Immunohistochemical effects of temporary cessation of long-term acitretin treatment in keratinocytic intraepidermal neoplasia of renal transplant recipients.
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Acitretin↗
Biomedical subjects
Dirk J Ruiter
Publications and source records attributed to Dirk J Ruiter.
Pathophysiological implications of stroma pattern formation in uveal melanoma.
Clinical outcome of cancer patients is mainly determined by the rate of metastasis and, also by primary tumor growth. Formation of extracellular matrix and interactions of neoplastic and non-neoplastic (host) cells in solid tumors have been shown to be essential for these processes. One result of such interactions is the outgrowth of new blood vessels from existing ones, angiogenesis, to provide the tumor tissue with oxygen and nutrients. It is assumed that the neovascular bed also facilitates the escape of metastatic cells from the primary lesions. In addition, recent reports suggested the existence of blood-conducting channels lined by melanoma cells (so-called "vascular channels") accompanied by depositions of extracellular matrix patterns in cutaneous and uveal melanoma. Since the presence of these matrix structures has been negatively associated with prognosis, we hypothesize that they play a role in melanoma outgrowth or metastasis. In this review, we will discuss the morphological and functional properties of the extracellular matrix patterns in that may underlie these clinical phenomena.
Extracellular Matrix↗
Cancer/testis-associated genes: identification, expression profile, and putative function.
Cancer/testis-associated genes (CTAs) are a subgroup of tumor antigens with a restricted expression in testis and malignancies. During the last decade, many of these immunotherapy candidate genes have been discovered using various approaches. Most of these genes are localized on the X-chromosome, often as multigene families. Methylation status seems to be the main, but not the only regulator of their specific expression pattern. In testis, CTAs are exclusively present in cells of the germ cell lineage, though there is a lot of variation in the moment of expression during different stages of sperm development. Likewise, there is also a lot of heterogeneity in the expression of CTAs in melanoma samples. Clues regarding functionality of CTAs for many of these proteins point to a role in cell cycle regulation or transcriptional control. Better insights in the function of these genes may shed light on the link between spermatogenesis and tumor growth and could be of use in anti-tumor therapies. This review outlines the CTA family and focuses on their expression and putative function during male germ cell development and melanocytic tumor progression.
Antigens, Neoplasm↗
The development of optimal pathological assessment of sentinel lymph nodes for melanoma.
1158 sentinel lymph nodes (SLNs), excised from patients with primary cutaneous melanoma, were assessed pathologically using histology with immunohistochemistry (IHC) on all nodes, and RT-PCR for Mart-1 and tyrosinase on 55 nodes. RT-PCR was compared with the histology and IHC assessed on the same nodes. The evaluation of progressively more detailed protocols for histology and IHC modulated by the RT-PCR results led to a procedure that consistently detects metastases in 34% of patients submitted to SLN biopsy for cutaneous melanomas with a vertical growth phase and a mean thickness of 2.02 mm (range 0.25, with regression, to 19 mm). As this technique is virtually free of false positives and produces only a marginally lower detection rate than RT-PCR, which was subject to false positives of 7% in our study, it is suggested that this extended protocol should be the basis on which further evaluation of the place of RT-PCR in SLN assessment takes place. The evolved protocol described here has been adopted by the EORTC as the standard procedure for pathological handling of sentinel lymph nodes for melanoma when SLN status is a criterion in their clinical trials or studies.
Clinical Protocols↗
[Melanoma-stroma interactions and melanoma progression].
Cutaneous melanoma is an aggressive tumor which can metastasize early in its course. Not only the melanoma cells but also the tumor microenvironment play an important role in tumor development and progression. We review the structural and functional aspects of interactions between melanoma cells and the stroma and discuss some clinical implications.
Biomarkers, Tumor↗
Current diagnostic problems in melanoma pathology.
