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Aims: Inflammatory myofibroblastic tumour (IMT) is a rare mesenchymal neoplasm of intermediate malignant potential, occurring at any age and at multiple sites. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive subtype of IMT, typically involving the abdomen. Most IMTs harbour kinase gene fusions, especially involving ALK and ROS1, but 20-30% of IMTs show no detectable translocations. The aim of this study is to further delineate clinicopathological and molecular characteristics of abdominal IMT and discover potential new therapeutic targets., Methods and Results: In 20 IMTs, including four EIMS, RNA fusion analysis was performed, followed by multiplex DNA analysis if no ALK or ROS1 fusion was detected. Fourteen IMTs (70.0%) had an ALK translocation and the fusion partner was identified in 11, including a RRBP1::ALK fusion, not previously described in classical (non-EIMS) IMT. RANBP2::ALK fusion was demonstrated in all EIMS. One IMT had a ROS1 fusion. In all ALK/ROS1 translocation-negative IMTs mutations or fusions - as yet unreported in primary IMT - were found in genes related to the receptor tyrosine kinase (RTK)/PI3K/AKT pathway. Three of four patients with EIMS died of disease [mean survival 8 months (4-15 months)], whereas only one of 14 classical IMT patients succumbed to disease [mean follow-up time 52 months (2-204 months); P < 0.01]., Conclusion: This study shows the wide clinical spectrum of abdominal IMTs and affirms the poor prognosis of EIMS, raising discussion about its status as IMT subtype. Furthermore, the newly detected alterations of the RTK/PI3K/AKT pathway expand the molecular landscape of IMTs and provide potential therapeutic targets., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background: Noninvasive treatments are frequently used in treatment of superficial basal cell carcinoma (sBCC) because of better cosmetic results, lower costs, and less burden on health care services when compared with surgical excision. However, probability of treatment failure is higher after noninvasive therapies and may depend on histologic tumor characteristics., Objective: We sought to investigate whether tumor thickness and adnexal extension are determinants of treatment failure in sBCC treated with topical methylaminolevulinate-photodynamic therapy, imiquimod, or 5-fluorouracil., Methods: Data were derived from a randomized controlled trial on the effectiveness of methylaminolevulinate photodynamic therapy, imiquimod, and 5-fluorouracil for treatment of sBCC (ISRCTN79701845). For tumors with treatment failure (n = 112) and a randomly selected control group of tumors without treatment failure (n = 224) data on tumor thickness and adnexal extension were retrospectively collected. Treatment failure was defined as a clinically and histologically persistent or recurrent tumor within 1-year posttreatment., Results: Tumor thickness of included patients ranged from 0.2 to 1.0 mm. Tumor thickness and adnexal extension of sBCC were not significantly associated with treatment failure of methylaminolevulinate photodynamic therapy, imiquimod, or 5-fluorouracil., Limitations: Follow-up period of 1 year is a limitation., Conclusion: There seems to be no need to determine tumor thickness or adnexal extension in sBCC before treatment., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

The clonal bone marrow stem cell disorders essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) belong to the group of Philadelphia chromosome negative myeloproliferative neoplasia (Ph- MPN). In 2005 the JAK2(V617F) mutation was discovered which has generated more insight in the pathogenetic mechanism of the MPNs. More mutations have been detected in MPN patients since. However, the underlying cause of MPN has not been discovered so far. The mechanism of increased angiogenesis in MPNs and the development of fibrosis in the bone marrow in PMF patients and in some ET and PV patients is still not known. This review will focus on the most important molecular pathogenetic mechanisms in MPN patients.

Diagnosis and subsequent treatment of cutaneous squamous cell carcinoma are frequently based on punch biopsies. Regarding the current TNM classification and stage grouping for cutaneous squamous cell carcinoma, it is important to identify the high-risk features (infiltration depth > 4 mm, perineural and/or lymphovascular invasion and poor differentiation). This study investigates the agreement of histological high-risk features and TNM grouping stage on 3 mm punch biopsies and subsequent surgical excision in 105 patients diagnosed with cutaneous squamous cell carcinoma. On punch biopsy, infiltration depth > 4 mm is not identified in 83.3% (30/36), perineural invasion in 90.9% (10/11) and poor differentiation in 85.7% (6/7) of cases. The TNM stage was underestimated on punch biopsy in 15.4% (16/104). This study shows that on a 3 mm punch biopsy, high-risk features in cSCC can remain undetected and that the actual TNM stage is not identified in 1 out of 6 tumours.

