The new 8th edition of TNM staging and its implications for skin cancer: a review by the British Association of Dermatologists and the Royal College of Pathologists, U.K.

The 8th edition of TNM (tumour, node and metastasis) has numerous and important changes compared with the 7th edition. Public Health England and the Royal College of Pathologists, U.K., have adopted the 8th edition of TNM (TNM8) published by the Union for International Cancer Control for skin cancer staging. These changes will have an impact on the management and commissioning of melanoma and nonmelanoma skin cancer (NMSC). The T1-T3 categories for NMSC staging require the clinician to measure the maximum dimension (usually diameter) of every potential invasive cancer. For squamous, basal and adnexal carcinomas, but not Merkel cell carcinoma (MCC), the T1-T3 categories are defined by new 20-mm and 40-mm divisions based on the maximum dimension of the lesion. In addition, new risk factors upstage T1 or T2 to T3. For melanoma, mitotic index no longer influences separation of pathological stage (pT1). There is a new, additional stratification level at 0·8-mm Breslow thickness. Subdivision pT1b, with a negative sentinel lymph node biopsy (SLNB) of pN0, is now stage IA compared with the previous IB. For MCC, SLNB is now included specifically in the pN staging system. The pT1 subdivision requires clinical information as to whether histologically involved nodes were clinically occult or detectable. For both melanoma and MCC the clinician must state whether the lymph nodes are occult or clinically detectable. Eyelid carcinoma continues to have a staging system different from that in general skin and the system is substantially revised in TNM8.

Cutaneous CD56 positive natural killer and cytotoxic T-cell lymphomas.

We report two cases of CD56 positive natural killer (NK) cell and cytotoxic T-cell cutaneous lymphomas and review the literature on these rare forms of non-Hodgkin's lymphoma. The first case was diagnosed to have extra nodal NK/T-cell lymphoma, nasal-type. She had a rapid downhill clinical course and died within 3 months of presentation. She had been started on systemic chemotherapy but did not respond. The second case was diagnosed as subcutaneous panniculitis-like T-cell lymphoma, CD56 positive variant. She presented with skin nodules that were quiescent for 10 years. Then the course of the disease suddenly changed and progressed rapidly. She had systemic chemotherapy and initially had a complete response, but she relapsed within 1 month of completion of chemotherapy. She then had partial response with further chemotherapy but relapsed rapidly. She died within 15 months of her lymphoma changing to its aggressive form. These cases illustrate the often poor prognosis of cutaneous CD56 positive lymphomas.

The synthesis of lipids from [1-14C]acetate by human venous endothelium in tissue culture.

Endothelial cells from human umbilical cords were harvested, using a trypsin technique, grown in tissue culture and lipid synthesis studied using [1-14C]acetate as a precursor. Radiosubstrate was incorporated into fatty acids, mono-, di- and triglycerides, cholesterol esters and phospholipids. Radioactivity was also present in the culture medium in the mono-and diglyceride fractions and in the phospholipids running with the solvent front.

The porcine endothelial cell in tissue culture.

Endothelial cells from porcine aorta and inferior vena cava have been harvested, using trypsin, EDTA or collagenase, and grown in tissue culture. Growth-behaviour, cytology, scanning and electronmicroscopy findings are reported. It is hoped that this technique will prove useful in the investigation of atherosclerosis.

Pancreatic transplantation in the rat. Long-term study following different methods of management of exocrine drainage.

A major problem in pancreas transplantation is the management of exocrine drainage. Isotransplantation has been performed in streptozotocin-induced diabetic rats using a microsurgical technique, and four methods of exocrine drainage have been compared over a nine-month period. The duct system was ligated, left open to drain into the peritoneal cavity, or obliterated with latex or with Ethibloc I occlusion gel. Biochemical follow-up included determinations of serum glucose concentration, intravenous and oral glucose tolerance tests (GTTs), and insulin assays. Histological studies were performed at 1 and 9 months posttransplant. All animals became normoglycemic after the operation. Although 25 out of 28 remained normoglycemic throughout the period of study, oral GTTs performed at six months indicated impaired endocrine function in some of the ligated, freely draining, and Ethibloc I-obliterated animals. Latex-obliterated grafts showed normal oral GTTs up to 9 months postoperatively. Intravenous GTTs showed impairment of endocrine function in all groups, but this was least evident in the latex-obliterated rats. These changes were supported by the peak serum insulin levels during the GTTs. Histologically, long-term ligated, freely draining, and Ethibloc I-obliterated pancreas grafts showed similar degrees of exocrine degeneration, fibrosis, and disruption of islets of Langerhans. In contrast, long term latex-obliterated pancreas grafts demonstrated minimal exocrine tissue and intact islets.