The histopathological diagnosis of cutaneous melanocytic lesions may be difficult to assess. Frequently encountered diagnostic problems include: 1) Dysplastic nevus or melanoma in situ?; 2) Melanoma in situ or superficial spreading melanoma?; 3) Lentigo maligna or lentigo maligna melanoma?; 4) Compound nevocellular nevus or nevoid melanoma?; and 5) Spitz nevus or Spitzoid melanoma? Moreover, less frequently encountered diagnostic challenges are discussed: 1) Deep penetrating nevus or nodular melanoma?; and 2) Cellular blue nevus or melanoma metastasis? In this contribution, these problems are discussed after a systematic approach involving a concise histopathological description of the classic lesions considered in the differential diagnoses, a presentation of the deviating histopathological features that give rise to the diagnostic problems, and finally diagnostic recommendations on the classification of the problematic lesions. We also briefly discuss the contribution of additional immunohistochemistry and molecular pathology in aiding to establish a correct diagnosis.
Carcinoma in Situ↗
The tumor microenvironment: a critical determinant of neoplastic evolution.
Evolution of neoplastic cells has generally been regarded as a cumulative intrinsic process resulting in altered cell characteristics enabling enhanced growth properties, evasion of apoptotic signals, unlimited replicative potential and gain of properties enabling the ability to thrive in ectopic tissues and in some cases, ability to metastasize. Recently however, the role of the neoplastic microenvironment has become appreciated largely due to the realization that tumors are not merely masses of neoplastic cells, but instead, are complex tissues composed of both a non-cellular (matrix proteins) and a cellular 'diploid' component (tumor-associated fibroblasts, capillary-associated cells and inflammatory cells), in addition to the ever-evolving neoplastic cells. With these realizations, it has become evident that early and persistent inflammatory responses observed in or around many solid tumors, play important roles in establishing an environment suitable for neoplastic progression by providing diverse factors that alter tissue homeostasis. Using cutaneous melanoma and squamous cell carcinoma as tumor models, we review the current literature focussing on inflammatory and tumor-associated fibroblast responses as critical mediators of neoplastic progression for these malignancies.
Animals↗
P16 and p53 expression in (pre)malignant epidermal tumors of renal transplant recipients and immunocompetent individuals.
Ultraviolet (UV) radiation is a prevailing factor implicated in the etiology of keratinocytic intraepidermal neoplasia (KIN) and squamous cell carcinomas (SCCs), as evidenced by the high frequency of UV-related mutations in the p53 and p16 tumor suppressor genes. In renal transplant recipients (RTRs), immunosuppression is considered another important risk factor in the enhanced carcinogenesis in these patients. So far, effects of UV and immune status on p53 and p16 immunoexpression in SCCs and precursors have not been studied. The aims of this study were to assess (1) the relation between risk factors for carcinogenesis, sun exposure and immune status, and p16 or p53 expression, and (2) to assess differences in p16 and p53 expression between KINs and SCCs. Immunostaining for p16 and p53 was performed on paraffin-embedded sections of 23 low-grade KIN (LKIN) lesions, 28 high-grade KINs (HKINs), and 35 SCCs from 44 RTRs and 42 immunocompetent controls (ICIs). In 74/86 lesions (86%), p53 was expressed, and in 63/86 (76%) lesions, p16 expression was present. Negativity for both p16 and p53 was found in 4/86 (5%) cases, whereas combined p53/p16 staining was most prevalent (55/86 lesions, 64%). P16 staining proved independent of p53 expression (P =.8), and immune status, sun exposure, and histological diagnosis (LKIN-HKIN-SCC) had no influence on this independence. Transplantation was associated with p53 expression in SCCs (P =.02; power = 34%) caused by higher prevalence of p53-negative SCCs in RTRs than in ICIs (30% versus 0). In HKINs, p16 was more frequently positive than in LKINs (P =.003; power = 49%) and SCCs (P =.03; power = 53%). HKINs showed more frequent transepidermal p16 and p53 staining than LKIN lesions (P <.001; power >/= 99%). This study demonstrates that in KIN lesions and cutaneous SCCs, p16 expression is independent of p53 expression, and immune status, sun exposure, and histological diagnosis have no influence on this independence. Furthermore, HKIN lesions express significantly more p16 than LKINs and SCCs.
