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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., (© 2011 John Wiley & Sons A/S.)

The optimal processing for the pathology of sentinel lymph nodes of patients with melanoma is still a matter of debate. We compared two protocols of sentinel lymph node processing, which were consecutively applied. For the first protocol, the sentinel lymph nodes were cut into 1-2 mm thick slices. From each slice, 12 microtome sections were stained (multiple slices protocol). For the second protocol, which is a modification of the recent European Organisation for Research and Treatment of Cancer protocol, the sentinel lymph nodes were bivalved. Five consecutive series of microtome sections, with gaps of 50 microm between them, were prepared from each cut surface (bivalving protocol). H&E and immunohistochemical staining were integral elements of both protocols. A total of 584 sentinel lymph nodes (1.8+/-0.9 per patient) were examined. The percentages of micrometastases (29 versus 27%) and of capsular naevi (13 versus 15%) detected were very similar for both protocols. As shown by multivariate logistic regression, Breslow thickness (P=0.003) and younger age (P=0.01) correlated with nodal metastasis. The type of histological preparation, ulceration and sex were not significant. The multiple slices protocol produced, on average, 4 paraffin blocks and 46 microtome sections per node. The bivalving protocol constantly produced 2 paraffin blocks and 42 microtome sections. For technical processing, the multiple slices protocol required, on average, 38 min per sentinel lymph node, whereas the bivalving protocol required 55 min. Both protocols yielded excellent detection rates with a similar amount of work being required on the part of the pathologist. Compared with the bivalving protocol, the multiple slices protocol was less labor intensive for the technical staff.

Blastic plasmacytoid dendritic cell (BPDC) neoplasm, formerly called blastic natural killer cell lymphoma or CD4+/CD56+ hematodermic neoplasm, is a rare tumor entity, now regarded to be derived from the plasmacytoid dendritic cell (PDC) lineage. Because over 90% of patients present with skin lesions usually early in their disease, dermatologists have to be familiar with the specific diagnostic features and the clinical course of this devastating disease. We present a woman with a long standing solitary skin tumor of BPDC neoplasm, who experienced a deleterious clinical course, which is typical for this disease. Phenotypic and karyotypic characteristics distinguishing this tumor from myelomonocytic leukemia with skin involvement are presented.

Background: In-transit metastasis is an important morbidity factor after sentinel lymphonodectomy (SLNE). So far, factors posing an increased risk after SLNE have not been adequately analyzed., Methods: Using Kaplan-Meier estimations and the Cox proportional hazards model, we analyzed the risk of developing in-transit metastases after SLNE for 328 consecutive patients (median tumor thickness, 2.0 mm; median follow-up period, 40 months)., Results: The 5-year probability of developing in-transit metastases as a first recurrence was 11.2%. After negative and positive SLNE, the probabilities were 6.3% and 24%, respectively. Patients in whom satellite metastases were excised concurrently with the primary tumor had a probability of recurrence with in-transit metastases of 41%. In sentinel lymph node (SLN)-negative patients with primary tumors having a thickness of more than 4 mm, the probability was 22.1%. Among the group of SLN-positive patients, significantly increased in-transit probabilities were observed in those with primary tumors that were thicker than 4 mm (41.8%), with tumors located on the distal extremities (42.1%), and with penetration of the nodal metastasis of >1 mm into the SLN (36%) and in patients with capsular breakthrough (63.3%). By using multifactorial analysis, the SLN status (P = .005), Breslow thickness (P = .0009), and extremity location of the primary melanoma (P = .005) significantly predicted the risk of in-transit recurrence. Satellite metastasis (P < .089), Clark level, and ulceration did not reach significance., Conclusions: Subgroups of patients can be identified who seem to have an increased risk of developing in-transit metastases as a first recurrence after SLNE. Individualized therapeutic strategies should be developed for these patients.

We analyzed the value of digital epiluminescence microscopy (DELM) for the long-term follow-up of atypical nevi. Patients (n=530) were prospectively categorized into defined melanoma risk groups and followed by clinical and epiluminescence microscopy (ELM) examinations. Atypical nevi (n=7001) were additionally followed by DELM. During follow-up (median 32.2 months), we detected 53 melanomas among 637 excised lesions (8.3% overall chance of success). The chance of success for melanoma detection among lesions suspicious by ELM criteria was increased to 17% when additional DELM-documented changes were present. Moreover, 18 of the 53 melanomas were exclusively identified by DELM-documented changes, indicating that DELM increased the sensitivity of the ELM analysis by identifying additional melanomas. However, for lesions exclusively excised due to DELM changes, the chance of success was lower than for ELM (5.2 vs 11.8%). Excisions due to mere DELM changes detected 66.7% of melanomas in familial atypical mole and multiple melanoma (FAMMM) and 32.5% of melanomas in atypical mole syndrome (AMS) patients. We conclude that DELM is a valuable tool for the long-term follow-up of atypical nevi, especially in the high-risk groups of FAMMM and AMS patients. Randomized controlled trials are needed to validate the data from this clinical trial.

