PATHOLOGY OF BREAST CANCERS IN LONG-TERM SURVIVORS

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actuarial survival of 78% at five years and 72% at ten years for mitral valve replacement with respective figures of 71% and 52% for aortic valve replacement.16,17 Results for tissue valves may seem better at five years, with survival of about 850/o for single valve replacement,7,20 but the comparison is unfair, because the zero is set fifteen years later. Twelve-year figures for porcine valves6 more closely resemble Starr valve data, five and ten year figures for mitral valves being 80% and 69% and for aortic valves 7807o and 57%. The variety of materials and designs available indicates that there is no ideal valve. The choice of valve is not easy, and published retrospective data, collected, analysed, and interpreted in different ways, can justify almost any valve policy. Few clear statements can be made. In children and young people tissue valves are likely to fail sooner than they would in older people. If life-long anticoagulation is unacceptable or unrealistic, a tissue valve should be used. Beyond that it is a trade-off between the proven durability of the best-tried mechanical valves with anticoagulation for life and the safer and perhaps better quality of life with a tissue valve, free from regular tablets, blood tests, and the risk of bleeding but with the prospect of a further valve replacement in ten to fifteen years. Most cardiac surgeons try to choose the best valve for individual patients, often - taking into account age, life style, and attitudes to surgery and medicines. This careful selection will make published series just as hard to interpret a decade from now as

they are today.

PATHOLOGY OF BREAST CANCERS IN LONG-TERM SURVIVORS AN important investigation into the clinical and pathological features of long-term survivors with breast cancer has been published from Edinburgh.’ The patients, all treated by simple mastectomy and irradiation, were divided into two groups. Long-term survivors (119 out of 626 individuals alive at 16-20 years after surgery) were compared with 200 consecutive patients, treated in the same manner during the same period, who died within 10 years. In contrast to the short-term survivors, the long-term survivors had a greater incidence of non-invasive caricers (7 [5’ 90/0] versus none), more microinvasive cancers (7 [5’ 90/0] versus 2 [1. 00/0]), and a striking excess of "special" morphological types of invasive carcinomas (72 [60.50/0] versus 32 [16%]). The incidence of invasive carcinomas of no specific morphological type (carcinomas not otherwise specified, NOS) was correspondingly lower-33 (27-7%) versus 166 (83%)-among the long-term survivors, but they included a larger proportion of better differentiated grade I and grade II lesions. Tumours from long-term survivors generally showed more

elastosis, and less necrosis and invasion of local

lymphatics and blood vessels. Fibrosis was similar in the two groups. Differences in the clinical features were less clear cut.

Page DL, Anderson TJ, et al. Long-term survivors after breast cancer Br J Surg 1985, 72: 445-48