Aged↗
EMAP-II expression is associated with macrophage accumulation in primary uveal melanoma.
PURPOSE: Primary uveal melanoma may contain arcs, loops, and networks of periodic acid-Schiff (PAS)-positive patterns, along which numerous macrophages are present. Their recruitment into tumor tissue is mediated by chemotactic cytokines, for which vascular endothelial growth factor (VEGF)-C and endothelial monocyte-activating polypeptide ((EMAP)-II are candidates. In this study, the extent of VEGF-C and EMAP-II immunoreaction was related to infiltration of macrophages. METHODS: Serial sections of 25 primary uveal melanoma lesions were analyzed by immunohistochemistry. RESULTS: The analysis showed no correlation of VEGF-C immunoreaction and localization of macrophages. However, accumulation of macrophages occurred at sites of EMAP-II expression, especially in areas containing nests of tumor cells, surrounded by arcs, loops, and network patterns. In tumors with a strong EMAP-II immunoreaction, the adhesion molecule intracellular adhesion molecule (ICAM)-1 was strongly expressed on endothelial cells. EMAP-II-positive endothelial cells did not express VEGF receptor-2. However, extensive release of von Willebrand factor was observed. Signs of apoptosis were found neither in tumor cells nor endothelial cells. CONCLUSIONS: In uveal melanoma, macrophages accumulate at sites of EMAP-II expression. Based on the results, it may be hypothesized that this process of chemotaxis is facilitated by EMAP-II-dependent expression of ICAM-1 on vascular endothelial cells and concomitantly leads to localized vascular damage, as indicated by release of von Willebrand factor.
Apoptosis↗
Induction of vascular endothelial growth factor receptor-3 expression on tumor microvasculature as a new progression marker in human cutaneous melanoma.
The anatomical relation between a malignant tumor and its vascular and lymphatic bed is an important factor influencing metastasis. Lack of specific markers for the lymphatic endothelium has long hampered a reliable detection of lymphatics. Here, we demonstrate that lymphatic endothelium can reliably be identified in a panel of different normal tissues and of benign and malignant tumors. Application of the previously described PAL-E/CD31 double staining protocol differentiates between blood capillaries and veins on one hand and lymphatic vessels on the other. Blood vessel marker CD34, absent from lymphatics, was used additionally to classify arteries. We found that the lymphatic vascular endothelial growth factor receptor-3 (VEGFR-3, also known as Flt-4) was present on both lymphatic and blood vessels in 76 of 113 malignant tumors [adenocarcinoma of kidney (n = 3), colon (n = 3) and liver (n = 3), breast (n = 9) and squamous cell carcinoma (n = 5), primary (n = 81), and metastatic (n = 9) melanoma]. No evident signs of tumor-induced lymphangiogenesis were observed. Evaluation of a series of 110 melanocytic skin lesions indicated that VEGFR-3 expression is confined to the lymphatic vasculature in benign lesions. However, its expression emerges on the blood neovasculature in malignant lesions as soon as metastatic potential develops. We conclude that induction of VEGFR-3 expression on tumor blood vessels may be a general phenomenon that would make VEGFR-3 a marker for tumor endothelium. In addition, we propose VEGFR-3 expression as a new microvascular progression marker in cutaneous melanoma.
Biomarkers, Tumor↗
The XAGE family of cancer/testis-associated genes: alignment and expression profile in normal tissues, melanoma lesions and Ewing's sarcoma.