Background: Basal cell carcinoma (BCC) is the most common cancer in Caucasians. Trichoepithelioma (TE) is a benign neoplasm that strongly resembles BCC. Both are hair follicle (HF) tumours. HFs are hypoxic microenvironments, therefore we hypothesized that hypoxia-induced signalling pathways could be involved in BCC and TE as they are in other human malignancies. Hypoxia-inducible factor 1 (HIF1) and mechanistic/mammalian target of rapamycin (mTOR) are key players in these pathways., Objectives: To determine whether HIF1/mTOR signalling is involved in BCC and TE., Methods: We used immunohistochemical staining of formalin-fixed paraffin-embedded BCC (n = 45) and TE (n = 35) samples to assess activity of HIF1, mTORC1 and their most important target genes. The percentage positive tumour cells was assessed manually in a semi-quantitative manner and categorized (0%, <30%, 30-80% and >80%)., Results: Among 45 BCC and 35 TE examined, expression levels were respectively 81% and 57% (BNIP3), 73% and 75% (CAIX), 79% and 86% (GLUT1), 50% and 19% (HIF1α), 89% and 88% (pAKT), 55% and 61% (pS6), 15% and 25% (pMTOR), 44% and 63% (PHD2) and 44% and 49% (VEGF-A). CAIX, Glut1 and PHD2 expression levels were significantly higher in TE when only samples with at least 80% expression were included., Conclusions: HIF and mTORC1 signalling seems active in both BCC and TE. There are no appreciable differences between the two with respect to pathway activity. At this moment immunohistochemical analyses of HIF, mTORC1 and their target genes does not provide a reliable diagnostic tool for the discrimination of BCC and TE.

Objective: Proliferative activity contributes to bone marrow cellularity in myeloproliferative neoplasia (MPN). Megakaryocytes are the most important cells in MPN bone marrow pathology. JAK2(V617F) mutation constitutively activates JAK2, pErk (phosphorylating extracellular signal-regulated kinase) and PI3K (phosphatidylinositol 3-kinase)-Akt signaling. Erk is involved in megakaryocyte differentiation, PI3K-Akt inhibits megakaryocyte apoptosis via Bcl-xL and two downstream effectors (p70S6k and Bnip3). Immunohistochemic expression of phosphorylated Erk, Akt, p70S6k and Bnip3 was studied along with microvessel density (MVD) in MPN bone marrow and megakaryocytes., Methods: 36 essential thrombocythemia (ET), 25 polycythemia vera and 45 primary myelofibrosis patients were analyzed for pErk, pAkt, Bnip3, p70S6k and MVD expression by immunostaining bone marrow biopsy sections followed by automated image analysis. JAK2(V617F) was analyzed through real-time PCR in blood samples., Results: pErk and pAkt were significantly higher expressed in MPN megakaryocytes, mainly in ET patients, compared to controls. Bnip3 was higher expressed in bone marrow of control patients and in MPN megakaryocytes. Mainly in ET patients, MPN megakaryocytes showed higher p70S6k expression compared to controls., Conclusion: Increased bone marrow cellularity in MPN patients might be influenced by increased pErk, pAkt and decreased Bnip3 expression. A dominant role for megakaryocytes in ET patients was shown. Increased amounts of megakaryocytes in MPN patients can be due to increased pAkt and p70S6k., (© 2013 S. Karger AG, Basel.)

Cutaneous squamous cell carcinomas (cSCC) can recur locally and can metastasize. The objective of this study was to identify clinical and histopathological prognostic factors for local recurrence and metastasis in cSCCs at any body site. Clinical and histopathological data were collected from 224 patients with cSCC. During the median follow-up period of 43 months (range 0-73 months) the cumulative probabilities of recurrence-free survival at 1, 2 and 4 years post-treatment were 98.0%, 96.9% and 94.7%, respectively, and for metastasis-free survival 98.1%, 97.0% and 95.9%, respectively. In univariate survival analyses, predictors for local recurrence were every millimetre increase in tumour diameter and in tumour thickness. Predictors for metastasis this was location on the ear, invasion of deeper structures, no surgical treatment, poor differentiation, every millimetre increase in tumour diameter and in tumour thickness. In multivariate survival analysis, every millimetre increase in both tumour diameter and tumour thickness were independent predictors for local recurrence as well as for metastasis and, therefore, it is important to report these in patients' files. Defining prognostic valuables is important for diagnostic work-up, treatment and follow-up for an individual patient.

Essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) belong to the group of Philadelphia chromosome-negative myeloproliferative neoplasia (Ph- MPN). MPNs are clonal bone marrow stem cell disorders characterised by a proliferation of one or more of the myeloid, erythroid or megakaryocytic cell lines. Due to the different affected cell lines, MPNs show typical clinical and histological features. In 2005, a mutation in the JAK2 gene was discovered which generated more insight into the pathogenetic working mechanism of MPNs. However, the treatment of MPN patients is still mainly only palliative, although progress in reducing the symptoms of MPN patients has been made. This review will give a general overview of MPN patients for internal medicine physicians.

Background: In patients with myeloproliferative neoplasia (MPN) the development of fibrosis and increased vessel density correlate with poor prognosis. The JAK2(V617F) mutation constitutively activates JAK2, which phosphorylates signal transducer activator of transcription (STAT), up-regulating vascular endothelial growth factor (VEGF), which might be responsible for angiogenesis in MPN. Galectins are involved in the development of fibrosis and angiogenesis and might also be involved in activation of the JAK/STAT pathway in MPN., Methods: 106 MPN patients, 36 essential thrombocythemia (ET), 25 polycythemia vera (PV) and 45 primary myelofibrosis (PMF), were analyzed for the expression pattern of galectin-1, galectin-3, pSTAT3, pSTAT5 and MVD by immunostaining of bone marrow biopsy sections followed by automated image analysis. The JAK2 mutational status was analysed through real time PCR in blood samples., Results: The expression of galectin-1 was significantly higher in all MPN patients compared to normal controls. Galectin-3 was expressed more in PV patients. MVD was significantly higher in all MPN patients and correlated with galectin-1 and pSTAT5 expression. pSTAT5 expression showed a trend of higher expression in patients carrying the JAK2(V617F) mutation as well as in PV patients. PMF patients and all JAK2(V617F) positive patients showed a significantly higher pSTAT3 expression compared to control and ET patients., Conclusion: The findings suggest the involvement of galectin-1 in MPN development, regardless of the subtype. Furthermore involvement of galectin-3 in PV development, pSTAT5 in that of PV and JAK2(V617F) positive patients and angiogenesis, as well as pSTAT3 is involved in the pathogenesis of PMF.

Background: The genetic background of Basal Cell Carcinoma (BCC) has been studied extensively, while its epigenetic makeup has received comparatively little attention. Epigenetic alterations such as promoter hypermethylation silence tumor suppressor genes (TSG) in several malignancies., Objective: We sought to analyze the promoter methylation status of ten putative (tumor suppressor) genes that are associated with Sonic Hedgehog (SHH), WNT signaling and (hair follicle) tumors in a large series of 112 BCC and 124 healthy control samples by methylation-specific PCR., Results: Gene promoters of SHH (P = 0.016), adenomatous polyposis coli (APC) (P = 0.003), secreted frizzled-related protein 5 (SFRP5) (P = 0.004) and Ras association domain family 1A (RASSF1A) (P = 0.023) showed significantly more methylation in BCC versus normal skin. mRNA levels of these four genes were reduced for APC and SFRP5 in BCC (n = 6) vs normal skin (n = 6). Down regulation of SHH, APC and RASSF1A could be confirmed on protein level as well (P<0.001 for all genes) by immunohistochemical staining. Increased canonical WNT activity was visualized by β-catenin staining, showing nuclear β-catenin in only 28/101 (27.7%) of BCC. Absence of nuclear β-catenin in some samples may be due to high levels of membranous E-cadherin (in 94.1% of the samples)., Conclusions: We provide evidence that promoter hypermethylation of key players within the SHH and WNT pathways is frequent in BCC, consistent with their known constitutive activation in BCC. Epigenetic gene silencing putatively contributes to BCC tumorigenesis, indicating new venues for treatment.

