Rooshdiya Z. Karim

The role of cell cycle regulatory proteins in the pathogenesis of melanoma

&NA; The transformation of melanocytes to melanoma cells is characterised by abnormal proliferation resulting from alterations in cell cycle regulatory mechanisms. This occurs through alterations in the two major cell cycle regulatory pathways, the retinoblastoma (Rb) and p53 tumour suppressor pathways. This review summarises the current knowledge of alterations in these two pathways at G1/S transition and specifically the role of the key cell cycle regulatory proteins pRb, p16INK4a (p16), cyclin D1, p27Kip1 (p27), p53 and p21Waf1/Cip1 (p21) in the pathogenesis of melanoma. It also considers their prognostic significance. Current data indicate that alterations of cyclin kinase inhibitor (cdki) levels are implicated in the pathogenesis of melanoma and may be useful prognostic markers. However, large validation studies linked to comprehensive clinical follow up data are necessary to clarify the prognostic significance of cell cycle regulatory proteins in individual patients.

False Negative Sentinel Lymph Node Biopsies in Melanoma May Result From Deficiencies in Nuclear Medicine, Surgery, or Pathology.

Objective:To investigate a cohort of melanoma patients with false negative (FN) sentinel node (SN) biopsies (SNBs) to identify the reasons for the FN result. Summary of Background Data:SNB is a highly efficient staging method in melanoma patients. However, with long-term follow-up FN SNB results of up to 25% have been reported. Methods:Seventy-four SNs from 33 patients found to have had an FN SNB were analyzed by reviewing the lymphoscintigraphy, surgical data, and histopathology, and by assessing nodal tissue using multimarker real-time quantitative reverse transcription (qRT) polymerase chain reaction, and antimony concentration measurements (as a marker of “true” SN status) using inductively coupled plasma mass spectroscopy. Results:Nine SNs (12%) from 9 patients (27%) had evidence of melanoma on histopathologic review. Twelve SNs (16%) from 10 patients (30%) were qRT(+). Four of these 12 SNs were positive on histopathology review and 8 were negative. Four patients (12%) were upstaged by qRT. Sixteen patients had their SNB histology, lymphoscintigraphy, and surgical data reviewed. Identifiable causes of the FN SNBs were not found after review of all modalities in 4 patients. SNs from all 4 patients had antimony levels indicative of an SN. Of the SNs evaluable by qRT, 1 was qRT(+) and 7 SNs from 2 patients were qRT(−). Conclusions:An FN SN can occur because of deficiencies in nuclear medicine, surgery, or pathology. qRT can detect “occult” metastatic melanoma in SNs that have been identified as negative by histopathology.

The advantage of using a synoptic pathology report format for cutaneous melanoma

Aims:  Although the synoptic format is being increasingly used for primary cutaneous melanoma pathology reporting, no study assessing its value has yet been reported in the literature. The aim was to determine whether the use of synoptic reports increases the frequency with which pathological features that may influence prognosis and guide management are documented.

Increased c-kit (CD117) expression in malignant mammary phyllodes tumors

Mammary phyllodes tumors are uncommon stromal neoplasms, and are divided into benign, borderline and malignant groups basing on histologic criteria. While benign phyllodes tumors may recur, borderline phyllodes tumors show higher propensity to recur locally and rarely metastasize, and malignant phyllodes tumors show even higher chances of local recurrences or distant metastases. c-kit is a proto-oncogene that encodes a tyrosine kinase receptor (CD117) and is a marker for gastrointestinal stromal tumors (GIST). With the advent of therapeutic agent targeted at this receptor for GIST, we investigated 179 phyllodes tumors (101 benign, 50 borderline, 28 malignant) for c-kit expression using immunohistochemistry. The staining was compared to the degree of malignancy, and to the degree of stromal cellularity, mitotic activity, nuclear pleomorphism and stromal overgrowth. The overall positive rate for c-kit was 29% (52/179) and 17% (17/101), 24% (12/50) and 46% (13/28), respectively, for benign, borderline malignant and frank malignant phyllodes and the differences between all categories were significant (χ2=13.844, P=0.001). In mammary phyllodes tumors, there was increasing c-kit expression with increasing degree of malignancy, up to 46% in malignant cases. This provides strong evidence that c-kit receptor mediated tyrosine kinase involvement in the pathogenesis of phyllodes tumors, and the therapeutic agent, STI571, Glivec, may be a potentially useful drug for its management.

