Primary cutaneous marginal zone B-cell lymphoma: clinical and therapeutic features in 50 cases.

BACKGROUND: Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is a low-grade B-cell lymphoma that originates in the skin, with no evidence of extracutaneous disease. Studies focusing on the optimal treatment of PCMZL have not been published thus far. We describe 50 patients with PCMZL to further characterize clinical characteristics and outcome and, in particular, to evaluate our current therapeutic approach. OBSERVATIONS: The majority of the patients (36/50 [72%]) presented with multifocal skin lesions, and 14 patients (28%) presented with solitary or localized lesions. The initial treatment of patients with solitary lesions consisted of radiotherapy or excision, whereas patients with multifocal lesions received a variety of initial treatments, most commonly radiotherapy and chlorambucil therapy. Cutaneous relapses developed in 19 (48%) of 40 patients who had complete remission and were more common in patients with multifocal disease. After a median period of follow-up of 36 months, 2 patients developed extracutaneous disease, but none of the patients died of lymphoma. CONCLUSIONS: Patients with PCMZL who have solitary lesions can be treated effectively with radiotherapy or excision. For patients with PCMZL who have multifocal lesions, chlorambucil therapy and radiotherapy are suitable therapeutic options. In case of cutaneous relapses, the beneficial effects of treatment should carefully be weighed against the potential adverse effects.

CD-34 and Ki-67 staining patterns of basaloid follicular hamartoma are different from those in fibroepithelioma of Pinkus and other variants of basal cell carcinoma.

BACKGROUND AND AIMS: Basaloid follicular hamartoma is a rare disorder regarded as a developmental malformation. It may be solitary or generalized, linear or regionalized, and is sometimes associated with myasthenia gravis or alopecia. We compared immunohistochemical staining patterns of selected markers in order to differentiate this hamartoma from fibroepithelioma of Pinkus, a basal cell carcinoma variant it can be confused with. METHODS: The expression of three immunohistochemical markers--CD-34, Ki-67, bcl-2--was studied in a basaloid follicular hamartoma and in a fibroepithelioma of Pinkus. Two basal cell carcinomas, a nodular and a fibrosing type, and a trichoepithelioma were included as controls. RESULTS: Basaloid follicular hamartoma shows a low proliferation index and an at least focally circumferential expression of CD-34 around the epithelial strands. This compares to the findings in trichoepithelioma. In contrast, fibroepithelial tumor of Pinkus and two other basal cell carcinoma subtypes display a high proliferative index and an absence of CD-34 expression around the epithelium. These findings support the non-neoplastic nature of basaloid follicular hamartoma.

Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment.

To evaluate our diagnostic and therapeutic guidelines, clinical and long-term follow-up data of 219 patients with primary or secondary cutaneous CD30(+) lymphoproliferative disorders were evaluated. The study group included 118 patients with lymphomatoid papulosis (LyP; group 1), 79 patients with primary cutaneous CD30(+) large T-cell lymphoma (LTCL; group 2), 11 patients with CD30(+) LTCL and skin and regional lymph node involvement (group 3), and 11 patients with secondary cutaneous CD30(+) LTCL (group 4). Patients with LyP often did not receive any specific treatment, whereas most patients with primary cutaneous CD30(+) LTCL were treated with radiotherapy or excision. All patients with skin-limited disease from groups 1 and 2 who were treated with multiagent chemotherapy had 1 or more skin relapses. The calculated risk for systemic disease within 10 years of diagnosis was 4% for group 1, 16% for group 2, and 20% for group 3 (after initial therapy). Disease-related 5-year-survival rates were 100% (group 1), 96% (group 2), 91% (group 3), and 24% (group 4), respectively. The results confirm the favorable prognoses of these primary cutaneous CD30(+) lymphoproliferative disorders and underscore that LyP and primary cutaneous CD30(+) lymphomas are closely related conditions. They also indicate that CD30(+) LTCL on the skin and in 1 draining lymph node station has a good prognosis similar to that for primary cutaneous CD30(+) LTCL without concurrent lymph node involvement. Multiagent chemotherapy is only indicated for patients with full-blown or developing extracutaneous disease; it is never or rarely indicated for patients with skin-limited CD30(+) lymphomas. (Blood. 2000;95:3653-3661)

Pyoderma gangrenosum as an early revelator of acute leukemia.