Cold storage of the pancreas with a view to preservation of islet cell function following transplantation.

Three solutions, hyperosmolar citrate, modified Collins' C2, and Sacks' II solutions were compared as media for cold storage preservation (arterial infusion and subsequent cold storage in the same medium at 0-4 C) of the rat pancreas with a view to preservation of endocrine function. Pancreatic isotransplantation was performed following cold ischemic intervals of 0, 24, 30, and 36 hr, into streptozotocin-induced diabetic recipients. Results were assessed by normoglycemic survival and insulin response, together with K values following i.v. glucose tolerance tests at 3 months postoperatively; 24-hr preservation was achieved with equal success using modified Collins' C2 solution or hyperosmolar citrate-but not with Sacks' II solution. Preservation for 30 hr was consistently successful using modified Collins C2 solution only, but the period could not be extended with success to 36 hr. Hypoglycemia and hyperinsulinemia occurred 24 hr postoperatively in the majority of animals receiving grafts stored in Sacks' II solution, but to a much lesser extent using modified Collins' C2 and hyperosmolar citrate. This was also temporarily seen in grafts stored for 36 hr in modified Collins C2 solution. At 3 months postoperatively after 30 hr cold ischemia, i.v. glucose tolerance tests showed the hyperosmolar citrate cold-stored grafts had lower K values and significantly reduced insulin responses compared with grafts stored in modified Collins' C2 solution. The modified Collins' C2 solution proved to be the most effective of the three solutions tested.

Cortical and vascular prostaglandin synthesis during renal allograft rejection in the rat.

Alterations in local prostacyclin and thromboxane synthesis could mediate the changes in vascular perfusion and platelet deposition in acutely rejecting renal allografts and prostaglandin E2 (PGE2) has been implicated in the regulation of the immune response. 6-Keto-prostaglandin F1 alpha (6 KetoPGF1 alpha), thromboxane B2 (TxB2) (the stable degradation products of prostacyclin and thromboxane A2 [TxA2], respectively) and PGE2 were measured in incubates of cortical slices taken from rat renal allografts or isografts one to seven days after transplantation. 6 KetoPGF1 alpha and TxB2 synthesis was also measured in incubates of blood vessels supplying and transplanted with the kidney in these animals. During the phase of cellular rejection (3-5 days), TxB2 synthesis was selectively elevated in allografted renal cortex, renal artery, renal vein, and abdominal aorta in comparison with isografted tissues. There was also a small but significant rise in cortical PGE2 synthesis at this time, but vascular and cortical 6 KetoPGF1 alpha production remained unchanged. Renal infarction, occurring 7 days after transplantation, was accompanied by a nonspecific rise in the synthesis of all three prostaglandins by renal cortical slices. Increased tissue TxA2 synthesis may contribute to local thrombosis and decreased graft perfusion during acute rejection, thereby potentiating graft destruction.

Platelet production in myocardial infarction and sudden cardiac death.

Megakaryocyte cytoplasmic volumes were studied in 13 subjects 18 +/- 2 days after admittance to the coronary care unit. Seven had suffered a myocardial infarction (MI group) while six had chest pain but no recent infarction. Megakaryocytes were also studied in 10 subjects suffering coronary sudden unexpected death (CSD group) and 11 subjects suffering sudden unexpected un-natural death. There was no significant difference between the megakaryocyte cytoplasmic volume distributions of the MI and CSD groups, although they had a significantly greater mean (p less than 0.01) and range (p less than 0.001) than their respective control groups. There was no significant difference in platelet volumes observed within 24 hr of the infarct and 18 +/- 2 days later. Mean platelet volume was significantly correlated (r = 0.89, p less than 0.006) to mean megakaryocyte cytoplasmic volume in the MI group. A computer simulation of platelet production showed no significant difference between platelet volumes observed in the MI group and those estimated to be circulating before death in the CSD group.

