Interstitial mycosis fungoides, a variant of mycosis fungoides resembling granuloma annulare and inflammatory morphea

BACKGROUND: Interstitial mycosis fungoides (IMF) is a rare variant of mycosis fungoides that resembles the interstitial form of granuloma annulare and inflammatory morphea. IMF has received little attention in the literature. METHODS: Clinical, histological, immunophenotypical, and genotypical findings of five cases of IMF were reviewed. The histological and immunophenotypical findings were compared with those of eight cases of interstitial granuloma annulare and six cases of inflammatory morphea. RESULTS: Five patients with IMF presented with non-indurated, erythematous macules; ill-defined erythematous plaques with slight scale; and nodules on the trunk and proximal limbs. Two of five patients had a prior diagnosis of mycosis fungoides. Skin biopsies revealed a striking dermal interstitial infiltrate of lymphocytes with rare histiocytes that resembled the interstitial form of granuloma annulare or inflammatory morphea. Epidermotropic lymphocytes were present at least focally in all cases. A band-like lymphocytic infiltrate was observed in two of five cases. In contrast, many plasma cells and histiocytes were observed in cases of inflammatory morphea and interstitial granuloma annulare, respectively. With Movat-pentachrome stains, increased dermal mucin deposition was observed in two of five IMF cases, in all cases of interstitial granuloma annulare, and in one of six cases of inflammatory morphea. There was focal loss of elastic fibers in all cases of inflammatory morphea. Immunohistochemical studies of IMF highlighted a dominant population of T cells (CD3+) in the dermis and epidermis. In contrast, moderate numbers of B cells (CD20+) were admixed with T cells and plasma cells in inflammatory morphea. Almost equal numbers of histiocytes (CD68+) and T cells comprised the infiltrate of interstitial granuloma annulare. In two of five IMF cases, a clonal T-cell population was detected by PCR T-cell gamma gene rearrangement analysis. CONCLUSION: Mycosis fungoides occasionally presents as an interstitial lymphocytic infiltrate that mimics granuloma annulare and inflammatory morphea. Hematoxylin & eosin (H&E) findings alone can sometimes distinguish the three disorders. Immunophenotyping and genotyping may be helpful in difficult cases.     

Cutaneous infections due to nontuberculous mycobacteria: histopathological review of 28 cases. Comparative study between lesions observed in immunosuppressed patients and normal hosts

To evaluate the histopathological features observed in patients with cutaneous infections due to nontuberculous mycobacteria (NTM) and to compare the histopathological patterns observed in immunosuppressed patients and normal hosts. Twenty-eight biopsy specimens corresponding to 27 patients with cutaneous infections due to NTM were reviewed. Eighteen biopsies corresponded to normal hosts (14 Mycobacterium marinum, 2 Mycobacterium chelonae, 1 Mycobacterium terrae and 1 Mycobacterium gordonae) and 10 biopsy specimens were obtained from 9 immunosuppressed patients (3 Mycobacterium chelonae, one of which had two biopsies, 1 Mycobacterium abscessus, 2 Mycobacterium kansasii, 1 Mycobacterium marinum, 1 Mycobacterium avium complex and 1 Mycobacterium simiae). A panel of histopathological features was evaluated by two independent observers in each biopsy specimen. Epidermal changes (acanthosis, pseudoepitheliomatous hyperplasia, exocytosis) were mainly observed in M. marinum infections. In immunosuppressed patients the infiltrate tended to be deeper, involving the subcutaneous tissue (100%) with a more diffuse distribution and constant abscess formation. A marked granulomatous inflammatory reaction was observed in 83% of immunocompetent and in 60% of immunosuppressed patients. In immunosuppressed patients a relationship between the chronic evolution of the disease and granuloma formation was demonstrated. A diffuse infiltrate of histiocytes with occasionally foamy appearance was noted in three biopsy specimens from three patients with AIDS. Acute and chronic panniculitis was detected in 8 biopsy specimens. In one biopsy (M. chelonae) an acute suppurative folliculitis was observed. Different histopathological patterns can be noted in biopsy specimens from cutaneous nontuberculous mycobacterial infections. The evolution of the disease and the immunologic status of the host may explain this spectrum of morphological changes. Tuberculoid, palisading and sarcoid-like granulomas, a diffuse infiltrate of histiocytic foamy cells, acute and chronic panniculitis, non-specific chronic inflammation, cutaneous abscesses, suppurative granulomas and necrotizing folliculitis can be detected. Suppurative granulomas are the most characteristic feature in skin biopsy specimens from cutaneous NTM infections. Some histopathological patterns seem more prevalent in immunosuppressed patients.     