Bullous pyoderma gangrenosum is an atypical, more superficial variety of the classical pyoderma and is often associated with myeloproliferative disorders. We present the case of a patient who presented initially with subcutaneous nodules and who developed bullous lesions afterwards. Histological evaluation showed the presence of neutrophilic infiltrates in both lesions. A few months after the diagnosis of bullous pyoderma gangrenosum, an underlying leukemia was revealed. Our case illustrates the importance of regular blood and bone marrow examinations in patients with atypical bullous pyoderma gangrenosum, resulting in a rapid diagnosis of the underlying disease.

Mycosis fungoides: disease evolution and prognosis of 309 Dutch patients.

OBJECTIVES: To determine the disease course of Dutch patients with mycosis fungoides and to define factors related to disease progression and survival. DESIGN: A multicenter, 13-year, retrospective cohort analysis. SETTING: Eight dermatology departments collaborating in the Dutch Cutaneous Lymphoma Group. PATIENTS: Three hundred nine patients with mycosis fungoides registered between October 1985 and May 1997, including 89 patients with limited patches or plaques (stage Ia), 135 with generalized patches or plaques (stage Ib), 46 with skin tumors (stage Ic), 18 with enlarged but uninvolved lymph nodes (stage II), 18 with lymph node involvement (stage III), and 3 with visceral involvement (stage IV). MAIN OUTCOME MEASURES: Response to initial treatment, sustained complete remission, actuarial disease progression, and overall and disease-specific survival per clinical stage. RESULTS: The median follow-up was 62 months (range, 1-113 months). For the entire group, the actuarial overall and disease-specific survival was 80% and 89% at 5 years, and 57% and 75% at 10 years, respectively. The actuarial 5-year disease-specific survival of patients with stage Ia, Ib, and Ic disease was 100%, 96%, and 80%, respectively, and only 40% for patients with stage III disease. Using multivariate analysis, the presence of extracutaneous disease, the type and extent of skin involvement, the response to initial treatment, and the presence of follicular mucinosis were independently associated with higher disease progression and mortality rates. The calculated risks of disease progression at 5 and 10 years gradually increased from 4% to 10% for those with stage Ia disease, from 21% to 39% for those with stage Ib disease, and from 32% to 60% for those with stage Ic disease; for those with stage III disease, the risk remained at 70% at 5 and 10 years. The overall risk of disease progression at 5 and 10 years was 24% and 38%, respectively, for the total study group. CONCLUSION: At least within the first 10 years after diagnosis, disease progression and mycosis fungoides-related mortality occur in only a subset of patients generally presenting with advanced disease.

Mutation analysis of P73 and TP53 in Merkel cell carcinoma.

The p73 gene has been mapped to 1p36.33, a region which is frequently deleted in a wide variety of neoplasms including tumours of neuroectodermal origin. The p73 protein shows structural and functional homology to p53. For these reasons, p73 was considered as a positional and functional candidate tumour suppressor gene. Thus far, mutation analysis has provided no evidence for involvement of p73 in oligodendrogliomas, lung carcinoma, oesophageal carcinoma, prostatic carcinoma and hepatocellular carcinoma. In neuroblastoma, two mutations have been observed in a series of 140 tumours. In view of the occurrence of 1p deletions in Merkel cell carcinoma (MCC) and the location of p73 we decided to search for mutations in the p73 gene in five MCC cell lines and ten MCC tumours to test potential tumour suppressor function for this gene in MCC. In view of the possible complementary functions of p73 and TP53 we also examined the status of the TP53 gene. Sequence analysis of the entire coding region of the p73 gene revealed previously reported polymorphisms in four MCCs. In one MCC tumour, a mis-sense mutation located in the NH2-terminal transactivation region of the p73 gene was found. These results show that p73, analogous to neuroblastoma, is infrequently mutated in MCC. This is also the first report in which the role of TP53 in MCC has been investigated by sequencing the entire coding region of TP53. TP53 mis-sense mutations and one non-sense mutation were detected in three of 15 examined MCCs, suggesting that TP53 mutations may play a role in the pathogenesis or progression of a subset of MCCs. Moreover, typical UVB induced C to T mutations were found in one MCC cell line thus providing further evidence for sun-exposure in the aetiology of this rare skin cancer.

Treatment of multifocal primary cutaneous B-cell lymphoma: a clinical follow-up study of 29 patients.

