Penetration of piperacillin and tazobactam into inflamed soft tissue of patients with diabetic foot infection.

We investigated the pharmacokinetics of piperacillin and tazobactam in the extracellular space fluid of inflamed soft tissues of six patients with diabetic foot infection using in vivo microdialysis and found similar penetration for piperacillin but not for tazobactam into inflamed and noninflamed soft tissue.

Penetration of fosfomycin into inflammatory lesions in patients with cellulitis or diabetic foot syndrome.

We investigated the distribution of the broad-spectrum antibiotic fosfomycin in infected soft tissue of patients with uncomplicated cellulitis of the lower extremities or diabetic foot infection using in vivo microdialysis. Our findings suggest that fosfomycin exhibits good and similar penetration into the fluid in the interstitial space in inflamed and noninflamed soft tissue in patients.

Melanoma with benign melanocytic naevus components: reappraisal of clinicopathological features and prognosis.

The clinicopathological features and prognosis of primary cutaneous malignant melanoma with benign melanocytic naevus (BMN) components are still under debate. The purpose of this study was to characterize further the clinical and histopathological features of naevus-associated melanomas, with emphasis on the BMN components, and to examine their prognosis based on a large series. Following a histopathological review of 667 consecutive cases of primary cutaneous melanoma, 148 melanomas with BMN components (22.1%) were identified for further study. A control group of 519 melanomas without BMN components seen in a similar period were also studied. Clinically, patients with melanomas containing BMN components (n = 148; age range 25-86 years, mean age 54 +/- 16 years; male to female ratio 1:1.02) presented with tumours located mainly on the trunk (34.5%), followed by the upper extremities (24.3%), lower extremities (20.3%), and head and neck (14.2%). Compared with tumours without BMN components (n = 519; age range 19-89 years, mean age 57 +/- 15 years; male to female ratio 1:1.3), melanomas with BMN components occurred in slightly younger individuals (P = 0.027). Histopathologically, BMN components mainly showed features of acquired naevi (total 87 cases; dysplastic, 80 cases; banal, seven cases) or congenital naevi (total 57 cases; superficial, 56 cases; deep, one case), but a minority of these lesions (four cases) could not be further subcategorized. Generally, melanomas containing BMN components were relatively thinner than melanomas without BMN components (mean Breslow index 0.95 +/- 0.83 mm and 1.3 +/- 1.6 mm, respectively) (P = 0.015). The follow-up data available in 69 patients with naevus-associated melanomas consistently revealed a relatively good outcome (5 year metastasis-free survival rate 93.75%), although no statistical difference in prognosis was observed between this group and a subset of 283 melanomas patients without BMN components stratified by tumour thickness. We conclude that BMN components in naevus-associated melanomas constitute a heterogeneous group morphologically, consisting mainly of dysplastic and superficial congenital naevi. This finding indicates a more important role for superficial congenital naevus as a precursor lesion of naevus-associated melanomas than presently recognized. Patients with naevus-associated melanomas generally show a good clinical outcome, reflecting their small Breslow index.

[Therapy of primary cutaneous B-cell lymphomas]. / Die Therapie der primären kutanen B-Zell-Lymphome.

BACKGROUND AND OBJECTIVE: Primary cutaneous B-cell lymphomas (PCBCL) represent a unique type of extranodal B-cell lymphomas. Recently, the "European Organization for Research and Treatment of Cancer (EORTC)-Cutaneous Lymphoma Study Group" classified PCBCL into two major groups: one with low-grade malignancy and excellent prognosis (follicle center cell lymphoma, immunocytoma/marginal zone B-cell lymphoma) and the other with intermediate malignancy and worse prognosis (large B-cell lymphoma of the leg). The clinical course and the prognosis of both groups clearly distinguish them from nodal lymphomas with similar morphological aspects, thus underlying the need for different treatment modalities. PATIENTS/METHODS: We investigated retrospectively the therapeutic data from 51 patients with PCBCL (40 low grade lymphomas, 11 large B-cell lymphomas). Several treatment modalities were used: total excision, radiotherapy, polychemotherapy, systemic corticosteroids, systemic antibiotics, as well as a variety of combination treatments. RESULTS: Recurrence, dissemination and/or death of the patients were not significantly related to any single treatment modality. CONCLUSIONS: In our opinion, the choice of treatment for PCBCL depends on the histologic classification, the number, spread and localization of the infiltrates, and on the general condition of the patient.