Histopathology of anti-p200 pemphigoid

Anti-p200 pemphigoid is an autoimmune subepidermal blistering disease characterized by circulating and tissue-bound antibodies against a 200-kd glycoprotein (p200) of the human dermis. We reviewed 10 lesional biopsies from seven patients with anti-p200 pemphigoid in an attempt to define typical histopathologic features of this disease. All biopsy specimens showed subepidermal blistering and a moderate to dense inflammatory infiltrate in the upper dermis. Immunohistochemical analysis localized type IV collagen to the dermal side of the blister, suggesting that split formation occurred within the lamina lucida of the cutaneous basement membrane. The inflammatory infiltrate was composed almost exclusively of neutrophils in six biopsies and contained a mixture of neutrophils and eosinophils in the remaining four. In three specimens, microabscess formation in the papillary dermis adjacent to the blister cavity was noted. Neutrophilic and eosinophilic spongiosis was found in five and three biopsies, respectively. We conclude that histopathology of anti-p200 pemphigoid is characterized by subepidermal blistering and a superficial inflammatory infiltrate, which is usually dominated by neutrophils but occasionally contains significant numbers of eosinophils. While this microscopic picture mimics that of linear IgA disease, dermatitis herpetiformis, or bullous pemphigoid, it should also alert a histopathologist to the possibility of anti-p200 pemphigoid and prompt immunofluorescence and immunoblotting studies for definite diagnosis or exclusion of this autoimmune subepidermal blistering disease.     

Clinical, electroneuromyographic and morphological studies of pure neural leprosy in a Brazilian referral centre

Nineteen patients with pure neural leprosy were analysed with clinical examination, electroneuromyography and histopathology of nerve biopsies. Clinical examination showed sensory loss (78.9%), paresis (78.9%), nerve enlargement (68.4%) and nerve pain (42.1%). Electroneuromyographic study revealed an axonal pattern in 18 patients (94.7%) and a demyelinating pattern in one (0.5%). Mononeuropathy multiplex was the most frequent presentation (78.9%), followed by mononeuropathy simplex (10.5%) and polyneuropathy (10.5%). The histopathological study showed the presence of inflammatory infiltrate composed of epithelioid granuloma (42.1%), mononuclear infiltrate (36.8%) or macrophages positive for bacilli (21%). Fibrosis was present in 78.9% of the biopsies. Examination of semithin sections revealed, besides inflammatory infiltrate, myelinated fibre loss (94.7%), remyelination (42%), axonal degeneration (10%) as well as regeneration (31.5%). Based on these results, the pathogenesis of leprosy neuropathy in this group of patients is briefly discussed.     

The buccal mucosa in erythrodermic psoriasis

The buccal mucosa was studied histologically in 12 patients with erythrodermic psoriasis and seven of these had repeat biopsies examined after treatment of the skin. An increased dermal vascularity was usually observed when the skin was crythrodermic, and in all but one patient this was reduced after treatment. There were conflicting changes in the inflammatory cell infiltrate, rete ridge and dermal papilla thickness, although spongiosis, parakeratosis and rete ridge clubbing were usually reduced after treatment.     

