Presence of free retinol receptor (cRBP) and retinoic acid receptor (cRABP) in human skin tumors

The concentrations of cellular retinoic acid binding protein (cRABP) and free cellular retinol binding protein (cRBP) were determined by ultracentrifugation in sucrose gradient in the cytosol of 41 human skin tumours (14 melanomas, 19 basal cell carcinomas, 8 squamous cell carcinomas). cRBP was found respectively in 36%, 42% and 37% of the studied samples. On the contrary, cRABP was more frequently found in carcinomas (89% in basal cell carcinomas and 100% in squamous cell carcinomas) than in melanomas (21%) (p less than 0.001). These results are discussed according to the different embryologic origin of carcinomas and melanomas. Furthermore, the better efficiency of synthetic retinoids in carcinomas than in melanomas should be explained by a different way of action in these 2 kinds of tumours.     

Reduced apoptotic levels in squamous but not basal cell carcinomas correlates with detection of cutaneous human papillomavirus

We have investigated the apoptotic levels and expression of the apoptotic inducer Bak in non-melanoma skin cancers. Squamous cell carcinomas of known human papillomavirus status from immunocompetent patients were analysed for the expression of the Bak protein, and the expression profile was compared both to the presence of apoptotic cells and the proliferation marker Ki-67. We demonstrate an inverse correlation between human papillomavirus positivity and Bak expression in squamous cell carcinomas, with concomitantly fewer apoptoic cells being detected in the human papillomavirus positive tumours. Bak expression was not observed in basal cell carcinomas irrespective of human papillomavirus status, suggesting that Bak only plays a role in signalling apoptosis in squamous, but not basal, cell cancers. No differences were observed in the proliferation rates between papillomavirus positive and negative squamous cell tumours. However, a significant decrease in the number of apoptotic cells was observed in human papillomavirus-positive squamous cell carcinomas which suggests that the virus may have significantly altered the relationship between proliferation and apoptosis in a proportion of these tumours.     

Circulating soluble tumour necrosis factor receptors in patients with epidermodysplasia verruciformis as compared to patients with cutaneous tumours in the general population

Soluble tumour necrosis factor receptors type I and II (sTNF-RI and II) were evaluated in sera from patients with epidermodysplasia verruciformis and patients with cutaneous warts, actinic keratoses, squamous cell carcinomas or basal cell carcinomas by specific enzyme-linked immunobiological assays. In patients with widespread epidermodysplasia verruciformis lesions, the levels of both sTNF-Rs were in normal range. Both types of sTNF-Rs were significantly increased in patients with warts. The levels of sTNF-RI were significantly increased in patients with multiple actinic keratoses, squamous cell carcinoma and basal cell carcinoma. Increased levels of circulating sTNF-Rs may facilitate development of cutaneous tumours. Normal levels of sTNF-Rs in patients with epidermodysplasia verruciformis might, at least partially, contribute to a slow growth and low metastatic potential of cancers in these patients.     

Skin Cancer in African Albinos

A review of 775 normally pigmented Africans and 18 African albinos with malignant skin tumours showed that squamous cell carcinoma was the most common tumour type, in contrast to Caucasians, in whom basal cell carcinoma is most frequent. in African albinos squamous cell carcinoma of the head and neck region was most frequent. However, the proportion of basal cell carcinomas was low also among albinos but higher than among normally pigmented patients. in contrast to the normally pigmented patients, there were no squamous cell carcinomas on the limbs in albino patients. We suggest that this difference was due to environmental factors, such as chronic leg ulcers, which might have been less influential in the albinos, who seldom lived more than 30 years. No cases of cutaneous melanoma or Kaposi sarcoma were found in the albino group.     

Cancers cutanés après transplantation : quoi de neuf ?

Skin cancers are the commonest cancers after organ transplantation, affecting in the long term 60–75% of the patients. They include mostly carcinomas, especially squamous and basal cell carcinomas, but also melanoma, Kaposi’s sarcoma and other rare skin tumours such as Merkel cell carcinoma. The management of these tumours necessitates a multidisciplinary approach comprising dermatological treatments and revision of immunosuppression. Prevention consists of strict sun protection and early treatment of premalignant lesions.     

C-erbB-2 expression in squamous cell carcinoma of the head and neck.

