Biomedical subjects
Publications and source records attributed to M G Cook.
A case of polymorphous low-grade adenocarcinoma arising within the parotid gland is described. This appears to be only the second case of this distinctive neoplasm to have arisen ab initio within a major salivary gland. It displayed the relatively indolent course associated with this adenocarcinoma subtype and emphasises that this diagnosis now has to be considered in tumours of major salivary glands.
CD44 is the major human cell surface receptor for hyaluronate and functions in a diverse range of physiological processes. Alternative splicing of a single gene generates a family of splice variants (CD44vl-10) in addition to the standard isoform, CD44H. Expression of CD44, particularly CD44v6, has been described to correlate with metastasis formation in various tumours, although evidence in malignant melanoma is inconclusive. In this study, we explored the immunohistochemical pattern of CD44 expression in a range of melanocytic lesions using a panel of monoclonal antibodies raised to CD44H and the variants v3, v4/5, v6 and v8/9. Skin biopsies of 106 lesions from 100 patients were assessed and included benign and dysplastic naevi, melanoma in situ, malignant melanomas in horizontal and vertical growth phase, and cutaneous and lymph node metastases. CD44H was highly expressed in benign and dysplastic naevi and in melanoma in situ. However, expression with melanomas diminished with increasing invasiveness, and the pattern of expression observed correlated significantly with the growth phase of the lesion rather than its Breslow thickness. CD44 splice variants were not detected in any lesions. These results suggest a possible role for downregulation of CD44H in modulating the biological behaviour of malignant melanoma.
Sections from 95 skin lesions excised at pigmented lesion clinics in England and Scotland were studied by eight histopathologists in order to evaluate consistency in the use of histopathological terms for features of diagnostic and prognostic importance for cutaneous malignant melanoma. The level of agreement (kappa) amongst the panel improved after discussion and re-definement of criteria for several features. These included, architectural and nuclear atypia, pagetoid infiltration and radial and vertical growth phases. A high level of agreement was achieved for an overall benign or malignant diagnosis (kappa = 0.77) but use of more specific terms such as benign naevi with atypia and melanoma < or = 0.76 mm thickness, was associated with only an intermediate level of agreement. Of the original diagnosis of melanoma, 17% were re-classified by the panel as benign with atypia and 2% reported to be benign were judged to be melanoma. This reflected the high proportion of borderline lesions in the study. The use of standardized diagnostic criteria with precise definitions has been shown to improve consistency in diagnosis and it is recommended for general application. From this should emanate more reliable incidence figures for thin melanoma, and improved understanding of the nature of these early lesions, to the benefit of patient and clinician alike. The poor concordance in distinguishing severe dysplasia in the junctional component of melanocyte proliferations from melanoma in situ and superficial dermal invasion improved only modestly despite intensive efforts. Since melanoma in situ and severe dysplasia cannot be distinguished by objective measurements and since their clinical management is the same, the panel suggests that attempts to separate them in diagnostic reports should be discontinued and they could both be referred to as melanocytic intraepidermal neoplasia (MIN). If it becomes accepted that dermal invasion without a vertical growth component can also be managed identically to MIN, then this invasive radial phase may be appropriately referred to as microinvasion and linked to MIN for the purposes of clinical management.
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Fifty eight large bowel adenocarcinomas and 20 adenomas were studied immunohistochemically, using fresh frozen tissue sections, with regard to lymphocyte subpopulations (CD3, CD4, CD8, CD19, and CD20) in the inflammatory infiltrate and to expression of human leucocyte antigens (HLA-ABC, HLA-A2, and HLA-DR). The findings were related to differentiation and Duke's stage of carcinoma. The inflammatory infiltrate was found to have a phenotype that remained constant irrespective of the intensity of the inflammation. CD4 and CD3 positive cells predominated with fewer CD8 positive cells and a scanty diffuse CD19/20 positive cell population. CD19/20 follicular aggregates were common at the advancing margin of the carcinomas. There was no significant association with Duke's stage, differentiation or HLA status. HLA changes (ABC loss, A2 loss, and DR gain) were associated with differentiation, being more common and more extensive in poorly differentiated carcinomas. HLA-A2 loss was also associated with stage of progression of carcinoma. Inflammation associated with adenomas was found to have a similar phenotype to that associated with carcinomas. HLA changes in adenomas were uncommon, being seen in only one of our 20 cases.