Clinical and histopathological differentiation between basal cell carcinoma (BCC) and trichoepithelioma (TE) is a frequent problem. Attempts have been made to identify immunohistochemical markers helpful in differentiating them. A correct diagnosis is important because the tumours are treated differently. Recent studies showed the absence of androgen receptor (AR) expression in benign hair follicle tumours like TE. This study examines whether AR immunostaining is a useful diagnostic test to differentiate between BCC and TE. We randomly selected 75 cases with histological diagnoses of either BCC (subtypes: superficial, nodular or infiltrative) or TE (subtypes: classic or desmoplastic) from the database of the pathology department of Maastricht University Medical Centre. The available haematoxylin &#38; eosin (H&#38;E) slides were reviewed by three independent investigators using predetermined characteristics. Fifty-six slides (38 BCC and 18 TE) with unequivocal histological characteristics of either tumour were used for immunohistochemistry with AR antibodies. Any nuclear expression within the tumour was considered positive. AR expression was present in 5/8 classic TE, 0/10 desmoplastic TE, 22/23 superficial or nodular BCC and in 10/15 infiltrative BCC. Immunohistochemical stain for AR is useful to differentiate between TE and BCC; particularly in desmoplastic TE versus infiltrative BCC (specificity and positive predictive value of 100%).

Early phases of polycythemia vera, essential thrombocythemia, and primary myelofibrosis (PMF) can be difficult to distinguish by morphologic studies alone because they share many morphologic characteristics. Histologic criteria according to the 2008 World Health Organization (WHO) classification are part of the myeloproliferative neoplasia (MPN) diagnosis. Our aim was to assess the reproducibility of morphologic characteristics and determine their relative importance for histologic diagnoses on selected trephine biopsy sections. For the study, 56 prefibrotic MPN trephine specimens were blindly reviewed by 4 hematopathologists using a scoring list of 16 histologic characteristics mentioned in the WHO classification. Consensus was defined as agreement by 3 of 4 hematopathologists. High degrees of consensus were reached for individual major morphologic features used in the WHO classification, especially for the nuclear features of megakaryocytes (83%). Some of the features correlated positively or negatively with the histologic diagnosis of PMF. Consensus for the histologic classification of MPN was reached in 39 (70%) of 56 cases without knowledge of clinical data. This finding indicates a difference in the relative importance assigned to individual histologic characteristics by different hematopathologists.

Background: The type of treatment for a basal cell carcinoma (BCC) depends on the histologic subtype. Histologic examination is usually performed on incisional biopsy specimens. In primary BCC, the histologic subtype is correctly identified with a punch biopsy in 80.7% of cases. In recurrent BCC, correct identification is more difficult because of discontinuous growth caused by scar formation. Because an aggressive histologic subtype has a significantly higher risk for recurrence in these tumors, the histologic subtype is at least as important in recurrent BCC as it is in primary BCC., Objective: To investigate the correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent BCC. Furthermore, we sought to clarify how often an aggressive histologic subtype was missed, based on the punch biopsy specimen., Methods: We compared the histologic subtype in a punch biopsy specimen with the subsequent excision specimen in recurrent BCC. All BCCs were coded and judged randomly by the same dermatopathologist., Results: In 24 of 73 investigated BCCs (32.9%), the histologic subtype of the initial biopsy did not match with the histologic subtype of the subsequent excision. Of the 37 excised BCCs with an aggressive histologic subtype, 7 (19%) were missed by the initial punch biopsy., Limitations: Intraobserver variation may have affected the results of this study., Conclusions: Discriminating tumors with any aggressive growth is relevant for treatment. However, in recurrent BCC, the histology of the biopsy specimen does not always correlate with the histology of the definitive excision. This may have important therapeutic implications., (Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

A 39-year-old man presented with a rapidly growing unilateral painless nodule on the right cheek. Histopathological examination and peripheral blood analysis both showed a population of T-cell large granular lymphocytes, which were CD1+, CD2+, CD5+, CD7+ and CD16+, with expression of cutaneous lymphocyte-associated antigen. Further laboratory examination revealed severe neutropaenia, relative lymphocytosis and a clonally rearranged T-cell receptor. The cutaneous manifestation of T-cell large granular lymphocytic leukaemia is very rare. In this particular patient, however, it was instrumental in establishing the diagnosis and may have been enabled by the expression of cutaneous lymphocyte-associated antigen on the cell surface.