Neonatal islet cell transplantation in the diabetic rat: effect on hepatic enzyme activity and glucose homeostasis.

Intraperitoneal transplantation of collagenase-digested, isogeneic, neonatal rat pancreatic tissue successfully reversed streptozotocin-induced diabetes in 77% of recipients. The low serum immunoreactive insulin, hyperglycaemia, glycosuria and weight loss, characteristic of the diabetic animal, were corrected and the reduced activities of hepatic glucokinase and pyruvate kinase, and the low glycogen concentration of the liver of diabetic rats were restored to normal. Forty-three per cent of the successfully transplanted rats became normoglycaemic within 1 month of transplantation whereas 57% took from 1 to 6 months to achieve normoglycaemia and displayed a mild glucose intolerance when subjected to a glucose load. The rats which had not become normoglycaemic 6 months after transplantation showed some amelioration of the diabetic state, as shown by increased serum immunoreactive insulin and hepatic glycogen concentration and a slow weight gain compared with diabetic controls.

Pantoprazole-based 10-day triple therapy is effective in Helicobacter pylori eradication.

AIM: To investigate the efficacy of a short course of pantoprazole-based triple therapy in Helicobacter pylori eradication in a single-centre pilot study. METHODS: Patients with active or healed duodenal ulcer or with gastric erosions or gastritis, all of whom were H. pylori-positive, received 10 days of twice-daily open treatment with pantoprazole 40 mg, plus clarithromycin 250 mg and tinidazole 500 mg. H. pylori was assessed at entry and 28-35 days after the end of treatment by rapid urease test (at entry only), culture and antimicrobial sensitivity, histology and 13C urea breath test. The criterion for eradication was a negative result in all three tests. RESULTS: Seventy patients were treated, of whom four were excluded from analysis due to major deviations from the study protocol. Eradication of H. pylori was achieved in 57/66 patients (per protocol analysis 86% (95% CI: 78-95%)) and was higher in patients with organisms sensitive to nitroimidazole before treatment (sensitive: 47/53 (89%), insensitive: 10/13 (77%)). There was marked reduction in acute gastritis throughout the stomach while chronic gastritis decreased only in the corpus. Healing was achieved in all 24 patients with active duodenal ulcer. Treatment was complied with; only one patient missed one of the 20 doses. Adverse events were of mild or moderate intensity and did not require withdrawal from treatment. CONCLUSION: A short course of pantoprazole-based triple therapy is well tolerated and effective in eradicating H. pylori.

Multifactorial audit of invasive cervical cancer: key lessons for the National Screening Programme.

AIMS: To audit factors associated with the development of invasive cervical cancer. METHODS: Twenty cases of invasive cervical cancer in one health district for 1991-93 were audited by multifactorial analysis. RESULTS: The average age was 53 years with 20% (4/20) aged over 65 years. Of the patients, 45% (9/20) were identified by a cervical smear, with 40% (8/20) from the National Screening Programme (NSP) and 5% (1/20) opportunistically; 30% (6/20) had not received a smear, 10% (2/20) being aged under 65 and 20% 65 or over. Those with no smear had all been hospital patients during the previous five years. No response to a smear invitation occurred in 5%. In 20%, there had been a true negative smear two to five years previously. Inappropriate laboratory diagnosis or inappropriate clinical management occurred in 30% and 15% (3/20), respectively. In 20%, two or more factors were present in the same patient. CONCLUSIONS: Why cervical cancer occurs after a true negative smear requires research and women aged over 65 with no smear must be targeted. Failsafe systems should incorporate inadequate smears and smear adequacy should be given priority in quality assurance (QA) and training. False negative reports must be minimised but accepted as an inherent part of the NSP and not an automatic indicator of poor laboratory performance. Comprehensive national QA standards are required, to which providers must conform. Postcoital bleeding is an absolute indication for a smear and, when appropriate, opportunistic smears offered at all hospital attendance. Cervical cancer audit must be guaranteed access to all clinical and laboratory information and be seen as a means to improve the effectiveness and quality of the NSP.