Seventy-five squamous cell carcinomas of the head and neck were analysed for c-erbB-2 expression using immunohistochemical techniques with four different c-erbB-2 antibodies. No membrane staining was seen in any of the squamous cell carcinomas studied with any of the antibodies; however, c-erbB-2 cytoplasmic staining was seen in 60 per cent of the tumours. The significance of cytoplasmic staining is discussed and that it may possibly represent elevated c-erbB-2 expression in squamous cell carcinomas. C-erbB-2 cytoplasmic staining was also observed in 10 of 23 normal specimens obtained from the resection margin of the tumours. No correlations were found between positive c-erbB-2 cytoplasmic staining and any of the clinicopathological parameters or survival.     

HPV 16 in multiple neoplastic lesions in women with CIN III

Paraffin embedded material of multiple primary cancers and other hyperplastic tumours from fifteen patients were analyzed by PCR and in situ hybridization for the presence of HPV DNA in the lesions. All patients had also high grade cervical intraepithelial dysplasia (CIN III) and breast carcinomas and were selected from a previous study enrolling 46 women with CIN III and breast carcinomas. HPV 16 was detected by PCR in 8/15 patients (53%), with eleven HPV 16 positive tumours. HPV 16 was detected in two malignant melanomas, one basal cell carcinoma, one squamous cell carcinoma of the vulva, one Bowen disease of the vulva, two high grade vaginal intraepithelial neoplasias, one cancer corporis uteri, one bronchial carcinoma and two lymphomas. Three cases, two high grade vaginal intraepithelial neoplasia and a squamous cell carcinoma of the vulva, were also reported to be positive by in situ hybridization. 5/8 patients (63%) with HPV 16 positive second cancers had also HPV 16 positive breast carcinomas. All fifteen patients with second cancers after CIN III had HPV 16 positive CIN III lesions; 53% of the patients had also a familial cancer history. We assume that HPV 16 may be involved in the development of different second cancers in women with HPV 16 positive CIN III.     

CGH analysis of ductal carcinoma of the breast with basaloid/myoepithelial cell differentiation

2-18% of ductal carcinoma-No Special Type (NST) are reported to express basal cell keratin 14 and such tumours may have a different metastatic pattern and prognosis. We performed immunohistochemistry for cytokeratins 19 (luminal) and 14 (basal) on 92 ductal carcinoma-NST. Those tumours showing CK14 expression were further characterized by immunohistochemistry for myoepithelial cell phenotype and analysed by comparative genomic hybridization. The 7 cases of ductal carcinoma-NST exhibiting a basal cell phenotype were all grade III tumours and showed a molecular cytogenetic profile similar to more conventional myoepithelial cell carcinomas. Therefore it appears that grade III invasive ductal carcinomas contain a subset of tumours with specific morphological and cytogenetic characteristics, and probably prognosis for the patient.     

Lectin bindings in non-neoplastic esophageal epithelium and esophageal carcinomas

Lectin binding was examined histochemically in 22 cases of primary esophageal carcinomas (10 well differentiated, 8 moderately differentiated and 3 poorly differentiated squamous cell carcinomas, and 1 undifferentiated carcinoma) and was compared with the adjacent non-neoplastic epithelium by means of a panel of 10 different lectins (RCA-I, WGA, Con A, LCA, SEA, UEA-I, HPA, PNA, DBA and GS-I) on formalin-fixed paraffin-embedded sections. In the non-neoplastic epithelium, RCA-I and WGA showed basal/parabasal binding, Con A, LCA, SEA, UEA-I, HPA and PNA revealed prickle cell binding, while DBA and GS-I only stained the surface cells of the squamous cell layer. In squamous cell carcinomas, no clear difference was evident regarding the grade of differentiation. However, basal/parabasal specific lectins were expressed in all the cases, the prickle cell-specific lectins were expressed less frequently, whereas lectins expressed at the surface cells of the squamous cell layer were only infrequently expressed. Therefore, basal/parabasal cell specific lectins were widely preserved in squamous cell carcinomas. One case of undifferentiated cancer tested was devoid of all the lectins.     

Gene amplification and overexpression of EGF receptor in squamous cell carcinomas of the head and neck

Tumours of the head and neck were examined for gene amplification and expression of the epidermal growth factor (EGF) receptor by Southern blot and Western blot analyses. The EGF receptor gene was found to be amplified in four (19%) of 21 squamous cell carcinomas. The EGF receptor was overexpressed in eight (53%) of 15 squamous cell carcinomas examined, including all four tumours showing gene amplification. No amplification or overexpression of the EGF receptor gene was detected in any of nine malignant or eight benign tumours of other types of the head and neck. The tumours showing amplification and/or overexpression of the EGF receptor gene (8/15) were all identified histologically as well differentiated squamous cell carcinomas, whereas none of the histologically less differentiated squamous cell carcinomas (0/9) showed amplification and/or overexpression of the EGF receptor gene. Within our sample set, no correlation was evident between amplification and/or overexpression and the clinical stage or tumour site. Our results support the possible involvement of gene amplification and overexpression of the EGF receptor in a subclass of squamous cell carcinomas of the head and neck.     

