Immune checkpoint analysis in ear cancer.

BACKGROUND: Among cutaneous squamous cell carcinomas, the ear (ecSCC) is one of the most common sites. Loco regional lymph node metastasis is found in six to eleven percent of cases, corresponding to increased metastasis compared to other sites. The aim of this study was to test the markers PD-L1, PD-1, CD4, CD8, and FoxP3 for suitability as prognostic predictive markers. METHODS: Sixty-four patients with ecSCC were included in this study. The expression of immunohistochemical markers (PD-L1, PD-1, CD4, CD8, FOXP3) was correlated with retrospective clinic pathological parameters (lymph node metastasis, distant metastasis, lymph node metastasis during follow-up, disease progression, disease-specific death). RESULTS: There was a correlation between increased disease specific death and a weak Foxp3 (p = 0.003) or reduced CD8 (p = 0.04). A PD-L1 expression > 1% was found in 39.1% of patients. CONCLUSION: The investigated markers (CD4, CD8, FoxP3, PD-1, PD-L1) seem overall rather inappropriate for prognostic evaluation in ecSCC. Only the correlation of disease specific death with CD8 or FoxP3 seems to be worth testing in larger collectives.

Immune checkpoint analysis in lip cancer.

The aim of this study was to establish whether PD-L1, PD-1, and markers of the tumor microenvironment (CD4, CD8, FOXP3) could have a prognostic value in squamous cell carcinoma of the lip (LSCC). In patients with histologically proven LSCC, tumor specimens were stained using immunohistochemistry (for PD-1, PD-L1, CD4, CD8, and FOXP3) on paraffin-embedded tissues. Patients with (N+) and without (N-) nodal metastasis were stratified and matched to each other according to prognostically relevant clinicopathological parameters. 58 patients (29 N+ and 29 N-) were included. PD-L1 expression was positive (>1%) in 56.1% (n = 33) of all LSCC cases, but its expression did not differ significantly between metastasis groups (65.5% in N+ versus 48.3% in N-; p = 0.144). Nodal disseminated LSCC showed a tendency for higher PD-L1 expression. None of the analyzed markers showed significant correlation with the risk for nodal disease, or revealed significant prognostic value. Due to their significant expression, PD-L1 and PD-1 are potential targets for checkpoint inhibitor therapy in LSCC. Their expression should be analyzed in advanced and metastasized LSCC cases.

Cutaneous Angiosarcoma of Head and Neck: A New Predictive Score for Locoregional Metastasis.

OBJECTIVES: Cutaneous angiosarcoma of head and neck (cAS-HN) is a malignant neoplasm with deficient data on prognostic factors. The aim of this study is to present our monocenter database on cAS-HN so far and a new predictive score for locoregional metastasis (LRM). METHODS: Retrospectively, tumor characteristics and outcome of 103 consecutive patients with cAS-HN were analyzed. The main predictors of LRM (identified by univariate and multivariate statistics) were combined to a LRM risk score. The prognostic values of stratification into high-, medium-, and low-risk groups concerning disease-specific survival (DSS), distant metastasis (DM), and progression-free survival (PFS) were evaluated. RESULTS: LRM (n = 29) and control (n = 74) groups differed significantly concerning several tumor characteristics and outcome (DM, PFS, and DSS). Patients developing LRM showed 3-, 5-, and 10-year survival rates of 32%, 16%, and 11% (mean DSS time of 36.7 months [95% confidence interval (CI) 20.5-52.8]) compared to 81%, 73%, and 69% (mean DSS time of 292.4 months [95% CI 208.4-376.5]) in controls without LRM (P < .001). The main predictors were American Joint Committee on Cancer (AJCC) stage, tumor extent, and origin of the primary tumor. The LRM risk score revealed significant higher values for the LRM group [7.14 (SD 1.46) vs 4.88 (SD 1.89), P < .001]. The high-risk group showed significantly higher risk for DM and more unfavorable DSS and PFS. CONCLUSION: The LRM risk score is a simple way to estimate the risk for LRM and DM, to stage patients, and to determine treatment options.

Prediction score for lymph node metastasis from cutaneous squamous cell carcinoma of the external ear.