Background: Compared with intraoperative sentinel lymph node identification using blue dye only, the introduction of a hand-held gamma probe has improved the identification rates. In this retrospective study, further aspects related to the introduction of gamma-guided preparation are analysed in detail., Patients and Methods: 81 patients who underwent sentinel biopsy using the blue dye technique were compared to 247 patients whose operations were guided by blue dye and gamma probe., Results: After the introduction of radio-guided surgery, the sentinel node identification rate increased from 87.7 % to 99.2 % (P < 0.00001). The number of harvested sentinel lymph nodes increased from 1.4 +/- 0.9 to 1.8 +/- 0.09 (P < 0.00001). The "clinical false-negative rate" decreased from 15.8 % to 9.6 %. The percentage of positive completion lymphadenectomy decreased from 50 % to 24.6 %. The risk of postoperative seroma decreased as a consequence of gamma guided preparation (5.1 % versus 15 %, P = 0.01). Regarding overall survival and recurrence-free survival, there were no significant differences between both groups. The 5-year-probability of nodal basin failure was 7.9 % after negative sentinel biopsy and 25.3 % after positive sentinel lymphonodectomy plus consecutive completion lymphadenectomy., Conclusions: Combined application of blue dye and gamma-probe improved sensitivity and decreased the risk of postoperative seroma. The probability of recurrence and survival was not influenced by the technique of intraoperative sentinel node identification.

Individuals with the rare DNA repair deficiency syndrome xeroderma pigmentosum (XP) are sensitive to the sun and exhibit a 1000-fold increased risk for developing skin cancers, including cutaneous melanoma. Inherited polymorphisms of XP genes may contribute to subtle variations in DNA repair capacity and genetic susceptibility to melanoma. We investigated the role of three polymorphic alleles of the DNA repair gene XPC in a hospital-based case-control study of 294 Caucasian patients from Germany who had cutaneous melanoma and 375 healthy cancer-free sex-matched Caucasian control subjects from the same area. We confirmed that the XPC intron 9 PAT+, intron 11 -6A, and the exon 15 2920C polymorphisms are in a linkage disequilibrium. Only 1.6% of the 669 donors genotyped were discordant for these three polymorphisms. The allele frequencies (cases: controls) were for intron 9 PAT+ 41.7%:36.9%, for intron 11 -6A 41.8%:37.0% and for exon 15 2920C 41.3%:37.3%. Using multivariate logistic regression analyses to control for age, skin type and number of nevi, the three polymorphisms were significantly associated with increased risks of melanoma: OR 1.87 (95% CI: 1.10-3.19; P = 0.022), OR 1.83 (95% CI: 1.07-3.11; P = 0.026), and OR 1.82 (95% CI: 1.07-3.08; P = 0.026), respectively. Exploratory multivariate analyses of distinct subgroups revealed that these polymorphisms were associated with increased risks for the development of multiple primary melanomas (n = 28). The results of our case-control study support the hypothesis that the intron 9 PAT+, intron 11 -6A and exon 15 2920C haplotype may contribute to the risk of developing cutaneous melanoma by increasing the rate of an alternatively spliced XPC mRNA isoform that skips exon 12 and leads to reduced DNA repair. Our results should be validated in independent samples in order to guard against false positive findings.

Xeroderma pigmentosum (XP) patients exhibit a 1000-fold increased risk for developing skin cancers including malignant melanoma. We investigated the role of three variant alleles of the DNA repair gene XPC and one variant allele of the XPG gene in a hospital-based case-control study of 294 Caucasian patients from Germany with malignant melanoma and 375 healthy control individuals from the same area matched by sex. The polymorphisms G1580A (XPC exon 8; Arg492His), T1601C (XPC exon 8; Val499Ala), G2166A (XPC exon 10; Arg687Arg), and C3507G (XPG exon 15; Asp1104His) were not in linkage disequilibrium. The allele frequencies (cases: controls) were for 1580A 6.29%: 5.63%, for 1601C 79.08%: 78.28%, for 2166A 26.19%: 28.13%, and for 3507G 79.86%: 78.61%. We found no association of the homozygous 1580A, 1601C, 2166A, and 3507G genotypes with increased risks of melanoma: OR 1.254 (95% CI: 0.486-3.217), OR 1.108 (95% CI: 0.629-1.960), OR 0.817 (95% CI: 0.490-1.358), and OR 1.168 (95% CI: 0.670-2.044), respectively. Exploratory analyses of subgroups of melanoma patients compared to all controls indicated no association of these genotypes with increased risks for development of multiple primary melanomas (n = 28), a negative family history for melanoma (n = 277), melanomas in individuals with a low number of nevi (n = 273), melanomas in individuals older than 55 years (n = 142), and melanomas thicker than 1 mm (n = 126).