Alterations induced in normal human skin by in vivo interferon-gamma

In a study of the direct effects of interferon-gamma (IFN-gamma) on normal human skin, healthy adult male volunteers received either 3 micrograms (n = 4) or 30 micrograms (n = 9) of recombinant IFN-gamma administered intradermally over 3 days. Biopsies were taken on day 6 and histopathological examination of fixed paraffin-embedded sections from sites which had received 30 micrograms IFN-gamma revealed a moderate perivascular lymphohistiocytic dermal infiltrate with mast cells. Immunophenotyping of 5 microns cryostat sections demonstrated that 3 micrograms IFN-gamma induced keratinocyte HLA-DR expression in the absence of any significant infiltrate. More intense keratinocyte HLA-DR expression was produced by 30 micrograms IFN-gamma in all specimens, with HLA-DP concurrently expressed in three biopsies. The ratio of CD4:CD8 cells within the infiltrate was approximately 3:1. CD1 + cells within the epidermis were markedly depleted by 30 micrograms IFN-gamma, while CD1-labelled cells were observed in the dermal perivascular infiltrate. Intradermal IFN-gamma induces similar immunopathological changes to those observed in many of the inflammatory dermatoses.     

Early activation of cutaneous vessels and epithelial cells is characteristic of acute systemic onset juvenile idiopathic arthritis

In biopsies of 16 patients (mean: 5.2 years) with acute systemic onset juvenile idiopathic arthritis (SOJIA), we analysed the initial cellular events during the characteristic cutaneous rash for composition of the infiltrate and for expression of activation markers on epithelial and endothelial cells. Despite the fleeting nature of the rash, there was a characteristic infiltration of neutrophils and monocytes, accompanied by a marked expression of endothelial adhesion receptors. In addition, we found a general activation of the cutaneous epithelium reflected by the expression of the pro-inflammatory S100-proteins - myeloid-related protein 8 (MRP8) and MRP14. In responders to therapy, follow-up biopsies showed a complete normalization of these inflammatory parameters, whereas non-responders presented with continuous signs of activation. In conjunction with the high level of epithelial activation, we detected an infiltrate of leucocytes within epithelium of sweat gland ducts during active SOJIA. Such a pattern has not been described for other inflammatory skin diseases nor did we find it in biopsies from nine patients with acute urticaria. It was accompanied by exclusive expression of MRP8, but not MRP14 by the secretory cells of sweat glands. Because MRP8 and MRP14, released by epithelial cells, exhibit pro-inflammatory effects on endothelial cells and leucocytes, the particular expression pattern of MRP8 and MRP14 in SOJIA is likely to represent a decisive early constitutive component in this inflammatory disease. Their differential expression further points to distinct roles of the individual molecules in inflammatory processes.     

Histological changes observed in the skin of patients with mycosis fungoides receiving photochemotherapy

Thirteen patients with histologically proven mycosis fungoides have had sequential biopsies performed in the course of photochemotherapy. In every case, pruritus was relieved after doses of UV-A ranging from 4–8 Jc/m². Complete clinical of clearing of lesions was observed in eleven of the thirteen patients. Despite objective and subjective clearance of lesions, persistence of a cutaneous infiltrate was observed in all biopsies carried out after commencing PUVA therapy. The quantity of infiltrate was, however, less and the epidermal component considerably reduced. Because of these observations we believe that maintenance therapy with PUVA is required in the mycosis fungoides patients and that careful follow-up is essential.     

