Christian Hallermann

High frequency of primary cutaneous lymphomas associated with lymphoproliferative disorders of different lineage

In patients suffering from primary cutaneous lymphomas, secondary malignancies of various origin may develop. However, the frequency of a second neoplasm deriving from another lymphoid lineage is still unclear and may be underestimated. We screened all our patients with primary cutaneous lymphomas from a 4-year recruitment period for a coexisting secondary lymphoproliferative disorder. The cohort comprised of a total of 82 patients with primary cutaneous lymphomas, 62 with primary cutaneous T-cell lymphoma (CTCL), 18 with primary cutaneous B-cell lymphomas, and two with CD4+/CD56+ hematodermic neoplasm/blastic lymphomas. Seven patients (8.5%) were identified with a coexisting lymphoma of a different lymphoid lineage. Four patients with Sézary syndrome (SS) suffered from systemic B-cell lymphoma. Two of these developed SS after chemotherapy of their B-cell lymphoma. The other three patients with various types of skin lymphomas (SS, Mycosis fungoides [MF], primary cutaneous marginal zone lymphoma) developed Hodgkin’s disease (hairy cell leukemia). Our data indicate that patients with primary cutaneous lymphomas have an elevated risk for the development of a secondary lymphoproliferative disorder even without previous chemotherapy. Possible explanations for this association include a genetic predisposition, alterations in early progenitor cells, underlying viral infections, and/or stimulation of a B-cell clone by the malignant helper T cells of the primary CTCL and vice versa.

Cytogenetic characterization of complex karyotypes in seven established melanoma cell lines by multiplex fluorescence in situ hybridization and DAPI banding.

We report the use of multiplex fluorescence in situ hybridization (M-FISH) to resolve chromosomal aberrations in seven established melanoma cell lines with hypotriploid to hypertetraploid complex karyotypes. By simultaneous identification of all human chromosomes in single FISH experiments using a set of 52 directly labeled, whole chromosome painting probes, cryptic chromosomal translocations and the origin of unclear chromosomal material in structural rearranged and marker chromosomes could be identified, refining the tumor karyotypes in all seven cell lines. The number of structural aberrations in each cell line assigned with combined M-FISH and DAPI banding analysis ranged from 15 to 45. Altogether, 275 breakpoints could be assigned to defined chromosomal regions or bands. The chromosome arms 1p, 6q, 7p, 9p, and 11q which are known to be nonrandomly associated with melanoma tumorigenesis, were frequently involved in chromosomal breaks and/or copy number changes. This study also demonstrated the practical usefulness of combining M-FISH with conventional cytogenetic banding techniques for the characterization of complex tumor karyotypes with massive genomic alterations.

Prognostic features in angiosarcoma of the head and neck: A retrospective monocenter study

BACKGROUND Cutaneous angiosarcoma of the head and neck (cAS-HN) is a rare malignancy with poor survival. Most of the histological markers and grading were not proven to be significant for prediction of outcomes in cAS-HN. This study aimed to find prognostic clinical features and histologic markers for cAS-HN. MATERIAL AND METHODS We retrospectively analysed primary cAS-HNs seen in a single institution between 1980 and 2009. Clinical data and specific histologic characteristics were assessed. Outcome parameters were analysed using uni- and multivariate statistics. RESULTS 80 patients (mean age 71.4 (SD 14.4) years, average follow-up time 55.3 (SD 74.4) months) were included. 5-year DSS rate was 62%. Univariate analysis revealed the extent of primary tumour (affecting more than one anatomical region), incomplete resection and initial metastatic disease as significant (p < 0.05) predictors for unfavourable disease specific survival (DSS) rates and time. Multivariate analysis confirmed age over 70 years, incomplete resection and initially distant metastasis influencing outcome adversely. Analysis of specific histological markers in 37 cases found patterns of growth (solid areas greater than 80%) associated with better survival (p = 0.011). CONCLUSION In conclusion age, number of affected regions, initial metastasis, complete initial resection and pattern of growth significantly affected mortality rates.

