaneous involvement. The immunohistochemical streptavidin-biotin-Horseradish peroxidase (HRP) analysis was performed on paraffin sections for the detection of CD68/KP-1, CD68/anti-human CD68 clone PGM1 (PGM1), lysozyme, S-100 protein, CD1a, CD3, CD20/L-26, CD4 and CD8. RESULTS: All 13 GA were characterized by typical palisading and interstitial granulomas. In 6 cases, the lesion extended to the subcutaneous fat, while a considerable perivascular lymphocytic infiltrate without any signs of vasculitis was observed in 10 cases. The DGA were located to the deep dermis and subcutaneous fat, showing palisading granulomas with central necrobiosis. Immunohistochemistry revealed a broad intense expression of CD68/PGM1 in the histiocytic population in all cases, a constant but fainter detection of CD68/KP-1 and a variable one of lysozyme. T-cell markers (CD3, CD4 and CD8) were mainly detected in the perivascular lymphocytic infiltrate of GA and DGA, with CD4+ T lymphocytes predominating over CD8+ in GA and DGA, while CD8+ T lymphocytes was the predominant population in AGA. CONCLUSIONS: CD68/PGM1 is a sensitive and reliable histiocytic marker in confirming the histiocytic nature of equivocal GA and DGA, but the histiocytic immunoprofile is of no particular usefulness in differentiating GA from other GD.

Subcutaneous (deep) granuloma annulare in children: a possible mimicker of epithelioid sarcoma.

Subcutaneous granuloma annulare (SGA) is a self-limited inflammatory lesion consisting of dermal or subcutaneous nodules usually affecting children. Lower extremity involvement is the most common anatomic site. Because of the subcutaneous location, the morphological diagnosis of SGA can be challenging, and differential diagnoses are both benign and malignant processes including epithelioid sarcoma. Our article examines the clinical, histopathological, and immunohistochemical aspects of SGA in comparison to ES. We present 3 cases of SGA in children, who were initially diagnosed with ES and discuss the differential diagnoses features between SGA and ES. Because SGA can simulate ES, the awareness of this possibility is important to avoid overtreatment, like amputation, of the benign condition (SGA).