Difficulty in differentiation between a solitary basal cell carcinoma, which is known as a malign skin lesion and a benign trichoepithelioma, is a frequent problem in all day dermatologic practice. Clinically as well as histopathologically there are a lot of resemblances between these skin tumors. By means of two real life cases, we give here an overview of the possible problems and appliances in distinguishing these two entities; at the end we do some recommendation about the policy.

Maculopapular exanthemas have a particular high incidence among patients treated with autologous hematopoietic stem cell transplantation (HSCT). In most cases, a viral or drug induced origin is easily identified. However, the transplantation itself may also induce similar skin changes. These exanthemas are known under various names, such as autologous graft-versus-host disease (GVHD), engraftment syndrome (ES) or eruption of lymphocyte recovery (ELR). Given the clinical and histopathological similarities of these disorders, it can prove difficult to establish a diagnosis. Here, we describe a patient who developed a maculopapular exanthema after autologous stem cell transplantation for multiple myeloma, diagnosed as autologous GVHD. We also briefly review the current knowledge of the pathogenesis of autologous GVHD, ES, and ELR. Based on these data we would like to suggest that the latter two do not reflect own disease entities but rather different presentations of autologous GVHD.

Flegel's disease, also known as hyperkeratosis lenticularis perstans, is a rare skin disease characterized by small, red-brown, hyperkeratotic, papules that are usually located on the lower extremities. The diagnosis is based on the clinical appearance in association with the typical histologic features of orthohyperkeratosis and a subepidermal band-like infiltrate. Treatment is difficult and rarely fully effective. We report on a woman with Flegel's disease who responded to a topical corticosteroid therapy with betamethasone dipropionate.

A 42-year-old man presented with fever, photosensitivity, headaches, myalgia, hyperhidrosis, muscle weakness, alopecia, nasal crustae, weight loss, painful nails, arthritis, oral ulcers, erythema, discoid cutaneous lesions, and painful subcutaneous nodes. We made a diagnosis of systemic lupus erythematosus (SLE), type II cryoglobulinemia, and nodular vasculitis. In the skin, different types of vasculitis may be observed. Typically, histology shows leukocytoclastic vasculitis of superficial vessels both in SLE and mixed cryoglobulinemia, which clinically results in palpable purpura. In our patient, however, histopathological examination of the subcutaneous nodes not only revealed leukocytoclastic vasculitis of the superficial vasculature but also showed even more extensive involvement of dermal and subdermal small and medium sized vessels, giving rise to a nodular vasculitis.

Pyoderma gangrenosum is an ulcerative skin disease with variable clinical outcomes. The diagnosis is based on clinical features and exclusion of other ulcerative diseases. To date, a specific treatment is not known. Since the disease can be destructive, aggressive treatment is preferable. Here, we present a patient with a penile pyoderma gangrenosum who was successfully treated with low-dose colchicine.

Primary cutaneous follicle center lymphoma (PCFCL) is a neoplasm with differentiation of centrocytes and centroblasts presenting in the skin. At the time of initial manifestation, extracutaneous involvement is absent. PCFCL is considered as an indolent variant of primary cutaneous B-cell lymphomas since dissemination to extracutaneous sites is rare and the prognosis is favorable. Here we describe a 30-year-old man who was diagnosed with a cutaneous FCL and did not show extracutaneous affection at the time of occurrence. Six months later, however, he developed a diffuse large B-cell non-Hodgkin lymphoma localized in several lymph nodes of the neck that most likely reflects the occurrence of a second primary tumor in the same patient.