Certifying the cause of death: an audit of wording inaccuracies.

AIMS: To audit wording and formulation inaccuracies in certifying the cause of death. METHODS: Five hundred causes of death were analysed from the counterfoils of medical death certificates (Form 66). Wording and formulation inaccuracies were defined as terms contrary to the notes given to doctors in books on death certificates. RESULTS: One or more inaccuracies were identified in 29% of cases. In 5.8% of cases, the inaccuracies were sufficiently serious to warrant further action or enquiry by the Registrar of Births and Deaths, including referral to Her Majesty's Coroner. CONCLUSIONS: Most inaccuracies could have been avoided by adhering to the notes for medical practitioners contained in books of death certificates. The wording and formulation of causes of death warrants special prominence in under-graduate and postgraduate medical education. The topic should be audited and medical practitioners should pay particular attention to cases worthy of referral to HM Coroner.

Do histopathology reports of primary cutaneous melanoma contain enough essential information?

AIMS: To audit the content of primary cutaneous malignant melanoma histopathology reports with special reference to Breslow thickness and lateral excision margins. METHODS: The Trent Regional Cancer Registry was asked to provide details of primary cutaneous malignant melanomas for the most recent year available (1990). Histopathology departments were then requested to provide copies of the relevant reports, which were then analysed. RESULTS: In total, 178 reports were obtained from 16 departments. Breslow thickness was present in 87.1% (155/178) and a comment had been made on lateral excision in 85.4% (152/178). A specific clearance measurement was recorded in 5.6% (10/178), and in 9.6% (17/178) tumour was stated to extend to the margin. In 4.5% (8/178) neither thickness nor a comment on excision was recorded. Clinical advice on excision was offered in 12.4% (22/178). A macroscopic description was absent in 6.7% (12/178). CONCLUSIONS: Deficiencies were identified in the quality of malignant melanoma histopathology reports in Trent Region. There is no reason to believe that significant improvements have occurred since 1990 or that other regions are performing differently. A national standard for reporting primary cutaneous malignant melanoma is recommended. As a minimum, all reports should include Breslow thickness and a specific measurement of lateral clearance. This will facilitate prognostic evaluation, clinical management and audit. This standard would not exclude the reporting of other information, depending on local policy. As with all standards, continual review must be undertaken and consideration given as to whether other more recent parameters, such as growth phase, also warrant future inclusion.

Audit of deaths from cervical cancer: proposal for an essential component of the National Screening Programme.

AIMS: To ascertain the type and relative frequency of major factors associated with deaths from cervical cancer. METHODS: Deaths from cervical cancer in Rotherham district for the period 1989-1991 were subjected to multifactorial audit by reviewing laboratory, hospital, and general practitioner records; together with, when appropriate, re-screening of cytology smears. This period represented the three to five years after a computerised National Screening Programme (NSP) had been implemented with a five year recall interval. RESULTS: Thirty six deaths were identified. The average age of death was 59 years with 39% occurring in those over 65. Only 6% of cases presented as a result of a cervical smear, comprising 3% derived from the NSP and 3% by chance. Forty seven per cent of cases in which the patient had died had no record of a previous smear invitation; 22% of patients were under 65 years and 25% 65 or over. Those under 65 had presented before the appropriate age band had been called. A non-response to a cervical smear invitation was identified in 22%. In 25% of cases a true negative smear had been reported one to eight years previously (average 4.8 years). An inappropriate laboratory diagnosis was identified in 17% of cases. Fourteen per cent represented false negative smears and 8% comprised inadequate smears that had been reported as negative. Inappropriate clinical diagnosis or management was identified in 19% of cases. In 22% two or more contributory factors were identified in the same patient. CONCLUSIONS: Areas highlighted by the audit warranting further attention included the targeting of women over 65 with no cytology record; those not responding to smear invitations; laboratory performance; clinical acumen; and the reasons for true negative cervical smears. Multifactorial audit of all deaths from cervical cancer should be advocated nationally to assess and improve the effectiveness of the NSP.