The diagnostic and prognostic importance of recurrent chromosomal aberrations in systemic B cell lymphoma is well documented. In contrast, limited data exist on genetic changes in primary cutaneous B cell lymphoma. In this study we investigated chromosomal aberration patterns in two types of primary cutaneous B cell lymphoma with a different clinical behavior. Twenty-two primary cutaneous B cell lymphomas, including nine follicle center cell lymphomas and 13 large B cell lymphomas of the leg, were analyzed by comparative genomic hybridization and in part by fluorescence in situ hybridization. The most frequent imbalances detectable were gains in 18q (eight of 22), 1q (six of 22), 7 (six of 22), 12q (six of 22), or Xp (four of 22), and losses in 6q (four of 22). In contrast to large B cell lymphomas of the leg, primary cutaneous follicle center cell lymphomas had fewer imbalances and lacked translocations affecting the IGH locus. Gains in 18q (eight of 13) and losses in 6q (four of 13) as well as breakpoints within the IGH locus (six of 11) were restricted to the large B cell lymphomas of the leg subtype. Translocation t(14; 18) was excluded in 16 primary cutaneous B cell lymphomas of both subtypes that were studied by fluorescence in situ hybridization. These results suggest that primary cutaneous follicle center cell lymphoma and large B cell lymphoma of the leg are characterized by different chromosomal aberration patterns, which in part might determine the different clinical course of these malignancies.

A 42-year-old man had a large speckled lentiginous nevus on the left side of his trunk. The involved area was painful when touched and paresthetic. Moreover, the ipsilateral half of his body showed a pronounced hyperhidrosis. This case can be categorized as a typical example of speckled lentiginous nevus syndrome, a recently recognized phenotype characterized by a speckled lentiginous nevus of the papular type and ipsilateral neurological abnormalities in the form of dysesthesia, muscular weakness or hyperhidrosis. Speckled lentiginous nevus syndrome represents a mosaic phenotype. Most likely it originates from loss of heterozygosity occurring in a heterozygous embryo at an early developmental stage.

Background: Dermabrasion is one approach to the treatment of treating giant melanocytic congenital nevi. Treatment is recommended to reduce the risk of spontaneous malignant transformation of giant nevi into malignant melanomas that usually occur in childhood., Objective: To describe the development of a multicentric malignant melanoma in a giant melanocytic congenital nevus after dermabrasion., Methods: We report about a 46-year-old male patient who developed a multicentric malignant melanoma in a giant melanocytic congenital nevus. The nevus was located on his left shoulder extending to his neck and chest. Previously, dermabrasion of the nevus was performed twice at the ages of 26 and 28., Results: To our knowledge, this is the first report of malignant transformation of a giant nevus into a multicentric malignant melanoma diagnosed 20 years after the procedure of dermabrasion., Conclusion: We conclude that a close follow-up of such patients is mandatory.

Peroxisome proliferator-activated receptor gamma is a member of the nuclear receptor superfamily involved in adipocyte differentiation and glucose homeostasis. There is evidence that peroxisome proliferator-activated receptor gamma may also act as a tumor suppressor. Here, we demonstrate expression of peroxisome proliferator-activated receptor gamma in benign melanocytic naevi, different variants of primary cutaneous melanomas, and melanoma metastases. Peroxisome proliferator-activated receptor gamma protein and peroxisome proliferator-activated receptor gamma1 mRNA were also detected in human melanoma cell lines. The peroxisome proliferator-activated receptor gamma specific agonists 15-deoxy-Delta12,14-prostaglandin J2, troglitazone, and rosiglitazone dose-dependently inhibited cell proliferation in four melanoma cell lines, whereas a specific agonist of peroxisome proliferator-activated receptor alpha had no such effect. At a concentration of 50 microM rosiglitazone, the most potent peroxisome proliferator-activated receptor gamma agonist tested suppressed cell growth by approximately 90%. Apoptosis could be induced in melanoma cell lines by incubation with tumor-necrosis-factor-related apoptosis-inducing ligand. In contrast, the growth inhibitory effect of peroxisome proliferator-activated receptor gamma activation was independent of apoptosis and seemed to occur primarily through induction of cell cycle arrest. Our data indicate that melanoma cell growth may be modulated through peroxisome proliferator-activated receptor gamma.