Evaluation of two histological classifications for actinic keratoses - PRO classification scored highest inter-rater reliability.

BACKGROUND: Actinic keratoses (AKs) can histologically be classified by the extent of atypical keratinocytes throughout the epidermis or their pattern of basal proliferation. Currently, no data on the inter-rater reliability of both scores is available. OBJECTIVE: To evaluate the inter-rater reliability of the two classification schemes; histological grade (AK I-III) and basal proliferation (PRO I-III). METHODS: Histological images of 54 AKs were classified by 21 independent dermatopathologists with regard to basal proliferation (PRO I-III), histological grade (AK I-III) and assumed risk of progression into invasive carcinoma. RESULTS: Overall, of the 54 AKs 16.7% (9/54) were classified as AK I, 66.7% (36/54) as AK II, and 16.7% (9/54) as AK III. With regards to basal growth pattern, 25.9% (14/54) were classified as PRO I, 42.6% (23/54) as PRO II, and 31.5% (17/54) as PRO III. We observed a highly significant inter-rater reliability for PRO-grading (P < 0.001) which was higher than for AK-grading (Kendall's W coefficient: AK = 0.488 vs. PRO = 0.793). We found substantial agreement for assumed progression risk for AKs with worsening basal proliferation (k = 0.759) compared to moderate agreement (k = 0.563) for different AK-gradings. CONCLUSIONS: Histological classification of basal growth pattern (PRO) showed higher inter-rater reliability compared to the established classification of atypical keratinocytes throughout epidermal layers. Moreover, experienced dermatopathologists considered basal proliferation to be more important in terms of progression risk than upwards directed growth patterns. It should be considered to classify AKs according to their basal proliferation pattern (PRO I-III).

Somatic mutations in kinetochore gene KNSTRN are associated with basal proliferating actinic keratoses and cutaneous squamous cell carcinoma.

BACKGROUND: Mutations in kinetochore gene KNSTRN accelerate the development of cutaneous squamous cell carcinoma (SCC) and may correlate with different histological classifications of actinic keratosis (AKs). OBJECTIVE: To determine KNSTRN gene mutation frequency in healthy skin (HS), actinically damaged skin (ADS), in AKs with different histomorphological gradings and invasive SCCs. METHODS: All samples were histologically evaluated. AK lesions were additionally classified according to their upwards (AK I-III) and downwards (PRO I-III) directed growth pattern. Mutation analyses of all samples were performed using the Sanger method. RESULTS: With one exception, all detected mutations in KNSTRN gene showed an alanine-to-glutamate substitution at codon 40 (p.Ala40Glu). p.Ala40Glu mutation was found in 6.9% (2/29) of HS, in 16.1% (5/31) of ADS, in 18.3% (20/109) of AKs and in 30.0% (9/30) of invasive SCCs. Further stratification of AKs using the common AK classification of Röwert-Huber revealed the p.Ala40Glu mutation in 14.7% (5/43), 13.3% (4/30) and 24.4% (11/45) (AK I, II and III). In contrast, the new PRO classification showed a distribution of 3.6% (1/28) in PRO I, 21.7% (13/60) in PRO II and 28.6% (6/21) in PRO III. Mutation frequency in HS showed significant differences compared to AKs classified as PRO III and invasive SCCs (P < 0.05). In contrast, there were no statistically significant differences between HS and AKs when classified according to Röwert-Huber. CONCLUSIONS: Recurrent somatic mutation p.Ala40Glu in KNSTRN gene is associated with basal proliferating AKs in accordance with invasive SCCs. This supports the impact of basal proliferative pattern in terms of progression.

Actinic keratosis: correlation between clinical and histological classification systems.

BACKGROUND: There are several clinical and histological classification systems for grading actinic keratosis (AK) lesions. The Olsen clinical classification scheme grades AK lesions according to their thickness and degree of hyperkeratosis (grades 1-3). The Roewert-Huber histological classification system grades AK lesions based on the extent of epidermal atypical keratinocytes (AK I-III). OBJECTIVE: The aim of this study was to determine whether there is a correlation between these clinical and histological AK classification schemes. METHODS: One AK lesion from patients in three pivotal clinical studies and routine practice was assessed clinically and histologically. A match in grading was defined as Olsen grade 1 being classified histologically as AK I, Olsen grade 2 as AK II and Olsen grade 3 as AK III. RESULTS: Of the 892 lesions included, 29.0% were classified as Olsen grade 1, 59.6% as Olsen grade 2 and 11.3% as Olsen grade 3; 19.2% were histologically classified as AK I, 69.6% as AK II and 11.2% as AK III. Only 480 lesions (53.8%) had a matching clinical and histological classification. Of these matches, most were 'Olsen grade 2 = AK II' (83.1%). The Spearman's rank correlation coefficient for clinical and histological classification was r = 0.0499 (P = 0.137). CONCLUSIONS: Clinical classification of AK lesions using the system of Olsen does not accurately match histological classification of the same lesions using the system of Roewert-Huber. Consequently, it is not possible to draw conclusions about the histology of AK lesions from their clinical appearance. This finding reinforces the need to treat all AK lesions as well as field cancerization.