Tumoral calcinosis is an uncommon ectopic calcification syndrome characterized clinically by the presence of irregular, painless, periarticular soft tissue calcifying masses, and pathologically by fibrous-walled cystic spaces containing structureless calcific debris and associated with a variable inflammatory reaction. The pathogenesis remains obscure but the condition probably represents a disordered tissue reparative process. Of the previous literature reports, almost all have been in patients of African origin. We report a case in a white English woman.
Lobular carcinomas have a distinct natural history with a better response to endocrine therapy and a higher incidence of local recurrence and are more often bilateral. The cytological diagnosis of lobular carcinoma permits a discriminating therapeutic approach with pre-operative Tamoxifen, more generous resection margins, and assessment of the contralateral breast. The cytological features of lobular cancer however are not well defined and the low cell yield from such neoplasms can result in a high false negative rate. To determine whether we could improve the pre-operative diagnosis, we reviewed the cytological features of 112 lobular carcinomas. They had small uniform sized nuclei with irregular outlines and inconspicuous nucleoli. The degree of dissociation was similar to duct carcinomas and the incidence of inadequate aspirates was no higher. We found no features that confidently diagnosed lobular cancer or its sub-types. However, using a combination of features, typing of lobular cancer on aspirated material is possible and should be attempted.
Extragenital Bowen's disease (EBD) has rarely been studied for the presence of human papillomaviruses (HPVs). Twenty consecutive patients with EBD were investigated for the presence of HPVs using in situ hybridization with a generic probe that can detect HPV DNA types 6, 11, 16, 18, 30, 31, 33, 35, 45, 51, and 52 and specific probes for HPV DNA types 6/11, 16/18, and 31/33/35. All cases were tested with the polymerase chain reaction (PCR) technique employing the L1 consensus primer pair, MY11 (primer for the positive strand) and MY9 (primer for the negative strand) complementary to genital and dermal HPV types. Seven caucasian patients, five males and two females, with an average age of 70.4 years, showed positive in situ hybridization (ISH) for HPV DNA. The positivity varied from 5 to 40% of neoplastic cells. Three of seven of the ISH DNA-positive cases showed a positive PCR for DNA HPVs. The role of HPVs in human tumors is not fully understood since oncogenic types of HPVs have been found in normal tissue and the actions of cofactors have been postulated. Bowen's disease usually occurs in elderly people in whom the efficiency of the immune systems may be compromised. The association between HPV infection and low efficiency of the immune response may be responsible for HPV-related Bowen's disease in elderly people.
AIMS: To investigate the changes in and relations among p53, CD44 and MIB-1 expression in adenocarcinomas of the colorectum and to determine whether these changes are progressive across the adenoma-carcinoma sequence. METHODS: Expression of p53 protein, CD44 adhesion molecule and MIB-1 proliferation antigen was detected using immunohistochemistry in 68 colorectal carcinomas and 32 colorectal adenoma. The staining characteristics were compared with degree of dysplasia in adenomas, and differentiation and Dukes' stage in carcinomas. Results were analysed and assessed using Spearman's rank correlation and independent t tests. RESULTS: p53 staining was present in som adenomas and correlated with the degree of dysplasia. There was significantly more staining in carcinomas than adenomas and significant correlation between staining and Dukes' stage. CD44 staining was maximal in adenomas, diminished in carcinomas and was minimal in metastasising carcinomas. There was inverse correlation between p53 and CD44 expression across the adenoma-carcinoma-metastasising carcinoma sequence. MIB-1 expression was highest in carcinomas but did not correlate with either p53 or CD44 expression. CONCLUSIONS: There are progressive changes in p53, CD44 and MIB-1 expression in adenomas and carcinomas. A combination of these tests may prove useful in assessing which patients with adenomas are at greatest risk of progressing to carcinoma.