CD56+ blastic transformation of chronic myeloid leukemia involving the skin.

We report on two patients with chronic myeloid leukemia (CML) who presented blastic transformation involving the skin, with leukemic infiltrates showing unusual morphologic and immunohistologic characteristics. Both patients were elderly men with a 36-month and a 40-month history of CML, respectively. They presented with disseminated, reddish to violaceous papules and plaques (case 1), and with localized reddish nodules on the left temporal area (case 2). Concurrent features of blastic transformation in the bone marrow were observed in one patient (case 1). Histopathologic examination of skin lesions revealed similar features in both cases. There was a moderate to dense dermal infiltrate composed mainly of medium-sized atypical mononuclear myeloid precursor cells with only few relatively well-differentiated cells of the granulocytic series. Histochemical staining for naphthol-ASD-chloroacetate esterase revealed strong positivity (>50% of neoplastic cells) in case 2 and only scattered positivity (< 10% of neoplastic cells) in case 1. Immunohistologic analysis performed on paraffin-embedded sections showed in both cases variable reactivity of neoplastic cells for leucocyte common antigen (CD45), lysozyme, myeloperoxidase, CD11c, CD15, CD43, CD66, CD68, HLA-DR, and the neural cell adhesion molecule (NCAM) CD56. A negative reaction was observed for CD3, CD34, and TdT. The immunohistologic findings were remarkably similar to those reported for acute myeloid leukemia (AML) with monocytic differentiation (French-American-British [FAB] classification, subtype M4). Examination of blasts from the bone marrow performed in one patient (case 1) revealed a similar phenotype also with CD56 expression. In conclusion, our observations show that specific cutaneous infiltrates in CML may show morphologic and immunohistochemical characteristics similar to those observed in AML with monocytic differentiation. Moreover, specific cutaneous manifestations of CML may express CD56.

Specific cutaneous infiltrates in patients with myelogenous leukemia: a clinicopathologic study of 26 patients with assessment of diagnostic criteria.

BACKGROUND: Few recent studies have analyzed the clinicopathologic features of specific cutaneous manifestations of myelogenous leukemia in a large number of patients. OBJECTIVE: We characterize the clinical and histopathologic spectrum of specific cutaneous manifestations in acute (AML) and chronic (CML) myelogenous leukemia, ascertain further diagnostic criteria, and examine current prognosis. METHODS: Thirty-six lesions of specific cutaneous infiltrates from 26 patients with myelogenous leukemia (AML: 17 patients; M:F = 1:2.4; mean age: 52.6 years; AML-French-American-British [FAB] classification subtypes:M1 = 1, M2 = 3, M4 = 8, M5 = 5. CML = 9 patients; M:F = 4.5:1; mean age: 60.6 years) were retrospectively collected for the study. RESULTS: Cutaneous manifestations presented as solitary or multiple reddish to violaceous papules, plaques, and nodules (17 lesions), or as a generalized erythematous maculopapular eruption (9 lesions). Concurrent extramedullary involvement in other peripheral sites (eg, gums, pharynx, orbits) was observed in 10 patients. Histopathologically, lesions revealed nodular/diffuse infiltrates, often with perivascular and periadnexal accentuation, sparing of the upper papillary dermis, and prominent single arraying of neoplastic cells between collagen bundles. Extension to the subcutis was noted in all deep biopsy specimens (26 lesions). Cytomorphologically, medium to large-sized mononuclear cells (myeloblasts and atypical myelocytes) predominated in AML-M1 and M2, whereas M4 and M5 mainly showed small, medium-sized, or large mononuclear cells with slightly eosinophilic cytoplasm and indented, bi-lobular, or kidney-shaped nuclei (atypical monocytoid cells). In CML, either a variable mixture of mature and immature cells of the granulocytic series (myelocytes, metamyelocytes, eosinophilic metamyelocytes, and neutrophils) or a rather monomorphous infiltrate of mononuclear cells were found. Staining for naphthol AS-D chloroacetate-esterase (NASD) was positive in 24 of 36 lesions (66.6%; AML: 16; CML: 8). Immunohistochemical analysis on paraffin sections using a large panel of antibodies (16 lesions: AML: 13; CML: 3) showed strong reactivity for LCA (CD45), lysozyme, myeloperoxidase (MPD), LN2 (CD74), HLA-DR, and MT1 (CD43) in the majority of cases, and variable staining for monocyte/macrophage markers (KP1/CD68, PGM1/CD68, Mac387, Ki-M1p). The neuronal cell adhesion molecule (NCAM) marker CD56 was reactive in 2 cases of CML, but negative in all cases of AML. MIB1(Ki67) stained 20% to 80% of neoplastic cells. CD34, CD15, CD20, and CD3 were negative in all cases. No correlation between histochemical/immunohistochemical features with type of leukemia or FAB-subtype of AML was observed. All patients with CML and AML with adequate follow-up died within 24 months after onset of skin lesions (mean survival, AML: 7.6 months; CML: 9.4 months). CONCLUSION: Specific cutaneous lesions in AML and CML show distinctive clinicopathologic features that allow diagnosis in most cases. Immunohistochemistry on routinely fixed, paraffin-embedded tissue sections provides useful adjunctive information. Simultaneous expression of lysozyme, MPD, CD45, CD43, and CD74 militates in favor of a diagnosis of specific cutaneous infiltrate of myelogenous leukemia. Pitfalls in immunohistologic diagnosis mainly include lack of expression of some myeloid markers (lysozyme, MPD), and aberrant expression of T-cell markers (eg, CD45RO). Regardless of type of myelogenous leukemia, onset of specific skin manifestations correlates with an aggressive course and short survival.