[Dysplastic melanocytic nevus]. / Dysplastischer melanozytärer Nävus.

Dysplastic nevus is still a controversial entity both clinically and histologically. The occurrence of dysplastic nevus especially in the context of dysplastic nevus cell syndrome is associated with an increased risk for melanoma. The following minimal histological criteria should be fulfilled: nests of melanocytes varying in size and shape, bridging and confluent, proliferation of single melanocytes basal and suprabasal, cytoplasmic and nuclear atypia of melanocytes and subepidermal fibroplasia. The biological behavior (common nevus variant or precursor of melanoma?) is difficult to evaluate by presently available methods. The further development of new molecular biology techniques may allow a better prognosis of dysplastic nevi in an objective and reproducible manner. Against this background complete excision followed by clinical surveillance has to be recommended for the routine practice.

[Actinic keratosis, Bowen's disease, keratoacanthoma and squamous cell carcinoma of the skin]. / Aktinische Keratose, Morbus Bowen, Keratoakanthom und Plattenepithelkarzinom der Haut.

Actinic (solar) keratosis is an intraepidermal squamous neoplasm of sun-damaged skin and by far the most frequent neoplastic skin lesion. A subdivison into three grades has been proposed with increasing acceptance not least because of the therapeutic consequences. The transition to invasive squamous cell carcinoma is reported in 5-10 % and with immunosuppression in 30 % of patients.Bowen's disease is a variant of squamous cell carcinoma in situ of the skin and the mucocutaneous junction. The differentiation from bowenoid papulosis as a lesion associated with human papillomavirus (HPV), actinic (solar) keratosis grade III, intraepidermal poroid lesions and in cases of clonal type from clonal seborrhoic keratosis and Paget's disease is very important.Keratoacanthoma is currently uniformly interpreted as a variant of highly differentiated squamous cell carcinoma of the skin with clinical and histomorphological characteristics. Clinically keratoacanthoma erupts rapidly and is capable of resolving spontaneously. Histologically, there is a characteristic growth pattern and various stages of regression. The final histomorphological diagnosis needs the entire specimen.Squamous cell carcinoma of the skin is the second most common type of skin cancer following basal cell carcinoma. With respect to reccurrencies and risk of metastases the subtyping of cutaneous squamous cell carcinoma is very important. The classification system of the Union Internationale Contra le Cancer (UICC) is based solely on the anatomical spread and the classification system of the American Joint Committee on Cancer (AJCC) also considers so-called high-risk features in the staging between stages I and II.

Optical coherence tomography imaging of erythroplasia of Queyrat and treatment with imiquimod 5% cream: a case report.

Lesion biopsy is currently used to diagnose erythroplasia of Queyrat (EQ), a rare squamous cell carcinoma in situ of the glans penis, or to determine whether the cancer is invasive, although the results only apply to the area from which the biopsy is taken. In this case report, we illustrate for the first time the use of optical coherence tomography (OCT) in imaging the entire lesion in a patient with EQ. The results confirmed that the patient had in situ rather than invasive carcinoma. Consequently, non-invasive treatment with imiquimod 5%, a topical immunomodulator with antitumour and antiviral properties, was initiated. Excellent clinical results were observed 4 weeks after the patient had been treated with imiquimod 5% three times a week for 8 weeks, which were confirmed using OCT imaging. One year later, there was still no evidence of pathology either clinically or via OCT imaging. OCT imaging should be used in conjunction with biopsy evaluation in the diagnostic work-up of EQ. Imiquimod 5% is a suitable treatment for patients with EQ, and the treatment response can be evaluated using OCT.

Topical 3.0% diclofenac in 2.5% hyaluronic acid gel induces regression of cancerous transformation in actinic keratoses.

BACKGROUND: Actinic keratoses (AKs) are frequently diagnosed in dermatological patients. As they represent in situ carcinomas, effective treatment is required. OBJECTIVES: We investigated the effect of topical 3.0% diclofenac in 2.5% hyaluronic acid gel on AK. METHODS: Sixty-five patients with AKs were clinically evaluated before and after 3 months' treatment with topical 3.0% diclofenac in 2.5% hyaluronic gel. Biopsy specimens were taken and stained with haematoxylin-eosin and immunohistological markers. Specimens were evaluated for histological type of AKs using the AK classification scheme suggested by Röwert-Huber et al. [(early) in situ squamous cell carcinoma type AK Grade I-III], number of mitoses per high-power field and expression of immunohistological markers. RESULTS: Complete clinical resolution was observed in 11 patients (16.9%). A significant (P<0.001) downgrading of AK grade was observed. Complete histological resolution was achieved in 15 patients (23.1%). The number of mitoses per high-power field was reduced significantly (P<0.001). The expression of anti-p53-antibody decreased significantly (P=0.009), as did the expression of anti-MiB-1 antibody (P=0.021). CONCLUSIONS: 3.0% diclofenac in 2.5% hyaluronic acid gel causes regression of signs of cancerous transformation after 3 months' therapy.