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Cultured adult rabbit cardiac myocytes treated with recombinant growth factors display enhanced rates of protein accumulation (ie, growth) in response to insulin and insulin-like growth factors (IGFs), but epidermal growth factor, acidic or basic fibroblast growth factor, and platelet-derived growth factor failed to increase contractile protein synthesis or growth of the heart cells. Insulin and IGF-1 increased growth rates by stimulating anabolic while simultaneously inhibiting catabolic pathways, whereas IGF-2 elevated growth modestly by apparently inhibiting lysosomal proteolysis. Neutralizing antibodies directed against either IGF-1 or IGF-2 or IGF binding protein 3 blocked protein accumulation. A monoclonal antibody directed against the IGF-1 receptor also inhibited changes in protein turnover provoked by recombinant human IGF-1 but not IGF-2. Of the other growth factors tested, only transforming growth factor-beta 1 increased the fractional rate of myosin heavy chain (MHC) synthesis, with beta-MHC synthesis being elevated and alpha-MHC synthesis being suppressed. However, the other growth factors were able to modestly stimulate the rate of DNA synthesis in this preparation. Bromodeoxyuridine labeling revealed that these growth factors increased DNA synthesis in myocytes and nonmyocytes alike, but the heart cells displayed neither karyokinesis or cytokinesis. In contrast, cocultures of cardiac myocytes and nonmyocytes and nonmyocyte-conditioned culture medium failed to enhance the rate of cardiac MHC synthesis or its accumulation, implying that quiescent heart cells do not respond to "conditioning" by cardiac nonmyocytes. These findings demonstrated that insulin and the IGFs promote passively loaded cultured adult rabbit heart cells to hypertrophy but suggest that other growth factors tested may be limited in this regard.
Because neoadjuvant therapy, including preoperative chemotherapy and tamoxifen, is becoming increasingly common for early breast cancer, it is desirable to grade tumours before surgery so that the most appropriate medical regimen can be selected. We have used a cytological grading system for ductal carcinoma of type not otherwise specified (NOS). Wet-fixed Papanicolaou-stained breast aspirates are examined for the extent of cell dissociation, cell size and uniformity, and the appearance of nucleoli, the nuclear margin, and chromatin. 377 invasive breast carcinomas were removed after preoperative diagnostic fine-needle aspiration cytology (FNAC) during the 25 months of the study. 286 tumours were ductal carcinomas NOS on histology. We established three cytological grades and found that cytological grade corresponded well with the established histological grades (Elston's modified Bloom and Richardson method). All cytological features included in the score were equally important on regression analysis. This study shows that grading of breast cancer on FNAC is feasible and reproducible. Cytological grade may substitute for histological grade, so a combination of FNAC and mammography can provide information on tumour type, grade, and size before surgery. We recommend this grading system to centres that use FNAC for the diagnosis of breast cancers.
This preliminary report describes the use of interstitial laser photocoagulation to manage small breast cancers. Forty-four patients were treated with a diode laser of 805 nm under local anaesthesia in the interval between diagnosis and surgery. Ultrasonography was used in 42 patients and computed tomography (CT) in two to place the fibre in the tumour and monitor laser effects. Laser-induced necrosis within the resected tumour varied from 0 to 25 mm in diameter. The presence of charring in the tumour around the fibre tip after treatment was associated with significantly larger diameters of necrosis than when charring did not occur (median 13 versus 6 mm, P = 0.002). Precharring the fibre resulted in a more predictable diameter of necrosis (median 14 mm). Ultrasonography was inaccurate in assessing laser damage; dynamic CT and magnetic resonance imaging may be of more use. Interstitial laser photocoagulation is simple and safe, and can produce necrosis of a reasonably predictable extent.