AIMS: The frequency of lymph node metastasis (LNM) is higher in cutaneous squamous cell carcinoma (cSCC) of the ear than in other head and neck cSCCs. Nodal dissemination is associated with a significantly worse prognosis and disease-specific survival. The aim of this study was to establish a prediction model for LNM in patients with cSCC of the ear. MATERIALS AND METHODS: Tumour characteristics of 353 patients with ear cSCC were analysed to assess differences between those with and without LNM and to calculate a prediction score for LNM occurrence. RESULTS: Regional LNM occurred in 10.5% of patients. Five-year disease-specific survival was significantly lower in the LNM group than in the control group (59% vs. 99%; p < 0.001). Recurrence number, invasion of cartilage, tumour depth, and tumour grading were the most important predictors for LNM, with correct prediction of LNM in 94.0% of cases. Our prediction score stratified patients into high and low risk groups (p < 0.001) with a sensitivity of 89.2%, a specificity of 94.6%, and an overall accuracy of 94.1%. CONCLUSION: Our new prediction model was able to accurately identify patients at high risk of LNM who may benefit from elective lymph node surgery.

Erythrocyte sedimentation rate as an independent prognostic factor in mycosis fungoides.

BACKGROUND: Mycosis fungoides has a characteristically indolent clinical course, with a slow progression from patches over plaques to tumours. In advanced stages, with generalized skin involvement or tumours, the prognosis is poor. Well defined prognostic parameters for the individual risc stratifications are rare. OBJECTIVES: To determine prognostic factors for mycosis fungoides. METHODS: In a retrospective monocenter study, we reevaluated 97 consecutive cases of mycosis fungoides seen at our clinic. We correlated various routinely accessed parameters with survival data. The parameters were "sex", "age at time of diagnosis", "age-adjusted erythrocyte sedimentation rate"?(ESR), and "anemia". RESULTS: We identified ESR as a highly significant prognostic marker for MF that also affects overall survival and disease specific survival (P = 0·0014). The five-years disease specific survival was 100% for patients without elevation of ESR, and 52·83% for patients with elevated ESR above normal range (P < 0·001). It is of main interest that the ESR is a significant prognostic marker also in the T2 stage of MF. For the other parameters there was no significant impact on disease specific survival. CONCLUSIONS: ESR has turned out as independent prognostic factor in mycosis fungoides.

[Malignant lymphoma of the skin: update on diagnostics and therapy of primary cutaneous B-cell lymphoma]. / Maligne Lymphome der Haut : Update zu Diagnostik und Therapie primär kutaner B-Zell-Lymphome.

The diagnosis of primary cutaneous B-cell lymphoma is made based principally on the results of histological investigations and staging. For an exact staging abdominal sonography and chest X-ray examinations and for appropriate clinical symptoms special investigations as well as radiological imaging procedures including PET are indicated in addition to conventional laboratory investigations. For therapy rituximab is normally administered as monotherapy in order to avoid over therapy of indolent lymphoma. Further options are radiotherapy and new approaches with electrochemotherapy as well as pegylated doxorubicin.

[Diffuse brown discoloration of skin, mucosa and urine]. / Diffuse Braunfärbung von Haut, Schleimhaut und Urin.

A 45-year-old woman presented with diffuse melanosis, icteric sclera and melanuria. Physical examination revealed a massive nodular melanoma with ulceration and satellite metastases on the back. Further investigation showed distant cutaneous and visceral metastasis. After palliative debulking along with postoperative multidrug chemotherapy, the patient has shown objective disease regression for more than 11 months. However, it remains to be seen if disease regression will translate into increased survival.

The regulatory T-cell phenotype in progressive mycosis fungoides.

In early stages mycosis fungoides (MF) often runs an indolent course. Nevertheless a small but significant part of these patients develop an aggressive, life threatening course. These patients usually were immunocompromised. In most of those cases the lymphoma cells express CD25. This raised the question if those lymphomas may express a regulatory phenotype. Recently a couple of in vitro and in vivo studies analyzed this issue with different methods. This review discusses the recent developments in this highly topical area of research.

[The history of lymphoma classifications with special consideration of cutaneous lymphomas]. / Zur Geschichte der Klassifikation von Lymphomen unter besonderer Berücksichtigung kutaner Lymphome.

For modern evidence-based medicine, classification systems are necessary to guarantee a uniform approach for therapy and for estimating prognosis. The comparability of clinical studies and international communication require a common language and are only possible with modern international classification systems. But because all classifications are artificial, they only mirror the current state of knowledge and may change dramatically over decades. This review discusses the history of lymphoma classifications systems with a special focus on the topic of primary cutaneous lymphomas, emphasizing special problems in terminology.

[Foreign body-induced angiosarcoma 60 years after a shell splinter injury]. / Fremdkörperinduziertes Angiosarkom 60 Jahre nach Granatsplitterverletzung.