Protein expression profiles of non-small cell lung carcinomas: correlation with histological subtype

Of the four major subtypes of lung cancer, three subtypes, namely squamous cell lung carcinomas, adenocarcinomas and large cell carcinomas are usually combined within the larger group of non-small cell lung carcinomas (NSCLC). However, the heterogeneity that exists within any given tumor has also been clearly demonstrated. In order to study whether or not the protein expression profile is different in the histological subtypes of NSCLC, the expression of several parameters including proto-oncogene and suppressor gene products, proliferative, apoptotic, angiogenic and resistance factors was evaluated immunohistochemically in 139 NSCLC (45 adenocarcinomas and 94 squamous cell lung carcinomas). In both histological subtypes the percentage of positively-stained parameters was determined. The expression of the proteins ERBB2, JUN, RAS and tissue factor was significantly higher in adenocarcinomas compared to squamous cell lung carcinomas. In contrast, all resistance proteins analyzed were more frequently expressed in squamous cell lung carcinomas in comparison to adenocarcinomas, though only GST-pi reached statistical significance. Apoptotic factors and angiogenic factors were higher in adenocarcinomas, but these differences did not reach statistical significance. In conclusion, the protein expression profiles of adenocarcinomas and squamous cell carcinomas differ from each other. Squamous cell lung carcinomas in comparison to adenocarcinomas are characterized by a down-regulation of some oncogenes and an up-regulation of several resistance factors. These findings could explain the different biological behaviour and treatment response of these tumours.     

Development of diffuse invasive (grade 4D) human oral squamous cell carcinoma model in severe combined immunodeficiency mice: microangioarchitectural analysis and immunohistochemical study

Among oral squamous cell carcinomas (OSCCs), the diffuse invasive (grade 4D) tumour exhibits the highest degree of malignancy. The TSU cell line, which has been established from a grade 4D OSCC, has not been successfully grown even in immuno-suppressed hosts. Here, invasive cells were selected by the repeated inoculation of TSU cells with Matrigel and gelatin sponge into the subcutaneous tissue of nude mice. The selected cells formed oral tumours temporarily in nude mice and produced lethal tumourgenicity in severe combined immunodeficiency (SCID) mice without the addition of other materials. The microangioarchitecture of the tumours in SCID mice showed neovascularization and the formation of a vascular network. An immunohistochemical study demonstrated that the expressions of vascular endothelial growth factor and matrix metalloproteinase-2 were strong, whereas desmoglein-1 and type-IV collagen were absent. These findings suggested that the loss of intercellular junctions and dissolution of basement membranes may underlie the pathogenesis of diffuse invasive growth in grade 4D tumours.     

Expression of hyaluronan in normal and dysplastic bronchial epithelium and in squamous cell carcinoma of the lung

A series of 85 lung/bronchial tissue samples from 76 patients consisting of normal, metaplastic and dysplastic epithelium and different types of lung carcinomas were analyzed for the distribution of hyaluronan (HA), using a biotinylated hyaluronan binding complex as an HA-specific probe. The normal pseudo-stratified columnar bronchial epithelium was either negative for HA or displayed a weak staining around the basal cells. The epithelia of serous and mucous bronchial glands were HA negative whereas the submucosal connective tissue was strongly positive. In metaplastic, dysplastic and carcinoma in situ lesions the whole epithelium from basal to uppermost cells expressed HA on plasma membranes. Epithelial HA was also found in squamous cell carcinomas, but not in adenocarcinomas, carcinoid tumors or small cell carcinomas of the lung. Whereas epithelial HA was present in all lesions of the squamous cell type, the staining intensity displayed great local variability in 50% of the cases with severe dysplasia, carcinoma in situ and squamous cell carcinomas. In squamous cell carcinomas, such an irregular staining pattern was significantly associated with poor differentiation. Our results indicate that the expression of HA in different bronchial lesions and lung tumors is restricted to those showing squamous cell differentiation, being absent from other types of lung carcinomas. The increase of HA-depleted areas in poorly differentiated squamous cell carcinomas emphasizes the important role of HA in tumor differentiation. HA on carcinoma cell surface may influence tumor growth and metastatic behavior. Int. J. Cancer (Pred. Oncol.) 79:251–255, 1998.© 1998 Wiley-Liss, Inc.     