[Rare presentation of a scleral nevus with progression in size]. / Seltene Präsentation eines skleralen Nävus mit Größenprogredienz.

A 52-year-old male caucasian patient presented with a limbal subconjunctival pigmentation of unknown origin with progressive enlargement over the past years. Differential diagnoses included a malignant melanocytic lesion; therefore, an excisional biopsy was performed. Prior investigations showed no ciliary body or anterior chamber angle involvement. Histological and immunohistochemical analysis revealed the rare diagnosis of a scleral nevus. The clinical, histological and immunohistochemical findings as well as the relevant differential diagnoses are discussed.

[Nodular eyelid margin and lip tumors without MEN2b syndrome in a 29 year old man]. / Lidkanten- und Lippentumoren ohne MEN2b-Syndrom bei einem 29-jährigen Mann.

Neuromas of the eyelid margin and lower lip were diagnosed in a 29-year-old man. As the combination of these lesions is indicative of multiple endocrine neoplasia type 2b (MEN2b) syndrome, the presence of a medullary thyroid carcinoma or a pheochromocytoma were excluded by a systematic work-up. A mutation in the RET proto-oncogene was not found by genetic testing. In summary, the patient presented with neuromas on the eyelid margin and lower lip without an association to a syndrome; however, patients with such neuromas should be screened for MEN2b syndrome due to the high mortality.

Evidence for a novel tumor suppressor gene on chromosome 15 associated with progression to a metastatic stage in breast cancer.

Loss of heterozygosity (LOH) studies have emerged as a valuable indicator for tumor suppressor genes involved in the formation or progression of carcinomas. We here present data indicating that human chromosome 15 harbours a novel putative tumor suppressor gene which appears to play a role during later stages of carcinogenesis and which may be associated with metastasis in breast cancer. In this study, 153 primary and metastatic carcinomas from 101 patients have been analysed for LOH with 13 polymorphic microsatellite markers on chromosome 15. The tumors included carcinoma of the lung in 49 patients, breast carcinoma in 29, colorectal carcinoma in nine, renal carcinoma in five, pancreatic carcinoma in five, urinary bladder carcinoma in two and prostate carcinoma and ovarial carcinoma in one patient each. LOH15 was seen in 42/99 (42%) informative patients. In metastatic tumors, LOH15 was observed in 37/68 (54%). High incidences of allelic losses were detected in metastases from lung (56%), breast (70%) and colorectal (67%) carcinomas. In carcinomas of the breast, there was a significant difference (P<0.01) in LOH15 frequencies between non-metastatic tumors (11%) and brain metastases (70%). Such a difference was not observed on the chromosomal arm 17p which yielded high proportions of LOH in both non metastatic breast tumor (73%) and breast carcinoma metastases (90%). In 16 patients, interstitial deletions could be detected. The common region of overlap extended from D15S231 to D15S641, thus mapping this putative tumor suppressor gene to chromosome 15q14. Our data indicate that a gene on chromosome 15 contributes to the pathogenesis of metastatic carcinoma.

p53 immunoreactivity in biopsy specimens of T1G3 transitional cell carcinoma of the bladder--a helpful parameter in guiding the decision for or against cystectomy?

The aim of this study was to determine whether p53 is helpful in making the decision to undergo cystectomy in T1, G3 transitional cell carcinoma (TCC) of the bladder, by prospectively comparing the p53 status of bladder biopsies with the histology and p53 status of the corresponding cystectomy specimens. From January 1996 to August 1997, 38 consecutive patients with T1G3 TCC at 6 different centres were enrolled into the study. Bladder biopsies and cystectomy specimens were examined with three different antibodies against p53. The p53 status of each bladder biopsy was compared with p53 status, tumour stage and grade of the cystectomy specimen. An independent evaluation of the histology and immunohistochemistry was carried out by two pathologists. 15 of 38 patients (39%) were found to have a higher tumour stage in the cystectomy specimen compared with the staging by transurethral resection of the bladder tumour (TUR-B). 3 patients did not show residual tumour in the cystectomy specimen. No differences in p53 positivity were noted between the different antibodies. 14 of 31 evaluable tumours (45%) were p53 positive at the time of the TUR-B. p53 staining of the TUR-B specimen did not correctly predict the residual tumour in the cystectomy specimen. We, therefore, concluded that compared with standard histopathology, the p53 status of the TUR-B specimen does not provide additional relevant information with regard to local tumour staging and, thus, is not helpful in making the decision for or against a cystectomy.