A 41-year-old man was diagnosed with a cutaneous leiomyosarcoma on the left shoulder. Family history revealed that his brother had died of a metastatic kidney tumor at young age. Although apparently rare, the familial occurrence of cutaneous leiomyosarcoma with renal cancer has been described in the context of hereditary cutaneous leiomyomatosis and renal cell cancer (HLRCC). This rare genetic syndrome is caused by heterozygous mutations in the fumarate hydratase (FH) gene. Hence, the manifestation of these two rare malignancies within one family was strongly suggestive of a common underlying genetic defect. However, mutation analysis in the FH gene excluded HLRCC in this family. Although the familial occurrence of these rare tumors might be coincidental, it cannot be ruled out that, beside FH, mutations in another as yet unknown gene could give rise to both leiomyosarcoma and kidney cancer.

Simplex vulvar intraepithelial neoplasia (VIN) is an important precursor of vulvar invasive squamous cell carcinoma and characteristically occurs in postmenopausal women. In this report, the absence of high-risk human papillomavirus (HPV) combined with specific p53 and p16INK4a expression patterns points to the HPV-independent pathway as the causative agent for vulvar squamous cell carcinoma in a 28-year-old woman. Its precursor simplex VIN was initially interpreted as eczema. Although simplex VIN has a predilection for postmenopausal women, it can occur in young patients. The development of invasive vulvar squamous cell carcinoma underlines the importance of including simplex VIN in the differential diagnosis of vulvar lesions, even at a young age. Furthermore, knowledge about the HPV status in the tumor and thus the underlying causative pathway can alert the gynecologist for the presence or absence of multicentric lower genital tract disease, as this is frequent in the HPV-dependent and not in the HPV-independent pathway.

Background: Venous thromboembolism (VTE) occurs frequently in multiple myeloma patients, especially during induction treatment with thalidomide in combination with anthracyclines and/or dexamethasone. Several coagulation abnormalities have been described in untreated myeloma patients, but these have not been prospectively evaluated during and after treatment., Patients and Methods: We performed a prospective study in 138 multiple myeloma patients in whom coagulation factor levels were evaluated longitudinally before, during induction and after intensification. Patients were randomized to induction treatment consisting of adriamycin and dexamethason, in combination with either vincristin (VAD), thalidomide (TAD), or bortezomib (PAD) followed by high-dose melphalan (HDM) and autologous stem cell transplant (ASCT)., Results: Factor VIII:C (FVIII:C) and von Willebrand factor (VWF) were significantly elevated before treatment (median FVIII:C 2.26U/ml, VWF:Ag 1.95 U/ml). Irrespective of the type of induction regimen, these variables increased strongly during induction therapy (FVIII:C 2.55 U/ml and VWF:Ag 2.96 U/ml). Fibrinogen also showed a significant increase after induction therapy (3.5 g/l pre-treatment and 4.0 g/l after treatment, respectively, P<0.001). This was significantly higher in TAD than VAD treated patients. Three to six month after ASCT levels of VWF and FVIII:C had decreased to values lower than observed before treatment (1.71 and 1.67 U/ml respectively). There was no correlation between the increased levels at start and the response of multiple myeloma to treatment. High levels of VWF, fibrinogen and FVIII:C before start of treatment were significantly associated with mortality. Fourteen patients (10%) developed a venous thrombotic event (VTE). The coagulation factor abnormalities before and during treatment were not associated with the development of VTE., Conclusion: During induction treatment several changes in coagulation factor levels are observed, which may result in a prothrombotic state. Larger studies are required to establish whether the changes in these coagulation factors during induction treatment contribute to the increased risk of venous thromboembolism in multiple myeloma patients.

An 18-year-old man presented multiple asymptomatic reddish-brown papules with a segmental distribution pattern confined to the left side of the trunk. These lesions had arisen two years before while the rest of the integument was unaffected. His further medical and family history was unremarkable. Histopathology revealed the characteristic features of syringoma. Since familial occurrence of syringoma with autosomal dominant inheritance has been described previously, we propose that the clinical phenotype observed in this patient reflects a type 1 segmental manifestation of familial syringoma and, thus, a cutaneous mosaicism.

Erythema nodosum is the most common form of septal panniculitis and the most frequent skin manifestation associated with inflammatory bowel disease. Since the development of erythema nodosum is closely related with a variety of disorders and conditions, it can serve as an important early sign of systemic disease. We report on a 25-year-old woman with Crohn's disease following a long history of recurrent erythema nodosum.