Langerhans cells in various benign and malignant pigment-cell lesions of the skin

Summary We used immunohistochemistry to study Langerhans cells (LCs) and the composition of the dermal inflammatory infiltrate both in normal skin and in biopsies from various benign and malignant pigment-cell lesions. In normal skin and most benign pigment-cell lesions, epidermal LCs are regularly distributed. OKT₆-Positive cells outnumber the OKIa-positive cells. The inconspicuous dermal infiltrate studied in these biopsies was composed of helper and suppressor/cytotoxic T cells and some dermal LCs. More epidermal LCs with an abnormal cytologic presentation were found in a halo naevus and in the radial growth part of primary malignant melanomas. This finding was associated with a dermal infiltrate composed of suppressor/cytotoxic T cells, suggesting a defense mechanism of the host towards abnormal melanocytes. Epidermal LCs were rare in the central part of the biopsies which showed a primary malignant melanoma in its vertical growth. A dermal inflammatory infiltrate was absent in that area. These findings are interpreted as the morphologic expression of a damaged immune system.F. Facchetti is on leave from Istituto di Anatomia Patologica, Spedali Civili di Brescia, Brescia, Italy     

Lethal T- and NK-cell lymphomas mimicking granulomatous panniculitidies: a clinicopathologic study of three cases

An infiltrate mimicking subcutaneous panniculitis associated with a granulomatous response represents an uncommon histopathologic presentation of lymphoma. We report three cases, comprising one case each of nasal-type extranodal NK/T-cell lymphoma, cutaneous γ/δ T-cell lymphoma and human T-lymphotropic virus-I associated adult T-cell leukemia/lymphoma, which based on initial histopathologic and/or clinical presentation were thought to represent systemic lupus erythematosus, sarcoidosis and psoriasiform dermatitis, respectively. Excisional biopsies of indurated lesions performed at our institute; however, in each case showed an atypical subcutaneous lymphohistiocytic infiltrate associated with a variable number of granulomas. Extensive immunophenotypic characterization, in conjunction with histomorphologic and molecular analysis, established the diagnosis of lymphoma in all instances. All patients had a rapidly progressive clinical course and death was attributable to complications of lymphoma shortly after diagnosis. These cases highlight the importance of using a multimodality diagnostic approach to distinguish lymphomas masquerading as granulomatous panniculitis from inflammatory or reactive disorders associated with such histopathologic patterns.     

An ultrastructural study of the mononuclear cell infiltrate of mycosis fungoides and poikiloderma atrophicans vasculare

Tissue from twenty-five patients with mycosis fungoides and three patients with poikiloderma atrophicans vasculare was examined ultrastructurally. Characteristic abnormal lymphoid cells were conspicuous in all biopsies comprising 30–60% of the cutaneous infiltrate. These cells possessed irregular nuclear outlines presenting a spectrum from mild indentation to grossly cerebriform shapes. The other prominent cell type was the histiocyte which occasionally appeared abnormal. Bizarre histiocytic cells resembling the interdigitating reticulum cell of lymph node T cell areas were also observed. In the epidermal infiltrate, abnormal lymphoid cells were seen singly infiltrating between keratinocytes and less frequently in groups, forming Pautrier microabscesses, or in close apposition to histiocytes. Langerhans cells appeared in normal numbers and were usually isolated but were occasionally seen in contact with lymphoid cells.     

A scanning microscopic clue to the diagnosis of arthropod assault reaction: alteration of interstitial tissue is more common than a wedge-shaped inflammatory infiltrate

Background:  A scanning microscopic clue to the diagnosis of arthropod assault reactions is a wedge-shaped inflammatory infiltrate. However, to describe an inflammatory infiltrate as wedge-shaped or not involves a high degree of subjectivity.
Methods:  We studied hematoxylin and eosin-stained sections of 137 biopsies of arthropod assault reactions for epidermal and dermal changes and for the composition, density and depth of the inflammatory infiltrate.
Results:  We found a wedge-shaped inflammatory component in only 10.2% of the cases. A much more common feature is an alteration of the interstitial tissue present in 85.4% of the biopsies. It consisted of a narrowing of the spaces between the collagen bundles, which was readily observable on scanning magnification. On higher magnification, a loosely textured basophilic material was often noted within the dermis.
Conclusions:  The hitherto often emphasized wedge-shaped configuration of the inflammatory component of arthropod assault reactions is not of great diagnostic value. The altered interstitial tissue is easily recognizable by its diminished interstitial spaces at low power magnification and can serve as a scanning magnification clue to the diagnosis of arthropod assault reactions.     