Molecular genetic analysis of 16 XP‐C patients from Germany: environmental factors predominately contribute to phenotype variations

Patients belonging to xeroderma pigmentosum (XP) complementation group C comprise one‐third of all XP patients. Only four major reports compiled larger groups of XP‐C patients from southern Europe (12 pts), North America (16 pts) and Africa (14 and 56 pts) as well as their genetic background (46 XPC mutations). We identified 16 XP‐C patients from Germany. Interestingly, only five patients exhibited severe sun sensitivity. The mean age of XP diagnosis was 9.4 years, and the median age of the first skin cancer was 7 years. Neurological symptoms were absent in all but two patients. Primary fibroblasts from all 16 patients showed reduced post‐UV cell survival (mean: 50% vs 93% in normal cells) and reduced reactivation of an UV‐treated luciferase reporter gene (mean: 6.4% vs 30.7% in normal cells). XPC mRNA expression was also greatly reduced compared with normal cells (mean: 14.3%; range 8.3–25.7%) except in XP47MA (274.1%). All patients carried homozygous XPC mutations. Four mutations have been described previously: c.1747_1748delTG (found in 4/16), c.567 C>T (4/16), c.1839 C>T (1/16) and a complex insertion/deletion mutation in exon 9 (1/16). The novel frameshift mutations c.446_447delAG (2/16), c.1525insA (1/16) and c.2271delC (1/16) lead to truncated XPC proteins as does the novel nonsense mutation c.843C>T (1/16). XP47MA carries an interesting mutation (c.2538_2540delATC; p.Ile812del) resulting in an in‐frame single amino acid deletion. This mutation results in a classical XP phenotype, a non‐functional XPC protein, but elevated XPC mRNA expression. Our study indicates that extrinsic factors may contribute to XP‐C symptom severity due to nonsense‐mediated message decay.

A new family with the rare genodermatosis keratosis punctata palmoplantaris Buschke-Fischer-Brauer

We describe a new family with the rare genodermatosis keratosis punctata palmo-plantaris Buschke-Fischer-Brauer (keratoma disseminatum). In all, 3 family members in 3 generations were affected, a pattern consistent with autosomal dominant inheritance. Clinical symptoms started in the third decade with disseminated, small, round, hyperkeratotic papules on the palms and soles. Punctate keratoses coalesced into hyperkeratotic plaques on pressure points. Identification of additional families is necessary to permit definitive genetic classification of this genodermatosis.

Granulocyte colony-stimulating-factor-induced psoriasiform dermatitis resembles psoriasis with regard to abnormal cytokine expression and epidermal activation.

Abstract:  Psoriasis is a chronic inflammatory skin disorder characterized by accumulation of Th1‐type T cells and neutrophils, regenerative keratinocyte proliferation and differentiation, and enhanced epidermal production of antimicrobial peptides. The underlying cause is unknown, but there are some similarities with the immunologic defense program against bacteria. Development of psoriasiform skin lesions has been reported after administration of granulocyte colony‐stimulating factor (G‐CSF), a cytokine induced in monocytes by bacterial antigens. To further investigate the relation between this type of cytokine‐induced dermatitis and psoriasis, we analyzed the cutaneous cytokine profile [tumor necrosis factor‐α (TNF‐α), interferon‐γ, transforming growth factor‐β1 (TGF‐β1), interleukin‐10 (IL‐10), IL‐12p35 and p40, and IL‐8] and expression of markers of epidermal activation [Ki‐67, cytokeratin‐16, major histocompatibility complex (MHC) class II, intercellular adhesion molecule‐1 (ICAM‐1)] in a patient who developed G‐CSF‐induced psoriasiform dermatitis by using quantitative real‐time reverse transcriptase‐polymerase chain reaction and immunohistology. The histologic picture resembled psoriasis with regard to epidermal hyperparakeratosis and the accumulation of lymphocytes in the upper corium. CD8+ T cells were found to infiltrate the epidermis which was associated with an aberrant expression of Ki‐67, cytokeratin‐16, MHC class II, and ICAM‐1 on adjacent keratinocytes. As compared to normal skin (n = 7), there was an increased expression of TNF‐α, IL‐12p40, and IL‐8, a decreased expression of TGF‐β1, and a lack of IL‐10, similar to the findings in active psoriasis (n = 8). Therefore, G‐CSF may cause a lymphocytic dermatitis that, similar to psoriasis, is characterized by a pro‐inflammatory Th1‐type cytokine milieu and an epidermal phenotype indicative of aberrant maturation and acquisition of non‐professional immune functions.