About 45 years ago, the association of lupus erythematosus with erythema multiforme and specific immunological laboratory changes was described for the first time. Since then, several patients with similar constellations of clinical symptoms and laboratory parameters have been reported. Today, this disease is known as Rowell's syndrome. However, the fact that not all patients described previously fit all clinical and immunological characteristics that had been originally reported raised the question if Rowell's syndrome really is an own entity or if the simultaneous occurrence of these clinical and immunological signs is rather incidental. Here, we describe a patient fulfilling most of the criteria of Rowell's syndrome and discuss what is currently known about this rare condition.

A 57-year-old man with rheumatoid arthritis and myasthenia gravis developed an asymptomatic erythematous plaque on his nose and skin-colored nodules on the elbows. Histopathological examination was suggestive of palisaded neutrophilic granulomatous dermatitis (PNGD). PNGD is a rather uncommon cutaneous finding in different collagen vascular disorders that can manifest with a broad range of clinical symptoms and histological signs. Based on the case report of the patient described here, we briefly discuss what is currently known about this disease.

A 75-year-old Caucasian female with a previous history of cutaneous lichen planus (LP) developed vesiculae and blisters on the lip. This special variant of oral LP is very rare and has to be distinguished from LP pemphigoides, bullous pemphigoid, pemphigus vulgaris, erythema multiforme, and herpes simplex virus infection. To date, there are only few reports on bullous oral LP on the lower lip. Although treatment is difficult, we successfully applied a topical combination of tretinoin 0.025% and triamcinolone 0.1%.

A 64-year-old woman developed slowly expanding asymptomatic red bumps on the hands and in the face since 1 year. Histopathological examination showed mononucleated and multinucleated giant cells with a characteristic "ground glass" appearance. Based on the clinical and histopathological findings, we made the diagnosis of multicentric reticulohistiocytosis (MRH). This rare variant of histiocytosis was described for the first time in 1950. Clinically, the disorder is characterized by papulonodular cutaneous lesions, and a severe and often destructive arthropathy. The reticulohistiocytoses are a rare group of closely related non-Langerhans cell histiocytosis that most commonly manifest in adults. Because MRH can be associated with an underlying malignancies, and an interdisciplinary examination and regimen of these patients is advisable.

In many haematological conditions the only curative option is stem cell (SCT) or bone marrow (BM) transplantation. Little information exists about BM morphology following non-ablative engraftment. During the pretransplantation period and depending on the kind of pretreatment, there may be hypoplasia, residual disease and varying degrees of fibrosis. In the post-transplantation period, after 1-3 weeks of transfusion-dependent pancytopenia, the first signs of successful engraftment are indicated by the recurrence of neutrophils, monocytes and erythrocytes in the peripheral blood. In the BM there is slow regeneration of erythropoiesis, followed by the other lineages of haematopoiesis and increase in reticulin fibres or even a resolution of fibrosis. Diagnostic problems arise when neoplastic lympho- or haematopoiesis are maintained following transplantation. Moreover, there may be a significant graft versus tumour response reaction or an already relapsing disease needing aggressive treatment. On the other hand, a conspicuous dyshaematopoiesis should not be mistaken as representing a myelodysplastic syndrome. The presence of granulomas being treatment-related or a manifestation of intercurrent granulomatous disease has to be considered. More advanced knowledge of the histological features of regenerating BM will certainly aid the recognition of relapsing disease and is needed for the adequate reporting of post-transplant alterations associated with a successful or failing engraftment.

Bone marrow biopsies are more and more often part of the work-up of patients with haematological disorders. The most important reason for this is the fact that a biopsy supplies important additional information compared to an aspirate alone. Biopsies are superior for the assessment of the bone marrow architecture, the vascularisation, the cellularity, the localisation and the extent of infiltrates and the degree of fibrosis. In addition, biopsy is a good way to evaluate the effects of therapy in the course of the disease. As is the case with aspirates, examination of a biopsy alone is usually sufficient for a correct diagnosis. However, a combination of both techniques makes possible an optimal assessment of the nature and extent of the disease process in the often very serious haematological conditions that we are dealing with here.