The existence of XAGE genes was first reported after database homology searches for PAGE-like sequences identified 3 XAGE EST clusters. One of these clusters, XAGE-1, has in later studies been identified as a cancer/testis-associated gene. Here, we report the expression profiles of all 3 reported XAGE genes, as well as several splice variants of XAGE-1, in normal human tissues, Ewing's sarcoma and melanocytic tumors. We also provide the genetic structure of the corresponding genes. Moreover, by searching the databases for XAGE homologues, we identified 3 additional GAGE-like genes. RT-PCR studies showed frequent expression in melanoma metastases and Ewing's sarcoma for 2 XAGE-1-derived transcripts. XAGE-2 was expressed at lower frequency in these tissues, while XAGE-3 was seen only in normal placenta. Due to a frameshift, the largest XAGE-1 putative protein is far less homologous to GAGE-like proteins than the other XAGEs. Interestingly, all GAGE-like genes contain a large secondary open reading frame, coding for putative proteins homologues to the XAGE-1 primary protein. The XAGE family of cancer/testis-associated genes is located on chromosome Xp11.21-Xp11.22. The data outline a superfamily of GAGE-like cancer/testis antigens, consisting of at least 19 genes.
Alternative Splicing↗
Expression profiling of MMA-1a and splice variant MMA-1b: new cancer/testis antigens identified in human melanoma.
Using high-density oligonucleotide array analysis, we have recently compared the gene expression profiles of 2 human melanoma cell lines with marked difference in metastatic behavior after subcutaneous inoculation into nude mice (de Wit et al., Melanoma Res, in press). We identified an expressed sequence tag (EST), which we called malignant melanoma-associated 1 (MMA-1a), showing evident differential expression between the 2 cell lines. The MMA-1a gene is localized on chromosome 21q22.2 and its mRNA exists of 4 exons. Homology search displayed a splice variant of MMA-1a that lacks exon 3 and that was called MMA-1b. Expression profiles of MMA-1a and MMA-1b are determined by reverse transciptase polymerase chain reaction (RT-PCR) analysis. Among 30 different normal tissue samples, expression of MMA-1a and MMA-1b was exclusively found in the testis after a first PCR of 30 cycles. Even more sensitive screening achieved by performing multiple semi-nested RT-PCR showed no or very low expression in the other normal tissues tested. During melanocytic tumor progression, MMA-1a and/or MMA-1b exhibited an emergence of expression in primary melanoma (20%) and melanoma metastasis samples (30%) after only 1 round of PCR. Expression of MMA-1a and/or MMA-1b was also identified in other tumor cell lines and fresh tumor samples of variable origin, e.g., lung, liver, bladder and soft tissues (sarcomas). We conclude that MMA-1a and MMA-1b are new members of the family of cancer/testis antigens.
Alternative Splicing↗
Vascular endothelial growth factor-A(165) induces progression of melanoma brain metastases without induction of sprouting angiogenesis.
We investigated the mechanisms of vascularization in a brain metastases model of malignant melanoma. Parenchymal metastases expressing little vascular endothelial growth factor-A (VEGF-A) co-opted the preexistent brain vasculature, leading to an infiltrative phenotype. Metastases of the human melanoma cell line Mel57, engineered to express recombinant VEGF-A(165), showed accelerated growth in a combined expansive and infiltrative pattern with marked central necrosis. This difference in growth profile was accompanied by dilation of co-opted intra- and peritumoral vessels with concomitant induction of vascular permeability. Our data show that modulation of preexistent vasculature can contribute to malignant progression without induction of sprouting angiogenesis.
Animals↗
Characterization of XAGE-1b, a short major transcript of cancer/testis-associated gene XAGE-1, induced in melanoma metastasis.