PURPOSE: Although patients with primary cutaneous B-cell lymphoma (CBCL) and localized skin lesions are generally treated with radiotherapy and have an excellent prognosis, the clinical behavior and optimal treatment of CBCL presenting with multifocal skin lesions are less well defined. In this study, we evaluated the clinical behavior of and results of treatment for multifocal CBCL in 29 patients, and we formulated therapeutic guidelines. PATIENTS AND METHODS: The study group included 16 patients with primary cutaneous follicular center-cell lymphoma (PCFCCL), eight with primary cutaneous immunocytoma (PCI), and five with primary cutaneous large B-cell lymphoma presenting on the legs (PCLBCL of the leg). RESULTS: Only one of the 24 patients with multifocal PCFCCL or PCI developed extracutaneous disease, and no patient died from lymphoma (median follow-up, 54 months). In patients with PCFCCL, treatment with either multiagent chemotherapy (nine patients) or radiotherapy directed toward all skin lesions (five patients) proved equally effective in terms of complete remission, relapse, and survival. In contrast, all five patients with PCLBCL of the leg developed extracutaneous disease, and four of the five died from systemic lymphoma, 8 to 36 months (median, 21 months) after diagnosis. CONCLUSION: The results of these preliminary studies suggest that patients with PCFCCL or PCI presenting with multifocal skin lesions have the same excellent prognosis that patients with localized PCFCCL or PCI have and that radiotherapy directed toward all skin lesions is as effective as multiagent chemotherapy. Patients with PCLBCL of the leg have a more unfavorable prognosis, particularly patients presenting with multifocal skin lesions. This last group should always be treated with multiagent chemotherapy.

Epidermolysis bullosa acquisita with combined features of bullous pemphigoid and cicatricial pemphigoid.

Epidermolysis bullosa acquisita (EBA) is an acquired subepidermal blistering disease associated with autoantibodies against type VII collagen. The classical or mechanobullous form of EBA is characterized by skin fragility, trauma-induced blisters and erosions with mild mucous membrane involvement and healing with scars. Furthermore, bullous-pemphigoid-like and cicatricial pemphigoid-like features have been described. We report a patient who developed a bullous skin disease with upper airway obstruction requiring tracheotomy. The diagnosis of EBA was established by immunoblot, showing a band at 290 kD (collagen VII), and NaCl-split skin immunofluorescence (IgG deposition at the floor of the split). This case presented with clinical features of both bullous pemphigoid and cicatricial pemphigoid which to our knowledge is the first report of such a combination in EBA. The patient also presented tracheal involvement that has never been described either.

Molecular analysis of 1p36 breakpoints in two Merkel cell carcinomas.

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine tumor of the skin. Only little information is available on the genetic alterations occurring in this tumor. Cytogenetic studies thus far have not shown recurrent chromosomal changes, although various structural chromosome 1 rearrangements, including deletions, often leading to loss of distal 1p material appear to be frequent. We report on fluorescence in situ hybridization and loss of heterozygosity analyses of an MCC tumor and MCC cell line UISO. The present study has shown that two distinct regions in the most distal band 1p36 on the short arm of chromosome 1 can be implicated in MCC. One region at 1p36.3 was delineated by a distal deletion in the MCC tumor as a result of an unbalanced translocation, resulting in loss of all markers distal to ENO1. This region was previously shown to be deleted in different tumor types including neuroblastoma. In cell line UISO an insertion in 1p36.2 was identified. The insertion breakpoint indicates a second, more proximal, region on 1p involved in MCC. The insertion breakpoint was mapped within a cluster of repetitive tRNA and snRNA genes and thus could coincide with the constitutional 1p36 breakpoint previously reported in a patient with neuroblastoma.

EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer.

Primary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas that show considerable variation in histology, phenotype, and prognosis. Recently, the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group has reached consensus on a new classification for this group of diseases. The EORTC classification for primary cutaneous lymphomas is based on a combination of clinical, histologic, and immunophenotypic criteria, and thus contains well-defined disease entities rather than histologic subgroups. In addition, this new classification contains a number of provisional entities, which may display characteristic histologic features, but are not yet well defined clinically. These provisional entities account for less than 5% of all primary cutaneous lymphomas. In this report the basic principles of this new classification, as well as the characteristic features of the different disease entities, are described. In addition, survival data of 626 patients with primary cutaneous lymphomas derived from the registry of the Dutch Cutaneous Lymphoma Working Group, illustrating the clinical validity of this new classification, are presented.

Xanthomas due to generalized oedema.

A unique case of normolipaemic eruptive xanthomas due to generalized oedema is described. We propose that in this patient eruptive xanthomas were caused by the capillary leak syndrome. The increased vascular permeability could be responsible for leakage of lipoproteins into the dermis with subsequent phagocytosis by histiocytic cells.