1. Dixon JM,

Age, menopausal status, and parity were comparable, but a significant excess of earlier stage tumours was found among the long-term survivors. Histological and clinical features were reanalysed in 101 pairs of long-term and short-term survivors matched for age, menopausal status, parity, tumour size and location, and clinical lymph-node status. All the histological differences were shown to be independent of the clinical features. The principal finding to emerge from this work is the excess of special morphological types of tumour among the long-term survivors. The 72 invasive cancers encountered in the Edinburgh survey were classified as follows: cribriform (16), variants of lobular (13), tubular (10), classical medullary (9), variants of tubular (8), classical lobular (6), invasive papillary (6), mucoid (2), and variants of medullary (2). A similar correlation between special tumour morphology and long-term survival has been previously described in reports from New York2and Chicago.3In the Chicago series, 97 patients who lived 25 years after radical mastectomy showeda clear preponderance of special tumour types compared with a matched series of short-term survivors living for a mean of 3’8 years after surgery ( 19% versus 2%). The authors comment that "While the presence of a tubular, medullary or colloid carcinoma does not guarantee 25 years’ survival,it makes it more likely". The Edinburgh findings on special types of tumour raise some general issues.4-6 The tumours in question are uncommon and sometimes extremely rare. Descriptive criteria and terminology vary in some instances. Individual tumours may show both mixed and transitional appearances under the microscope which can make classification difficult or impossible. Thorough tissue sampling and expert review of pathological material are essential. Survival patterns are inevitably based on small numbers of patients. The tumours in the Edinburgh survey exemplify the dilemmas. The classic lobular infiltrating carcinoma, for example, is usually easy to diagnose, composed of small regular cells with distinctive "indian-file" and "targetoid" growth patterns.4-6,9 But increasing numbers of variant infiltrating lobular carcinomas have now been described and their identification is sometimes extremely difficult:6- 10"several criteria have to be considered in combination and ... no single pattern can be regarded as diagnostic". Precise tissue diagnosis is far from academic in such circumstances, in view of the association between morphology and survival. Tubular carcinomas are very well differentiated lesions, sometimes confused with sclerosing adenosis, which constitute about 5% of invasive breast cancers.4-6,II"Pure" tubular carcinomas infrequently metastasise to axillary lymph nodes and carry a good prognosis. Some of them contain a minor cribriform 2. Adair F, Berg J, Joubert L, Robbins GF Long-term follow-up of breast cancer patients. the 30-year report. Cancer 1974; 33: 1145-50. 3. Dawson PJ, Ferguson DJ, Karrison T. The pathologic findings of breast cancerin patients surviving 25 years after radical mastectomy Cancer 1982; 50: 2131-38. 4. McDivitt RW, Stewart FW, Berg JW. Tumors ofthe breast. Atlas of tumor pathology, second series, fascicle 2. Washington, DC: Armed Forces Institute of Pathology, 1968. 5. Fisher ER, Gregorio RM, Fisher B, Redmond C, Vellios F, Sommers SC, and cooperating investigators. The pathology of invasive breast cancer. A syllabus derived from findings of the national surgical adjuvant breast project (protocol no. 4) Cancer 1975, 36: 1-85. 6. Azzopardi JG. Problems in breast pathology. Philadelphia: W. B. Saunders, 1979. 7. Fechner RE. Histologic variants of infiltrating lobular carcinoma of the breast. Hum Pathol 1975; 6: 373-78. 8 Fisher ER, Gregorio RM, Redmond C, Fisher B. Tubulolobular invasive breast cancer a variant of lobular invasive cancer. Hum Pathol 1977; 8: 679-83. 9. Martinez V, Azzopardi JG. Invasive lobular carcinoma of the breast: incidence and variants Histopathology 1979; 3: 467-88. 10. Dixon JM, Anderson TJ, Page DL, Lee D, Duffy SW. Infiltrating lobular carcinoma of the breast Histopathology 1982; 6: 149-61

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component which does outcome.

Infiltrating

not

likely favourable composed solely or

diminish their

tumours

predominantly of cribriform elements, a somewhat debatable group described by the2 Edinburgh workers as invasive cribriform carcinomas,’ also have a good prognosis. Definitions of "pure" and "minor" are obviously crucial here because tumours with tubular and/or cribriform components admixed with a larger proportion of undifferentiated elements lose their favourable prognostic status, in whole or m pan,IH3 and are probably best classified as infiltrative carcinomas NOS. Invasive papillary carcinomas, generally regarded as extremely rare,4-ó are differentiated tumour with (sometimes) a partly adenomatoid growth pattern and variable amounts of fibrous stroma within the papillary tuftS.14 Spread to axillary lymph nodes is uncommon and survival is comparable with that recorded for tubular cancers. The tumour has been described most often in postmenopausal and non-caucasian women. Medullary carcinomas again exemplify the need for rigid diagnostic criteria and expert review. 6,15 In a study from New York described as a "classic milestone",6 Ridolfi et al 15 reevaluated 192 tumours and accepted a diagnosis of medullary carcinomas in 57 of them. The typical features are well known-circumscribed tumours composed of large pleomorphic cells arranged in a syncytial growth pattern with nucleoli and mitoses, and a moderate to marked lymphoplasmacytic infiltrate. Compared with invasive carcinomas NOS, they show a lower incidence of axillary node metastases and higher 10-year survival rates; deaths from medullary carcinoma characteristically occur within 5 years of diagnosis. The definition and status of atypical medullary carcinomas remain unclear.4-ó,15 10-year survival rates are significantly worse than those of classic medullary carcinomas but (in most reports) better than the rates for invasive carcinomas NOS. They may well represent a

heterogenous group. The generally favourable long-term prognosis of mucinproducing colloid carcinomas, representing about 2% of all invasive cancers, has been recognised since the 1960s.4-6 The incidence of axillary node metastases is substantially lower than for invasive carcinomas NOS. As with other tumours described here, a sharp distinction has to be drawn between pure colloid cancers and infiltrating carcinomas with a minor colloid component in which no prognostic advantage is apparent. Mucin production is also found in some lobular and papillary cancers, and in signet-ring carcinomas. 16, 17 The status of signet-ring cancers is still unclear, but the tumour seems to be separate from colloid carcinomas in terms of its morphology, prognostic implications, and (probably)

histogenesis.ó

It will be obvious that the recognition of "special" morphological types of breast cancer by the pathologist is of considerable practical importance. It will, however, be

equally obvious that the underlying reasons for their better prognosis remain obscure. The incidence and number of axillary node metastases are usually low among these tumours, but this observation merely emphasises the hiatus that still exists between accurate description of a tumour’s morphology and accurate prediction of its behaviour. The major category of breast cancer-invasive carcinomas NOS-includes tumours with a wide variety of behaviour and prognosis that cannot yet be precisely identified and separated by conventional morphology.