Suppression subtractive hybridization, comparing mRNA expression profiles of common nevocellular nevi and melanoma metastases, was used to identify potential markers of melanoma progression. From the metastases we isolated XAGE-1b, a 470 bp transcript of the XAGE-1 gene. In general, expression of XAGE-1b was much more prominent than expression of the longer XAGE-1 transcript, isolated from Ewing's sarcoma. The XAGE-1b open-reading frame codes for a putative protein of 81 amino acids, harboring a functional bipartite nuclear localization signal and a C-terminal acidic transcription-activation-like domain. On the nucleotide level, XAGE-1b has a 50% homology with members of the GAGE family. However, homology between the corresponding proteins is weak. Expression of XAGE-1b in normal tissues was mainly restricted to testis, while placenta and brain were sporadically positive. In human tumor cell lines as well as in human tumor lesions, expression was most frequently found in melanocytic tumors and Ewing's sarcoma. In the different stages of melanocytic tumor progression, expression was exclusively seen in melanoma metastases (38%; n = 61), while all tested common and atypical nevi (n = 10) as well as primary melanomas (n = 8) were negative. Upregulation of expression after treatment with demethylating agent 5-aza-2'-deoxycytidine was detected in 1 of 4 human melanoma cell lines tested. The XAGE-1 gene consists of 4 exons and is located on chromosome Xp11.21-Xp11.22. After transfection into COS cells, the corresponding protein can direct the coupled fluorescent protein to the nucleus, showing a distinct speckled staining aspect. Our data imply the nuclear cancer/testis-associated XAGE-1b to be a marker for late melanocytic tumor progression.
Amino Acid Sequence↗
Pegylated liposomal tumor necrosis factor-alpha results in reduced toxicity and synergistic antitumor activity after systemic administration in combination with liposomal doxorubicin (Doxil) in soft tissue sarcoma-bearing rats.
Previously we reported that encapsulation of tumor necrosis factor-alpha (TNF) in pegylated (STEALTH) liposomes (TNF-PEGL) dramatically improved circulation times of the protein and augmented accumulation in tumor tissue. We and others have demonstrated enhanced antitumor activity of doxorubicin or melphalan by free TNF when used in high doses in an isolated limb perfusion setting. In the present study the antitumor activity of TNF-PEGL was studied in combination with liposomal chemotherapy. BN rats with subcutaneous BN175 sarcomas (8-12 mm diameter) received no treatment or pegylated liposomal doxorubicin (Doxil) alone or in combination with various doses of TNF-PEGL (15-200 microg/kg). The evaluated endpoints were tumor response and toxicity of the treatment regimens. Here we demonstrate that TNF-PEGL at a dose of 15 microg/kg markedly augments the antitumor activity of liposomal doxorubicin, without resulting in the increased toxic side effects observed with free TNF at doses resulting in a similar enhancement of the antitumor effects. Even at a TNF dose of 200 microg/kg TNF, repeated administration of TNF-PEGL did not result in severe weight loss or cause diarrhea. Repeated dosing of free TNF at this dose resulted in severe, life-threatening weight loss and occurrence of diarrhea in all animals. These results indicate that pegylated liposomal encapsulation may be effective in systemic application of TNF for combined treatment with liposomal chemotherapy of advanced solid tumors.
Animals↗
Retinoids strongly and selectively correlate with keratin 13 and not keratin 19 expression in cutaneous warts of renal transplant recipients.
OBJECTIVE: To compare the expression of keratin (K) 13 and K19 in cutaneous warts of renal transplant recipients (RTRs) and immunocompetent individuals (ICIs). DESIGN: Retrospective, nonrandomized immunohistochemical study. PATIENTS AND METHODS: Specimens from cutaneous warts of RTRs and ICIs were retrieved from the archives of the Department of Pathology, University Medical Center St Radboud, Nijmegen, the Netherlands. Twenty-one warts from RTRs and 21 from ICIs were examined. Nine RTRs (10 specimens) received either systemic acitretin or topical all-trans retinoic acid, and their effect on both keratins was assessed. MAIN OUTCOME MEASURES: Frequency and expression patterns of K13 and K19 in warts of RTRs vs ICIs and the effect of retinoids. RESULTS: A significantly higher percentage of warts of RTRs expressed K13 compared with warts of ICIs (86% vs 14%, 18 vs 3 cases, respectively; P<.001). In warts of RTRs, retinoid treatment correlated significantly with a particularly strong, segmental K13 expression pattern, which we termed zebroid. Without use of retinoids, K13 was mostly restricted to suprabasal single cells. Keratin 19 was absent in all warts of both patient groups. CONCLUSIONS: Retinoids strongly correlate with K13 in a characteristic zebroid pattern in warts of RTRs, making K13 a sensitive marker for retinoid bioactivity in skin (lesions) of RTRs. In non-retinoid-treated RTRs, K13 is also frequently found in warts but without the dramatic zebroid pattern noted in retinoid-treated warts.