An immunopathological study of herpes-associated erythema multiforme

Any pathogenetic mechanism proposed for erythema multiforme (EM) must account for the prominent mononuclear cell infiltrate in the skin lesions. The purpose of this study was to characterize immunopathologically, with monoclonal antibodies to human leukocyte antigens, the inflammatory cells in early target lesions of recurrent herpes-associated EM. Cryostat sections of snap-frozen skin biopsies were studied by the avidin-biotin immunoperoxidase technique with use of the following monoclonal antibodies: anti-HLA-DR, anti-Leu M5, anti-Leu 4 + 5b, anti-Leu 3a + 3b, anti-Leu 2a, anti-Leu 14, and anti-Leu 6. The dermal mononuclear inflammatory infiltrate in the EM biopsies consisted of monocyte-macrophages and T-lymphocytes, with both helper and suppressor T cells present. Both the dermal inflammatory infiltrate and the overlying keratinocytes were strongly HLA-DR positive. No definite alteration of Langerhans cell number or distribution was noted. These findings are consistent with the characteristics seen in cell-mediated immune reactions in the skin and point to this as a likely immune mechanism for the tissue damage of EM.     

Pruritic urticarial papules and plaques of pregnancy (PUPPP): a clinicopathological review of 35 patients

The clinical features of 35 cases of Pruritic Urticarial Papules and Plaques of Pregnancy (PUPPP) seen over an 8 year period were reviewed with regard to age and gestational stage of onset, evolution and severity of disease and response to therapy. The histologic features in biopsies from 15 patients were analysed for pattern and extent of inflammatory change and the composition of the inflammatory cells were studied with a panel of monoclonal antibodies. This study confirmed PUPPP to be a well defined clinical entity mainly occurring in young primagravidas in the third trimester and usually responsive to topical treatments. Histologically, perivascular upper and mid-dermal inflammatory changes were present in all biopsies with epidermal spongiosis and vesiculation a prominant feature in many cases. The inflammatory infiltrate was composed of an admixture of T lymphocytes and macrophages.     

The frequency of dual TCR-PCR clonality in granulomatous disorders

Background: A granulomatous infiltrate in association with cutaneous T‐cell lymphoma is uncommon. The diagnosis of mycosis fungoides can be difficult in the setting of an exuberant granulomatous infiltrate that obscures the neoplastic lymphoid infiltrate, thereby mimicking a granulomatous dermatitis. Therefore, the clinical context and supplemental molecular analysis, such as the demonstration of a monoclonal T‐cell population, may assist in diagnosis. Monoclonal T‐cell populations have been reported in association with inflammatory conditions and serve as a diagnostic pitfall. The frequency of T‐cell clonality in association with granulomatous dermatitides has not yet been established. Methods: We identified 29 patients with granulomatous dermatitis who had biopsies at two distinct body sites. Results were correlated with clinical follow up and with clonal T‐cell receptor‐gamma chain rearrangement as detected by polymerase chain reaction‐based analysis (dual TCR‐PCR). Results: Clinical follow up was obtained in 17 of 29 cases (58.6%). Twenty‐five of 29 cases of granulomatous dermatitis lacked T‐cell monoclonality. Three cases of granuloma annulare contained a T‐cell clone in one of the two biopsies. One case of necrobiotic xanthogranuloma showed an identical T‐cell clone in multiple biopsies. Conclusions: The use of dual TCR‐PCR analysis, that is, T‐cell clonality analysis in biopsy specimens from two different sites, serves as an adjunct to assist in distinguishing granulomatous inflammatory reactions from granulomatous T‐cell lymphoma, including granulomatous mycosis fungoides. The occasional finding of a T‐cell clone in a granulomatous dermatitis underscores the importance of clinicopathological correlation in daily diagnosis. Dabiri S, Morales A, Ma L, Sundram U, Kim YH, Arber DA, Kim J. The frequency of dual TCR‐PCR clonality in granulomatous disorders.     