An 84-year-old gentleman developed an angiosarcoma in the lateral temporal fossa 60 years after a World War II injury. The tumour resection confirmed the close spatial relationship of the tumour and a shell splinter. Analysis of the metallic composition showed no clear carcinogenic potential of the ingredients; an inflammation-related carcinogenesis seems more probable. A review of the literature revealed two similar cases.

CD4+ CD56+ blastic tumor of the skin: cytogenetic observations and further evidence of an origin from plasmocytoid dendritic cells.

We here report on a case of a blastic tumor, recently described to belong to a new entity sharing phenotypic similarities with blood derived plasmocytoid dendritic cells and formerly regarded as belonging to the group of natural killer cell lymphomas. Besides immunophenotypic characteristics such as the absence of T- cell markers and almost complete absence of markers of the myeloid lineage, these tumors express CD4, CD56 and CD123, the receptor for interleukin-3. Moreover, using the comparative genomic hybridisation technique, CGH, we demonstrate a gain of chromosome 7q, 22 and a loss of chromosome 3p and 13q. Since this type of hematologic disorder often shows its primary manifestation in the skin and often runs a rapidly fatal course, it is important to distinguish this from other types of primary cutaneous lymphomas.

Molecular cytogenetic analysis of chromosomal breakpoints in the IGH, MYC, BCL6, and MALT1 gene loci in primary cutaneous B-cell lymphomas.

Chromosomal translocations affecting the IGH locus and various oncogene loci are recurrent in many types of systemic B-cell lymphomas. Hardly any data exist, however, on such translocations in primary cutaneous B-cell lymphomas (PCBCL). Here, a series of 29 PCBCL was investigated by interphase fluorescence in situ hybridization with probes for the IGH, MYC, BCL6, and MLT1 loci. None of the six follicle center cell lymphomas and nine marginal zone lymphomas showed evidence for any translocation affecting these loci. In contrast, 11 of 14 large B-cell lymphomas of the leg harbored breakpoints in at least one of the loci. Translocations involving the MYC locus were detected in six cases, five of them derived from a MYC/IGH juxtaposition and one from a translocation involving a non-IG gene partner. Rearrangements of the BCL6 locus were detected in five B-cell lymphomas of the leg, and involved IGH (two cases), IGL (one case), and non-IG genes (two cases). This study shows that large B-cell lymphomas of the leg display a pattern of chromosomal translocations similar to their systemic counterparts whereas primary cutaneous follicle center cell lymphomas and marginal zone lymphomas lack these typical chromosomal translocations.

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

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-alpha (TNF-alpha), interferon-gamma, transforming growth factor-beta1 (TGF-beta1), 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-alpha, IL-12p40, and IL-8, a decreased expression of TGF-beta1, 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.

Results of a surveillance programme for patients at high risk of malignant melanoma using digital and conventional dermoscopy.

Patients with a high number of atypical naevi and a personal and/or family history of melanoma are at high risk of malignant melanoma. The objective of this study was to design a special documentation and surveillance programme using epiluminescence microscopy (ELM) and digital epiluminescence microscopy (DELM) to improve the surveillance of these patients. High-risk patients (n=212) were categorized by the number and phenotype of their naevi and their personal and family history of melanoma. Then patients were screened by the unaided eye, conventional photography, ELM and, in selected cases of atypia, DELM. Median follow-up was 18 months, and 2939 pigmented lesions were followed by DELM. Examination on the first visit identified 17 cutaneous melanomas. During the following observation period, another 17 melanomas were identified. Fifteen of these follow-up melanomas were exclusively identified based upon DELM. In these cases, subtle lesional changes occurred over time, and ELM diagnostic algorithms for differentiating benign melanocytic lesions from melanoma did not score a suspicion of melanoma. All melanomas, either pre-existing or developing during follow-up, were identified in an early, curable phase of tumour growth. We conclude that DELM follow-up for patients at high risk allows the early detection of melanomas that have not yet acquired melanoma-typical ELM features.

Carcinoma of the pancreas with neuroendocrine differentiation and nodular panniculitis.