The role of MT2 and anti-bcl-2 protein antibodies in the differentiation of benign from malignant cutaneous infiltrates of B-lymphocytes with germinal center formation.

MT2/CD45RA and anti-bcl-2 protein (Bcl-2) monoclonal antibodies are useful markers in distinguishing follicular lymphomas from reactive follicular hyperplasia of the lymph nodes. We examined biopsy specimens from 11 patients with primary cutaneous B-cell follicle center lymphomas, 10 patients with cutaneous pseudolymphomas with germinal centers, and 6 patients with inflammatory infiltrates with germinal centers in non-lymphoid cutaneous tumors (3 basal cell carcinomas, 2 malignant melanomas, and 1 solar keratosis), in order to evaluate the utility of MT2 and anti-Bcl-2 antibodies in differentiating benign from malignant germinal center cell proliferations in the skin. Immunohistochemical evaluation of MT2 and Bcl-2 was focused exclusively on the reactivity of germinal center cells. Specific membranous MT2 positivity was found in 2/11 cutaneous follicle center lymphomas; a diffuse, non-specific staining pattern was identified in 3/11 follicle center lymphomas and in 1/6 inflammatory infiltrates in non-lymphoid tumors. A negative MT2 reaction was observed in 6/11 follicle center cell lymphomas, in all cases of pseudolymphomas and in 5/6 inflammatory infiltrates in non-lymphoid tumors. Bcl-2 positivity was detected only in 1/11 follicle center lymphomas. Germinal center cells in all other cases were Bcl-2 negative. Our results suggest that MT2 and anti-Bcl-2 antibodies are only of limited value in differentiating primary cutaneous follicle center lymphomas from cutaneous pseudolymphomas with germinal centers.

Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia: a clinicopathologic and prognostic study of 42 patients.