The onychomatricoma: an electron microscopic study.

The electron microscopic findings in the onychomatricoma are described. In the proximal zone of the onychomatricoma, basal cells have various aspects, some being lacunar while others have only a limited cytoplasmic rim containing mitochondria and tonofilaments. In the parakeratotic cell columns the cells elongate and homogenized tonofilaments appear. Around the lacunae the cells are poorly differentiated and their cytoplasm is granular. It can be concluded that in an onychomatricoma the basal cells have a decreased amount of tonofilaments and desmosomes and that their evolution is not uniform. The tumour can be considered as being the result of a disturbed differentiation of nail matrix cells.

Primary cutaneous large B-cell lymphomas of the legs. A distinct type of cutaneous B-cell lymphoma with an intermediate prognosis. Dutch Cutaneous Lymphoma Working Group.

BACKGROUND AND DESIGN: Primary cutaneous follicular center cell lymphomas represent a distinct type of cutaneous B-cell lymphoma, clinically characterized by localized skin lesions on the head or trunk and an excellent prognosis. Histologically similar lymphomas may occur on the legs. The clinical behavior of this group is still undefined, and controversy exists whether these lymphomas should be classified as follicular center cell lymphoma or B-immunoblastic lymphoma. We reviewed the clinical, histologic, and follow-up data of 18 patients with primary cutaneous large B-cell lymphoma of the legs. RESULTS: Primary cutaneous large B-cell lymphoma of the legs generally occurred in elderly patients (median age at diagnosis, 76 years), in particular women (male-female ratio, 7:2), and preferentially affected the lower legs (14 of 18 patients). Radiotherapy and/or systemic polychemotherapy resulted in complete remissions in 16 of 17 patients. Follow-up data demonstrated estimated 2- and 5-year survival rates of 77% and 58%, respectively. Histologic evaluation showed diffuse dermal infiltrates with variable proportions of centroblasts (large noncleaved cells), large centrocytes (large cleaved cells), and B immunoblasts. Seventeen of 18 patients were diagnosed as having primary cutaneous follicular center cell lymphoma; only 1 patient, whose histologic examination showed more than 30% immunoblasts, was diagnosed as having B-immunoblastic lymphoma. CONCLUSIONS: Primary cutaneous large B-cell lymphoma of the legs is a distinct clinicopathologic entity that mainly affects elderly patients and has an intermediate prognosis. Although most cases have a follicular center cell origin, primary cutaneous large B-cell lymphoma is proposed as the most appropriate term for this type of cutaneous lymphoma.

Sucrose laurate gels as a percutaneous delivery system for oestradiol in rabbits.

In this study sucrose laurate was formulated in hydrogels and investigated as a suitable transdermal penetration enhancer for oestradiol. Using rabbits as an animal model, the absolute bioavailability and the skin irritation were evaluated after single and multiple application. Three hydrogels containing 60 mg% oestradiol were evaluated: Oestrogel, and two hypromellose gels containing 5 and 15% sucrose laurate (w/w), respectively. No stability problem of the sucrose laurate was detected during a storage period of four months at 7 +/- 2 degrees C. After single application no significant difference (P < 0.05) was observed between the bioavailability parameters of Oestrogel and the 5% sucrose laurate gel. The values obtained for the 15% sucrose laurate gel were significantly higher than for the other gels. When applied on day 7 after a 6-day treatment, twice daily with the respective placebo gel, no significant difference was seen amongst the three formulations for any of the parameters evaluated. When the results after multiple application were compared with those after single application, a significant increase in oestradiol bioavailability was seen for the gel containing 30% ethanol and a significant decrease in oestradiol bioavailability was seen for the 5 and 15% sucrose laurate gels. Histological evaluation of the untreated and treated skin biopsies, showed a significantly higher incidence of infiltrate for all treated skin biopsies in comparison with the untreated ones. A significant increase in skinfold thickness was seen for the skin biopsies treated with gel containing 15% sucrose laurate. It can be concluded that sucrose laurate shows a potential as an absorption enhancer for percutaneous drug delivery.

Erythromelalgia: a clue to the diagnosis of polycythemia vera.

We report the case of a 74-year-old woman with recurrent episodes of symmetrical congestion and erythema in the distal lower legs causing a burning distress. Laboratory and clinical investigations revealed an underlying myeloproliferative disorder. The cutaneous symptoms were atypical of erythromelalgia. Salicylates and treatment of the underlying polycythemia were able to eliminate the skin lesions but not entirely suppress the subjective discomfort.