Purpose: Prenylation is essential for membrane localization and participation of proteins in various signaling pathways. The following study was conducted to examine the importance of protein farnesylation and geranylgeranylation for the regulation of lymphoma cell survival and proliferation., Experimental Design: Lymphoma cells were treated with the beta-hydroxy-beta-methylglutaryl-CoA reductase inhibitor lovastatin, which inhibits protein farnesylation and geranylgeranylation by the depletion of intracellular pools of farnesylpyrophosphate and geranylgeranylpyrophosphate. In addition, farnesyl transferase and geranylgeranyl transferase activities were specifically inhibited by FTI-277 and GGTI-298, respectively., Results: Only inhibition of geranylgeranylation by lovastatin led to reduction of cell viability in lymphoma cell lines and purified tumor cells from lymphoma patients in a time- and dose-dependent way. Reduction in the number of viable cells was mediated by both induction of apoptosis and inhibition of proliferation. In addition, GGTI-298 was more effective in induction of apoptosis and inhibition of proliferation than FTI-277. Apoptosis induced by inhibition of protein geranylgeranylation was associated with a reduction of Mcl-1 protein levels, collapse of the mitochondrial transmembrane potential, and caspase-3 activation. Inhibition of proliferation resulted from the induction of G(1) arrest. Furthermore, lovastatin at low concentrations sensitized lymphoma cells to dexamethasone, including cells resistant to this drug., Conclusion: These results indicate that protein geranylgeranylation is critical for the regulation of lymphoma tumor cell survival and proliferation and that pharmacological agents such as lovastatin or geranylgeranyl transferase inhibitors, alone or in combination with other drugs, may be useful in the treatment of lymphoma.

In the present study the clinicopathologic and immunophenotypic features of 82 patients with a CD30- peripheral T-cell lymphoma, unspecified, presenting in the skin were evaluated. The purpose of this study was to find out whether subdivision of these lymphomas on the basis of cell size, phenotype, or presentation with only skin lesions is clinically relevant. The study group included 46 primary cutaneous CD30- large cell lymphomas and 17 small/medium-sized T-cell lymphomas as well as 17 peripheral T-cell lymphomas with both skin and extracutaneous disease at the time of diagnosis. Patients with primary cutaneous small- or medium-sized T-cell lymphomas had a significantly better prognosis (5-year-overall survival, 45%) than patients with primary cutaneous CD30- large T-cell lymphomas (12%) and patients presenting with concurrent extracutaneous disease (12%). The favorable prognosis in this group with primary cutaneous small- or medium-sized T-cell lymphomas was particularly found in patients presenting with localized skin lesions expressing a CD3+CD4+CD8- phenotype. In the primary cutaneous T-cell lymphoma (CTCL) group and in the concurrent group, neither extent of skin lesions nor phenotype had any effect on survival. Our results indicate that peripheral T-cell lymphomas, unspecified, presenting in the skin have an unfavorable prognosis, irrespective of the presence or absence of extracutaneous disease at the time of diagnosis, cell size, and expression of a CD4+ or CD8+ phenotype. The only exception was a group of primary cutaneous small- or medium-sized pleomorphic CTCLs with a CD3+CD4+CD8- phenotype and presenting with localized skin lesions.

Background: The number of positive atopy patch test (APT) results in patients with atopic eczema (AE) varies in different studies, probably because of different test techniques. Variables that may influence the outcome of the APT were evaluated., Methods: APTs were performed in 84 patients with AE, 30 control patients with atopic disease, and 85 healthy volunteers, with house dust mite and grass pollen allergens in concentrations of 100, 1000, 10,000, and 100,000 allergenic units/ml. The influence of 0, 10, or 20 tape strippings was investigated. The tests were performed on the back and/or the antecubital fossa and evaluated after 20 minutes and 24, 48, and 72 hours. In all patients the total and specific serum IgE levels were measured., Results: The maximal number of positive APT results were obtained under the following conditions: an allergen concentration equal to 10,000 allergenic units/ml, 10 tape strippings and readings at 24 and 48 hours. Positive APT results were observed in five of 30 control patients with atopic disease and in none of 85 healthy volunteers. Statistically significantly higher total and allergen-specific serum IgE levels were found in the group of patients with AE with positive APT results., Conclusions: We recommend the previously described conditions to get an optimal method for APT. The correlation between the APT and the total and specific serum IgE suggests an important role for IgE in the reaction mechanism behind the APT.