The clinical and histopathologic features of specific skin infiltrates in patients with B-cell chronic lymphocytic leukemia (B-CLL) have rarely been reported in detail. In this study we analyzed the clinical, histopathologic, immunophenotypic, and molecular features of 84 skin lesions from 42 patients (M:F = 1.3:1; mean age, 66.0 years; range, 42-83 years) with specific cutaneous manifestations of B-CLL. The duration of B-CLL before skin manifestations varied from 0 to 142 months (mean, 39 months). In seven patients (16.7%), skin lesions represented the first sign of disease. Clinical presentations included localized or generalized erythematous papules, plaques, nodules, and large tumors. Ulceration was uncommon. In six patients lesions were confined at the sites of scars from previous herpes zoster (four patients) or herpes simplex (two patients) eruptions. Histologically, three main patterns were recognized: (a) patchy perivascular and periadnexal, (b) nodular-diffuse, and (c) band-like. Cytomorphologically, small monomorphous lymphocytes predominated. Proliferation centers were observed in only four specimens. In two patients presenting with tumors, a high content of large cells with feature of centroblasts and immunoblasts was found (Richter's syndrome). Immunohistologic analyses were performed on paraffin-embedded specimens in 40 biopsies from 20 patients and on cryostat sections in 17 biopsies from 11 patients. Neoplastic B lymphocytes in all cases showed an aberrant phenotype (paraffin sections: CD20+/CD5+/CD43+; cryostat sections: CD19+/CD5+; immunoglobulin light-chain restriction). Proliferation markers (Ki67, PCNA, MIB1) stained 5 to 80% of cells (mean, 25%; median, 20%). Polymerase chain reaction performed in nine cases on paraffin-embedded tissues using consensus primers for immunoglobulin heavy-chain genes showed a monoclonal population of B lymphocytes in all cases. Several discrete bands in addition to the prominent ones were noted in five cases, indicating the additional presence of B lymphocytes whose immunoglobulin genes were not monoclonally but oligoclonally rearranged. Follow-up data could be obtained from 31 patients. The two patients with Richter's syndrome died after 5 and 8 months, respectively. The 5-year survival of patients with small-cell cutaneous B-CLL was 66.6%. Our study indicates that cutaneous specific manifestations of B-CLL present with characteristic histologic, immunophenotypic, and molecular patterns. Prognosis in these patients is probably not affected by skin involvement.

Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia arising at the site of herpes zoster and herpes simplex scars.

BACKGROUND: Cutaneous lymphoid infiltrates at sites of herpes zoster scars in patients with B-cell chronic lymphocytic leukemia (B-CLL) often are diagnosed as benign lymphoid hyperplasia ("pseudolymphomas"). The histologic and immunophenotypic features of these lesions are not well characterized. Appearance of skin lesions in B-CLL patients is considered a poor prognostic sign. METHOD: Eight punch biopsies from five patients (three males, two females; mean age, 66.7 years) affected by B-CLL and presenting with lesions at sites of previous herpes simplex (upper lip, one patient) or herpes zoster (trunk, four patients; forehead, one patient) infections were included in the study. Histologic examination was performed on routine sections stained with hematoxylin and eosin and Giemsa. Immunohistologic stainings were performed with a standard three-step immunoperoxidase technique on formalin fixed, paraffin embedded tissue sections. RESULTS: Specific cutaneous infiltrates of B-CLL were diagnosed histopathologically and immunophenotypically in eight biopsies from all five patients. Clinically, patients presented with erythematous papules or plaques confined to the area of previous herpes virus eruptions. Histopathologic features in most cases were characterized by a variably dense perivascular and periadnexal infiltrate of small hyperchromatic lymphocytes throughout the entire dermis, reaching the subcutaneous fat. In one case, a dense, diffuse infiltrate involving the entire dermis was observed. A granulomatous reaction with presence of epithelioid and multinucleated giant cells was a prominent feature in four biopsies from three patients. Light areas containing large lymphoid cells with features of prolymphocytes and paraimmunoblasts (so-called "proliferation centers") could be observed only in the case characterized by a diffuse infiltrate. Immunohistology revealed an aberrant CD20+/CD43+ phenotype of neoplastic B cells, which is not found in normal B lymphocytes (CD20+/CD43-). Reactive T lymphocytes were present in all lesions and had a normal CD20-/CD43+/CD45Ro+ phenotype. At the time of this writing, four patients were alive without signs of skin disease after a mean follow-up of 58.5 months, and one patient died of B-CLL 24 months after the cutaneous eruption. CONCLUSIONS: Specific cutaneous infiltrates of B-CLL are not uncommon at sites of herpes virus scars. The diagnosis can be confirmed by histopathologic and immunophenotypic criteria. The prognosis is better than previously reported.