IgM-lambda paraproteinemia with associated cutaneous lymphoplasmacytic infiltrate in a patient who meets diagnostic criteria for POEMS syndrome

POEMS is a rare multisystem paraneoplastic syndrome featuring polyneuropathy, organomegaly, endocrinopathy, a monoclonal protein, and skin changes. In the relatively few reported biopsies of POEMS-associated cutaneous hyperpigmentation, the most common skin finding seen in patients with the disorder, only a non-specific inflammatory infiltrate has been demonstrated histologically. We present the case of a 79-year-old man with polyneuropathy, autoimmune thyroiditis, pancytopenia, and a history of lymphadenopathy who presented to the inpatient dermatology service with cutaneous hyperpigmentation. A skin biopsy of a hyperpigmented area showed a cutaneous lymphoplasmacytic infiltrate, prompting further investigation. A monoclonal IgM-lambda paraprotein was subsequently identified, leading to administration of combination chemotherapy for a diagnosis of POEMS syndrome. The novel finding of a lymphoplasmacytic infiltrate in POEMS-associated hyperpigmentation suggests a diagnostic role for skin biopsy in these patients.     

Clinical, histopathologic, and therapeutic aspects of subepidermal autoimmune bullous diseases with IgG on the floor of salt-split skin

BACKGROUND: About 12% of patients with subepidermal autoimmune bullous disease and immunoglobulin G (IgG) at the dermal-epidermal junction present diseases other than bullous pemphigoid. MATERIALS AND METHODS: We report the clinical, histopathologic, and therapeutic aspects of eight cases of subepidermal bullous disorder with IgG on the floor of salt-split skin. RESULTS: A predominant neutrophilic infiltrate was detected in six of the eight patients. In one patient, the inflammatory infiltrate was neutrophilic and eosinophilic in the same proportion. A good response to dapsone alone or combined with prednisone was observed in six patients. CONCLUSIONS: The salt-split skin direct immunofluorescence test is useful for its diagnostic and therapeutic implications.     

Histopathologic features of exanthematous drug eruptions of the macular and papular type

Although exanthematous drug eruptions of the macular and papular type are common and often cause diagnostic problems, histopathologic features are not precisely defined in the literature. We present the first prospective histopathologic study of maculopapular drug eruption in 48 patients in whom the diagnosis had been made on the basis of clinical examination, history of a known offending drug, and follow-up. Because more than 1 biopsy was taken in 11 patients, 60 biopsy specimens could be examined. The most consistent epidermal features were mild spongiosis mainly of the lower layers (97% of biopsies), some hyperplasia (72%), a few lymphocytes (82%), and neutrophils (32%). The dermoepidermal junction revealed discrete vacuolization (97%), scattered lymphocytes (75%), and rare necrotic keratinocytes (32%). All cases showed a dermal perivascular inflammatory infiltrate that was superficial only in 72% of biopsies and superficial and deep in 28% of biopsies. An interstitial infiltrate in the papillary dermis could be found in 93%, more often patchy than lichenoid. In general, the perivascular infiltrate was mild and composed of lymphocytes (100%), eosinophils (60%), and neutrophils (50%). In the papillary dermis, neutrophils often outnumbered the eosinophils. Another feature were the clusters of neutrophils (38%) and eosinophils (20%) in the lumina of dilated, otherwise normal, blood vessels. Rashes induced by anticonvulsants and anxiolytics were characterized by predominance of neutrophils and largish lymphocytes. Edema of the papillary dermis was encountered frequently (85%), whereas wiry collagen bundles were an exceptional finding. In conclusion, our study defined a constellation of histopathologic findings highly suggestive of the diagnosis of exanthematous drug eruption of the macular and papular type.