HYPOGLYCAEMIA AND THE NERVOUS SYSTEM MOST body tissues have the ability to derive energy from a variety of substrates; the central nervous system (CNS) is unique in that oxidative metabolism of glucose is the only source of energy, except in extreme starvation. Coupled with the small reserves of glucose and glycogen within the CNS, this substrate dependence renders the brain especially vulnerable to large changes in systemic glucose supply. If the glucose supply is cut off CNS function deteriorates rapidly, ultimately leading to irreversible damage. The exact mechanism of this decline in function is unclear, however, since high-energy phosphates seem to be plentiful in spite of the loss of nearly all the CNS glucose when stupor

supervenes.2,3 Hypoglycaemic symptoms depend on the rate at which the blood glucose falls. In acute hypoglycaemia (typically the result of excess insulin administration or secretion) the initial symptoms are due to excessive adrenergic activity-the patient is tremulous, anxious, sweats profusely, and has palpitations. Cerebral dysfunction follows, with alterations in behaviour, especially slowness and irritability, preceding clouding of consciousness and coma. Seizures occur in 10-20% of adults and are more common in children.There may be features of decortication or decerebration5 and, not infrequently, focal abnormalities, particularly hemiplegia.6 Function may be restored if the hypoglycaemia is corrected by intravenous glucose, but some patients remain in irreversible coma or have pronounced residual deficits. In subacute or chronic hypoglycaemia, excessive sympathetic nervous system activity does not occur, although irreversible neurological disturbance, especially intellectual deterioration or ataxia, can result. The selectivity of damage caused by hypoglycaemia is of considerable interest; it might be expected that all parts of the nervous system would be equally vulnerable but this is not so. In the numerous pathological studies of hypoglycaemia in animals and man there is some disagreement about the exact distribution of lesions but it is agreed that neurons of the middle layers of the cerebral cortex (with the exception of the striate area) and hippocampus are most affected, the basal ganglia and anterior thalamus are the next most sensitive,

11 Carstens PHB, Greenberg RA, Francis D, Lyon H. Tubularcarcinoma of the breast. A

12

long term follow-up Histoparthology 1985, 9: 271-80. Page DL, Dixon JM, Anderson TJ, Lee D, Stewart HJ Invasive cribriform carcinoma

13

of the breast. Histopathology 1983, Cooper HS, Patchefsky AS, Krall RA

1

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7: 525-36

Tubular

carcinoma

Duffy TE, Plum F. Seizures, coma and major metabolic encephalopathies In Albers RW, Siegel GJ, Katzman R, Agranoff BW, eds Basic neurochemistry. Boston-

ofthe breast. Cancer 1978;

42: 2334-42 14 Fisher

ER, Palekar AS, Redmond C, Barton B, fisher B Pathologic findings from the national surgical adjuvant breast project (protocol no 4). VI Invasive papillary cancer Am J Clin Pathol 1980, 73: 313-22 15 Ridolfi RL,Rosen PP, Port A,Kinne D,MikeV Medullarycarcinomaof thebreast A clinicopathologic study with 10 year follow-up. Cancer 1977, 40: 1365-85 16 Harris M, Wells S, Vasudev KS Primary signet ring cell carcinoma of the breast Histopathology 1978, 2: 171-76

17 Harris M, Vasudev KS, Anfield C, WellsS Mucin-producing carcinomas of the breast ultrastructural observations Histopathology 1978, 2: 177-88

JA, Chiang MM Brain metabolism during hypoglycemia Arch Neurol 1973, 28: 173-78 Lewis LD, Ljunggren B, Ratcheson RA, Siesjo BK Cerebral energy state in insulin induced hypoglycemia, related to blood glucose and to EEG J Neurochem 1974; 23:

2 Ferrendelli 3.

673-79. 4

Mulder DW, Rushton TG. Hyperinsulinism A rare cause of epilepsy Neurology 1959, 9: 288-89

5. Seibert DG. Reversible decerebrate posturing 6

secondary

to

hypoglycemia JAMA

1985; 78: 1036-37 Montgomery BM, Pinner CA. Transient hypoglycemic hemiplegia Arch Intern Med 1964, 114: 680-84.