Evidence for a polyclonal nature of the cell infiltrate in sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease).

Sinus histiocytosis with massive lymphadenopathy (SHML), or Rosai-Dorfman disease, is rare histiocytic disorder of known origin which shares several cell markers with Langerhans' cell histiocytosis (LCH). Although Rosai-Dorfman cells exhibit an aberrant immunophenotype, the indolent clinical course of SHML suggests a reactive disorder rather than a neoplastic process. Until recently this was prevailing opinion concerning LCH also, but recent studies have detected clonal histiocytes in all forms of this latter condition, which is therefore considered a clonal neoplastic disorder with highly variable biological behaviour. To determine whether the histiocytic proliferation in SHML is polyclonal or clonal we used X-linked polymorphic loci to assess clonality in lesional tissues in two women. Polymorphic regions of the human androgen receptor (HUMARA) locus were amplified by polymerase chain reaction (PCR) analysis. The HUMARA locus was informative in both cases and, following digestion with methylation-sensitive enzymes, typical polyclonal X-inactivation patterns were observed. Since abnormal cells accounted for > 90% lesional tissue cells, we conclude that Rosai-Dorfman histiocytic proliferation was polyclonal in the women studied.

Fibrillin immunofluorescence in pseudoxanthoma elasticum.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a rare heritable connective tissue disorder manifested by skin, ocular, and cardiovascular anomalies. The basic defect is unknown; however, the microscopic findings are indicative of defects in elastic fibers. Among the components of the elastic fibers are elastin and elastin-associated microfibrils. OBJECTIVE: We assessed the fidelity of this fibrillar system in PXE with the use of antibodies to fibrillin, a major component of elastin-associated microfibrils. METHODS: Using a well-established immunofluorescence assay, we studied fibrillin deposition in dermal fibroblast cultures from 16 patients with PXE. RESULTS: Six of the 16 patients (37%) showed some abnormality of fibrillin deposition in fibroblasts derived from lesional skin. Fibroblasts from nonlesional skin displayed normal fibrillin immunofluorescence. The only sibship studied, however, was discordant for fibrillin immunostaining. CONCLUSION: Unlike the findings in Marfan syndrome, these data are not suggestive of causal fibrillin defects in PXE.

Skin involvement in myelogenous leukemia: morphologic and immunophenotypic heterogeneity of skin infiltrates.

A systematic morphological analysis of cutaneous infiltrates in acute myelogenous leukemia and myelodysplastic syndrome revealed that in many cases the infiltrating cells have a different phenotype from those in the bone marrow. This study sought to answer two questions: (a) How wide is the range of cytological features and immunoreactivity of the cutaneous infiltrates and what danger is there of misinterpretation? (b) What are the possible causes of the wide spectrum of differentiation of the cells infiltrating the skin? Skin biopsy specimens from 16 patients with myelogenous leukemia or myelodysplastic syndrome were investigated. The diagnosis was acute myelomonocytic leukemia (M4, according to the French-American-British/FAB system of classification of acute leukemias) in eight cases, acute monocytic leukemia (M5) in four cases, aleukemic leukemia cutis as a recurrence of M2 leukemia after treatment in one case, and myelodysplastic syndrome in three cases, including one case of myelodysplasia with an excess of bone marrow blasts (RAEB-T) and two cases of chronic myelomonocytic leukemia, one of which presented as aleukemic leukemia cutis. Reactivity with the macrophage-associated antibodies anti-CD68, Ki-M1p, and anti-lysozyme was the most consistent. However, the naphthol AS-D chloroacetate esterase reaction and staining with DAKO-M1, Ki-My2p, anti-neutrophil elastase, and anti-CD34 were found to be of little value for identifying the cutaneous infiltrate as myelogenous. Some antibodies (e.g., anti-S100 protein and MB2) even produced staining in a few cases that could have led to a mistaken diagnosis of histiocytic neoplasm or malignant lymphoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Mantle-cell lymphomas of the skin.

The skin lesions of two elderly women lead us to the diagnosis of small cleaved lymphocytic B-cell non-Hodgkin's lymphoma, TNM stage IVb after clinical staging examinations. Relapses occurred within less than 1 year. Morphology, enzymhistochemistry (alkaline phosphatase in the first case), and immunohistochemistry (CD 5 positivity in the second case) in the skin biopsies supported the diagnosis of mantle-cell lymphoma. The histogenesis of the mantle-cell lymphoma is reviewed.