What is known about tumour proliferation rates to choose between accelerated fractionation or hyperfractionation?

Repopulation of surviving clonogenic tumour cells during fractionated radiotherapy is one of the crucial factors determining cure probability in radiotherapy. Clinical and experimental data suggest that repopulation rates vary considerably between different tumours but may be similar to the cell production rates in the untreated tumour. For those tumours which repopulate fast, such as squamous cell carcinomas, bladder cancer and colorectal carcinomas, accelerated fractionation may be indicated.     

Low incidence of ras oncogene activation in human squamous cell carcinomas

Activation of the ras gene family by point mutation at codons 12, 13 and 61 has been demonstrated in up to 20% of unselected series of human tumours. The present study was carried out to assess the incidence of ras activation in 37 squamous cell carcinomas of the head and neck, seven squamous cell carcinomas of the skin and eight squamous carcinoma cell lines. Oligonucleotide probes and the polymerase chain reaction were used on DNA extracted from achival paraffin embedded material. Mutations in codon 12 of the Harvey ras gene was found in a carcinoma of the larynx and a carcinoma of the lip, both of which had received prior irradiation. A cell line (LICR-LON-HN8) established from the same laryngeal cancer showed the same mutation. This study indicates that there is a low incidence of ras mutation in human squamous cell carcinomas and that activation of this family of genes is probably not a common factor in the development of this group of tumours.     

Dehydroretronecine-induced skin tumors in mice.

Female Swiss mice susceptible to skin tumors received 6 sc injections and/or topical applications of dehydroretronecine, a metabolite of the pyrrolizidine alkaloid monocrotaline, and were observed for 15 months for tumor development. Of 92 animals examined, 63 had tumors at the site of application or injection; 47 of these had skin tumors, mainly basal cell and squamous cell carcinomas. These data indicate that dehydroretronecine is a proximate carcinogen capable of causing a high incidence of skin tumours in mice at the site of sc injection or topical application.     

Differential patterns of stromelysin-2 (MMP-10) and MT1-MMP (MMP-14) expression in epithelial skin cancers

Co-expression of several members of the matrix metalloproteinase (MMP) family is characteristic of human malignant tumours. To investigate the role of stromelysin-2 (MMP-10) in growth and invasion of skin tumours, we studied cutaneous carcinomas with high metastatic capacity (squamous cell carcinomas, SCCs), only locally destructive tumours (basal cell carcinomas, BCCs) and pre-malignant lesions (Bowen's disease and actinic keratosis) using in situ hybridization. Expression of MMP-10 was compared with that of stromelysin-1 (MMP-3) and of MT1-MMP, the expression of which has been shown to correlate with tumour invasiveness. MMP-10 was expressed in 13/21 SSCs and 11/19 BCCs only in epithelial laminin-5 positive cancer cells, while premalignant lesions were entirely negative. MT1-MMP mRNA was detected in 19/21 SCCs both in epithelial cancer cells and stromal fibroblasts and in 14/18 BCCs only in fibroblasts. The level of MMP-10 was upregulated in a cutaneous SCC cell line (UT-SCC-7) by transforming growth factor-alpha and keratinocyte growth factor, and by interferon-gamma in combination with transforming growth factor-beta1 and tumour necrosis factor-alpha both in UT-SCC-7 and HaCaT cells. Our results show that MMP-10 expression does not correlate with the invasive behaviour of tumours as assessed by their histology and MT1-MMP expression, but may be induced by the wound healing and inflammatory matrix remodelling events associated with skin tumours.     

Argyrophilic nucleolar organizer regions (AgNOR) in tumours of pharynx and larynx

Benign and Malignant squamous cell tumours from pharynx and larynx have been studied by silver colloidal staining technique for quantitative analysis of argyrophilic nucleolar organizer regions (AgNOR) per nucleus and to assess its significance in differentiating the benign from malignant tumours. A total of 23 neoplasms including 8 squamous papillomas from larynx, 5 squamous cell cracinomas from larynx and 10 squamous carcinomas from pharynx have been studied. AgNOR count from benign papillomas showed a mean count of 2.56 whereas that in squamous cell carcinoma of Pharynx and larynx was 12.61 and 11.43 respectively. This simple staining method can be used to differentiate benign from malignant tumours in pharynx and larynx.