Two techniques for the histological handling of breast specimens, namely conventional sampling using small blocks (SB) and a large block (LB) macrosectioning technique have been compared, with special emphasis on tumour size and in situ carcinoma, in an attempt to objectively demonstrate the advantages of the latter method. This is considered to be of particular importance in guiding the clinicians in their use of the many treatment modalities available for breast carcinoma. All cases were from the routine surgical caseload; 100 examined by the LB technique and 111 using conventional SB. The LB technique gave a reliable measurement of invasive carcinoma in 100% of cases compared to only 63% of SB cases. Ductal carcinoma in situ (DCIS), was found more frequently (80% versus 64%) and its extent was more easily and reliably measured in the large blocks. The extent of DCIS was significantly greater in all cases using large block techniques. Concurrent carcinomas were found more frequently in the LB series and these tumours were smaller than those in the SB series. Similar differences were noted with radial scars, and other proliferative lesions also had a higher incidence in the LB series. We conclude that the LB technique has sufficient advantages to recommend it as a standard technique in breast pathology.
A 66-year-old woman had a long-standing, scaly erythematous lesion on her left temple which histologically showed features of amelanotic lentigo maligna. It had recurred on numerous occasions over a period of 17 years, in spite of multiple attempts at curative surgery. There were also recurrences within a skin graft which, to our knowledge, has not been documented previously with lentigo maligna. In spite of the prolonged course, and extensive intraepidermal melanocytic proliferation amounting to melanoma in situ, there has been no evidence of dermal invasion. The lack of pigmentation in such lesions means that clinical definition of margins is highly inaccurate. In view of the aggressive horizontal growth phase of this lesion, with rapid recurrence following surgery, it was treated with electron beam therapy, and this has resulted in complete clinical remission. This most unusual case illustrates the potential difficulties in diagnosis and management of amelanotic lentigo maligna.
Pigmented lesions of palmar and plantar skin may cause diagnostic problems, partly because they are infrequently excised and also because some features of benign lesions in these sites may raise the suspicion of melanoma if considered alone. We have examined a series of benign melanocytic lesions and compared them with melanomas from these sites. The presence of severe melanocytic atypia was the most valuable feature in distinguishing between naevi and melanomas. Pagetoid infiltration of the epidermis by single atypical cells, or small groups of cells with abundant pale cytoplasm was seen only in melanomas, while transepidermal elimination of well-circumscribed nests was present only in benign lesions. A lymphocytic infiltrate was present in the dermis in 13 of 14 malignant lesions, but only two of the 26 naevi showed a sparse infiltrate: we suggest that the presence of a lymphocytic infiltrate should prompt a careful search for other features of malignancy. Other features examined, including elongation of rete ridges, pattern of melanocyte distribution at the dermo-epidermal junction, dermal sclerosis, and pigment in the stratum corneum or in the dermis, were seen in both naevi and melanomas and were not found to be useful in distinguishing benign from malignant lesions.
Several papers have recently assessed whether immunohistochemistry increases the accuracy of staging in node negative colorectal carcinomas, by showing micrometastases. The results have been contradictory. In this paper 542 nodes which were negative for tumour on routine sectioning, were stained with CAM 5.2. In addition, the tissue was levelled three times, this technique being more economical, to see if either or both techniques increased the pick up of micrometastases. Six nodes showed positive staining of occasional cells in the subcapsular and paracortical sinuses, but these were cytologically benign on review and were not thought to represent metastatic tumour. Triple levelling did not show any additional micrometastases.
Local excision of early rectal tumours is an attractive proposition, avoiding the morbidity and mortality of major resection and possible permanent stoma. This study was designed to investigate the incidence of lymph node metastases associated with tumours that are locally confined to the bowel wall. A total of 454 rectal excision specimens were reviewed. Twenty-two (20 per cent) of 109 patients with tumours locally confined to the bowel wall had metastases in local lymph nodes, although 14 of these had only one or two involved nodes. Three of 27 patients with tumours that did not penetrate through the submucosa had lymph node metastases. Less well differentiated tumours were more likely to have metastasized but there was no significant difference in the height or size of tumours or in the depth of invasion between patients with or without lymph node metastases.