Stromal CD10 expression in mammary fibroadenomas and phyllodes tumours

Background/Aims: CD10 (CALLA) has recently been reported to be expressed in spindle cell neoplasia, and has been used to differentiate endometrial stromal sarcoma from leiomyoma and leiomyosarcoma. In the breast, myoepithelial cells express CD10, but there are few studies of the expression of CD10 in mammary fibroepithelial lesions. Methods: Stromal CD10 expression was studied in 181 mammary phyllodes tumours (102 benign, 51 borderline malignant, and 28 frankly malignant) and 33 fibroadenomas using immunohistochemistry, to evaluate whether differences in expression correlated with the degree of malignancy. Results: There was a progressive increase in the patients’ age and tumour size, from fibroadenoma to phyllodes tumours with an increasing degree of malignancy (p < 0.001). Stromal CD10 expression was positive in one of 33 fibroadenomas, six of 102 benign phyllodes tumours, 16 of 51 borderline malignant phyllodes tumours, and 14 of 28 frankly malignant phyllodes tumours. The difference was significant (p < 0.001) and an increasing trend was established. Strong staining was seen in subepithelial areas with higher stromal cellularity and activity. Stromal CD10 expression had a high specificity (95%) for differentiating between benign lesions (fibroadenomas and benign phyllodes tumours) and malignant (borderline and frankly malignant) phyllodes tumours. Conclusions: CD10 may be a useful adjunct in assessing malignancy in mammary fibroepithelial lesions.

Interobserver reproducibility of histologic parameters of melanoma deposits in sentinel lymph nodes: implications for management of patients with melanoma.

Histologic parameters of melanoma deposits in sentinel lymph nodes (SLNs) have been shown to be predictive of clinical outcome and the presence or absence of tumor in non‐SLNs, but assessment of these parameters is prone to interobserver variation.

Phyllodes tumours of the breast : a clinicopathological analysis of 65 cases from a single institution

The aim of this study was to document the clinical and pathological features of a large single institutional series of ethnically diverse patients with phyllodes tumours (PTs), and to determine which characteristics were predictive of outcome. Sixty five PTs were analysed; 34 were benign, 23 borderline and eight malignant (34 low grade and 31 high grade PTs on a two tiered grading system). Nine patients (15%) had local recurrences. A greater percentage of higher grade tumours recurred and women of Asian origin had a higher recurrence rate compared to the non-Asian patients. The 5 year disease-free survival was 81% and time to recurrence was significantly lower in the high grade group. No metastases or deaths from disease were recorded. The mean age at diagnosis significantly increased with tumour grade. The mean tumour volume also significantly increased with grade. Tumour grade was the only parameter related significantly to outcome.

Surgical biopsy with intra-operative frozen section: AN ACCURATE AND COST-EFFECTIVE METHOD FOR DIAGNOSIS OF MUSCULOSKELETAL SARCOMAS

The most appropriate protocol for the biopsy of musculoskeletal tumours is controversial, with some authors advocating CT-guided core biopsy. At our hospital the initial biopsies of most musculoskeletal tumours has been by operative core biopsy with evaluation by frozen section which determines whether diagnostic tissue has been obtained and, if possible, gives the definitive diagnosis. In order to determine the accuracy and cost-effectiveness of this protocol we have undertaken a retrospective audit of biopsies of musculoskeletal tumours performed over a period of two years. A total of 104 patients had biopsies according to this regime. All gave the diagnosis apart from one minor error which did not alter the management of the patient. There was no requirement for re-biopsy. This protocol was more labour-intensive and 38% more costly than CT-guided core biopsy (AU

Increased epidermal growth factor receptor (EGFR) expression in malignant mammary phyllodes tumors.

1804 vs AU

Reduced p16 and Increased Cyclin D1 and pRb Expression Are Correlated With Progression in Cutaneous Melanocytic Tumors

1308). However, the accuracy and avoidance of the anxiety associated with repeat biopsy outweighed these disadvantages.