BACKGROUND: On rare occasions tumours of the pancreas produce high amounts of pancreatic lipase. The enzyme activity in the blood and in different tissues causes a syndrome called nodular panniculitis by focal necrosis of lipids and a concomittant inflammatory reaction. CASE REPORT: A 72-year-old man was admitted to the dermatology clinic with the diagnosis of erythema nodosum. The patient had been well until 3 months earlier when painful red nodes developed on the skin of both shanks. He complained of profuse night sweating and a weight loss of 10 kg within that time but did not have fever. He also had noticed a painful swelling of his right index finger, left middle finger and the third toe on his left foot. Biopsy of the nodes revealed a focal necrosis of fatty tissue. Laboratory examinations showed a highly elevated concentration of serum pancreatic lipase. Further investigations showed a tumour in the pancreas and several osteolytic lesions. Tumour biopsy revealed a neuroendocrine carcinoma. After tumour resection serum lipase level immediately fell to almost normal values, and all skin and bone manifestations disappeared quickly. CONCLUSION: Due to its clinical appearance the panniculitis syndrome is most often mistaken for either erythema nodosum or rheumatoid arthritis. A resection of the tumour after correct diagnosis should always be considered because the widespread manifestations in the skin and bones do not represent distant metastasis and have a very good chance to dissolve completely.

Cytogenetic analyses of culture failures by comparative genomic hybridisation (CGH)-Re-evaluation of chromosome aberration rates in early spontaneous abortions.

Comparative genomic hybridisation (CGH) represents an alternative molecular-cytogenetic technique capable of detecting chromosomal imbalances by reverse fluorescence in situ hybridisation. As the technique uses genomic DNA for assessment it does not rely on metaphase chromosomes in the test material and thus circumvents technical problems associated with tissue culturing. In the present study, we applied CGH to identify chromosome anomalies in 60 spontaneous abortions of the first trimester, that had failed to grow in culture. In 57 out of 60 cases CGH analyses were successful. The overall aneuploidy rate detected was 72%. Trisomy was the predominant chromosome anomaly accounting for 68.0% of abnormal abortions, followed by triploidy (17.1%) and monosomy X (9.8%). An unbalanced structural rearrangement was found in one (2.4%) abortion. Most frequently involved in trisomies were chromosomes 16 (32.1%), 7 and 22 (10.7% each), 4, 13, 15, and 21 (7.2 % each). Three triploid cases and one complete mole were detected by microsatellite analysis as supplementary method. CGH data on culture failures were compared with data derived from 4693 successfully karyotyped first trimester spontaneous abortions, resulting in a chromosome aberration rate of 64.8%. The distribution of the different chromosome anomalies was similar with the exception of a higher rate of trisomies 7 and of XYY-triploidies in the culture failures. Based on our data we suggest that the genetic contribution to pregnancy loss is still underestimated. Investigating abortion tissues hitherto unassessed by conventional methods, we suggest that the contribution of chromosome aberrations to first trimester pregnancy loss is nearly 70%.

Prenatal diagnosis of a fetus with a cryptic translocation 4p;18p and Wolf-Hirschhorn syndrome (WHS).

Wolf-Hirschhorn Syndrome (WHS) is caused by distal deletion of the short arm of chromosome 4 and is characterized by growth deficiency, mental retardation, a distinctive, 'greek-helmet' facial appearance, microcephaly, ear lobe anomalies, and sacral dimples. We report a family with a balanced chromosomal translocation 4;18(p15.32;p11.21) in the father and an unbalanced translocation resulting in partial monosomy 4 and partial trisomy 18 in one living boy and a prenatally diagnosed male fetus. Both showed abnormalities consistent with WHS and had in addition aplasia of one umbilical artery. Karyotyping of another stillborn fetus revealed a supernumerary derivative chromosome der(18)t(4;18)(p15.32;p11.21) of paternal origin and two normal chromosomes 4. The umbilical cord had three normal vessels. A third stillborn fetus with the same balanced translocation as the father had a single umbilical artery and hygroma colli.

Renal tubular dysgenesis (RTD) - an important cause of the oligohydramnion-sequence. Report of 3 cases and review of the literature.

Renal tubular dysgenesis (RTD) is a disorder characterized by neonatal renal failure and regular gross renal architecture, although the histological features of immature and shortened proximal tubules lead to neonatal death. The pathogenesis of this condition includes a congenital familial condition, a twin-twin transfusion syndrome, and an angiotensin-converting enzyme inhibitor intake by the mother. The clinical picture shows an association with oligohydramnia, pulmonary hypoplasia, and skull ossification defects. In the present paper, we report the occurrence of RTD in three infants of a consanguinous couple and compared our data with those of the literature. Our data confirm that late second trimester demonstration of oligohydramnion, with structurally normal kidneys and with or without skull ossification defects, allows the diagnosis of renal tubular dysgenesis, which, however, has to be confirmed by histological and immunohistological examinations of the kidney.