Basosquamous Carcinoma of the Head and Neck: Clinical and Histologic Characteristics and Their Impact on Disease Progression

OBJECTIVES: Basosquamous carcinoma (BSC) is a rare tumor entity, and the most common onset is in the head and neck region (BSC-HN). The data on diagnosis, treatment, and especially risk assessment concerning disease course and outcome are deficient or inconsistent. This study aimed to evaluate risk factors for local relapse (LR) and lymph node metastasis (LNM) and their impact on progression-free survival (PFS). MATERIALS AND METHODS: In a retrospective monocentric study, patients with BSC-HN treated between 1999 and 2011 were analyzed regarding clinical and histologic characteristics. Prognostic parameters for LR, LNM, and PFS were evaluated. In total, 89 patients (55 male, 34 female, mean age of 71.8 years) with a mean follow-up time of 47.7 months (range 12-112) were included. RESULTS: LR occurred in four patients (4.5%), LNM occurred in five patients (5.6%). Patients with LNM had a significantly shorter PFS time (16.1 months) compared with patients without LNM (154.2 months; P < .001). Tumor depth and size (T classification), incomplete resection, localization at the ear, deep maximal vertical infiltration, muscle and vessel invasion all showed significant (P < .05) associations with LR, LNM, and shorter PFS time. BSC showed more histologic features of basal cell carcinoma (BCC), especially with regard to BerEP4 expression. CONCLUSION: While histology shows some typical characteristics of BCC, the biologic behavior and aggressiveness of BSC are similar to those of cutaneous squamous cell carcinoma. This is the first study to show that LR and, especially, LNM indicate a higher risk of an unfavorable outcome.

Simultaneous aberrations of single CDKN2A network components and a high Rb phosphorylation status can differentiate subgroups of primary cutaneous B-cell lymphomas

Abstract:  The cyclin‐dependent kinase inhibitor 2A (CDKN2A) gene on chromosome 9p21 encodes p16 (INK4A), the inhibitor of the CDK4/retinoblastoma (Rb) cell proliferation pathway, as well as p14 (ARF), which controls p53‐dependent pathways. Inactivation of p16 has previously been associated with the prognostically unfavourable primary cutaneous diffuse large B‐cell lymphoma, leg type (PCLBCL, LT). In this work, we analysed 22 tumors [nine primary cutaneous follicle centre lymphomas (PCFCL), seven primary cutaneous marginal zone lymphomas (PCMZL) and six PCLBCL, LT] not only for alterations of the p16 gene but also for p14, p53 and Rb by fluorescence in situ hybridization (FISH) and immunohistochemistry. In most PCLBCL, LT (4/6) alterations of CDKN2A (two biallelic deletions, one monoallelic deletion and one trisomy 9) and in addition the highest frequency of deletions of p53 (3/6) and Rb (3/6) were detected. p16 was not expressed but very high levels of phosphorylated Rb, indicating a functional effect of genomic CDKN2A alterations on the protein level in PCLBCL, LT. Regarding the p14/p53 axis, PCLBCL, LT showed a variable expression. Neither PCFCL nor PCMZL showed alterations of CDKN2A and also deletions of p53 or Rb were extremely rare in these subtypes. Exclusively in PCMZL, p53 protein was consistently lacking. In conclusion, only PCLBCL, LT is characterized by a high frequency of aberrations of the CDKN2A network components in both important tumor suppressor pathways regulated by the CDKN2A gene. Moreover, PCLBCL, LT appears to be distinguishable from PCMZL not only by its level of p53 expression but also by its stage of Rb phosphorylation. The latter may also apply to a subgroup of PCFCL.

New and established treatment options for mycosis fungoides and Sézary syndrome – an update

At the time of diagnosis primary cutaneous lymphomas are limited to the skin. T‐cell lymphomas represent at least two thirds of all primary cutaneous lymphomas with mycosis fungoides and Sézary syndrome being the most frequent entities. A precise staging based on clinical, histological, immunohistological and molecular biological criteria is crucial for selecting the appropriate therapy. Since curative treatment is only possible in exceptional cases, the aim of any therapy is to achieve healing of the skin lesions, minimizing relapses, preventing progression and maintaining the quality of life. While in early disease stages skin‐directed therapy is being used, in later stages systemic treatments become more important. This work aims to provide an overview of established and new therapies for the treatment of mycosis fungoides and Sézary syndrome.

Prognostic value of S100/CD31 and S100/podoplanin double immunostaining in mucosal malignant melanoma of the head and neck.

In uncommon mucosal melanomas of the head and neck established prognostic factors are rare and controversially discussed. The purpose of this study was to evaluate outcome and value of S100/podoplanin and S100/CD31 double immunostaining in head and neck mucosal melanomas.