Acitretin↗
Identification of histological features associated with metastatic potential in thin (<1.0 mm) cutaneous melanoma with metastases. A study on behalf of the EORTC Melanoma Group.
Contrary to expectations, a small number of thin (<1 mm) melanomas do metastasize. This collaborative study was performed in an attempt to identify the morphological basis of such aggressive behaviour. Regression was expected to be the explanation for the lack of thickness in some cases. Whether a vertical growth phase (VGP) was present in the remainder was carefully assessed. A pilot study had identified two other patterns associated with metastasis in thin melanomas. These were termed 'junctional expansion nodules' and 'melanomatous follicular invasion'. Both were seen in the absence of other dermal invasion. These two patterns were included in the study, which comprised 54 cases and 56 controls, which were thin melanomas which had not metastasized 5 years after excision. Regression was present in 50% of test cases (30.4% in controls, p=0.036) and VGP was present in 59.3% of cases and 48.2% of controls. The thinnest metastasizing melanoma without regression was 0.27 mm. Eight (14.8%) cases, however, had metastasized but showed neither regression nor VGP; seven of these showed a junctional expansion nodule, present in only three controls (p=0.016). Five of these seven also showed melanomatous follicular invasion. One of these five showed this follicular involvement without a junctional nodule. Melanomatous follicular invasion was not seen in the control cases (p=0.012). Mitoses were seen in the VGP of both test and control cases, but high counts (>3 per mm(2)) were much more common in the metastasizing lesions (p=0.007). These findings support the idea that in most cases, regression and/or a VGP are required for metastasis to occur. However, a small number of thin melanomas without these features, as conventionally described, still metastasize. This implies that VGP may require redefinition and that junctional expansion nodules and melanomatous follicular invasion may be variants of VGP.
Adult↗
Allelic imbalance in the diagnosis of benign, atypical and malignant Spitz tumours.
To test the diagnostic usefulness of allelic imbalance (AI) analysis based on routinely paraffin-embedded tissue, a series of 55 benign Spitz naevi, Spitz tumours with uncertain malignant potential, and malignant Spitzoid melanomas was investigated. Laser microdissection was used to ensure representative sampling of lesional cells and to investigate AI in separate tumour areas of four melanomas. AI was found in 2/12 (17%) typical Spitz naevi, 3/9 (33%) atypical Spitz tumours, 12/17 (65%) atypical Spitz tumours suspicious for melanoma and 15/17 (88%) Spitzoid melanomas. Additional immunohistochemical staining for Ki-67 using the MIB-1 antibody revealed positive deeply situated lesional cells in 0/6 (0%) Spitz naevi, 1/8 (13%) atypical Spitz tumours, 5/14 (35%) atypical Spitz tumours suspicious for melanoma, and 7/14 (50%) Spitzoid melanomas, respectively. Two of the melanomas examined for AI in separate tumour areas showed intratumoural genetic heterogeneity. In view of the finding of AI and deeply situated Ki-67 positive cells not only in melanomas but also in Spitz tumours with uncertain malignant potential, these approaches appear to have no direct diagnostic applicability for the distinction between benign and malignant Spitz tumours. Further molecular studies will be required to determine whether Spitz tumours and Spitzoid melanomas are unrelated entities, or whether there is a true spectrum of tumour progression.
Adolescent↗