- Email: [email protected]
CALCIUM IN BREAST BIOPSY SPECIMENS
763
shown to inhibit corticotropin-induced cortisol secretion from guineapig adrenal cells in vitro.2O Inhibition preceded cAMP generation and therefore was probably due to a receptor antibody. Without a receptor binding assay for corticotropin, direct interaction of IgG with the receptor could not be shown. In a more extensive study, IgG preparations from 23 of 25 patients with idiopathic Addison’s disease blocked the in-vitro effects of corticotropin.21 Guineapig adrenal segments in organ culture were exposed to corticotropin and graded concentrations of patient IgG. Biological effects were assessed by radioimmunoassay of cortisol in the culture fluid, and DNA synthesis was determined by Feulgen densitometry on frozen sections of cultured adrenal segments. 19 of the 25 patients had antiadrenal cytoplasmic antibodies. However, the specificity of these antibodies is unclear, because they were also present in some patients with Cushing’s disease or primary hypothyroidism who had no evidence of adrenal insufficiency. Nevertheless, it seems reasonable to conclude that Addison’s disease in some patients is another example of a receptor-blocking-antibody disease. The list of disorders in which blocking antibodies have a pathogenic role continues to grow and now includes insulin-resistant diabetes with acanthosis nigricans (insulin receptor), premature ovarian failure (follicle-stimulating
hormone
receptor), myasthenia gravis (acetylcholine receptor), and pernicious anaemia (gastrin receptor). Receptor antibodies are not the only antibodies found in autoimmune endocrine disease and it has been suggested that a triad of autoantibodies exists for many, if not all, the endocrine organs 22 The best characterised autoantibody system is in the thyroid gland, for which there are well-documented cytoplasmic (microsomal/ lactoperoxidase), receptor (thyrotropin), and product (thyroglobulin, thyroid hormone) antibodies. The pancreatic &bgr; cell has islet cell (cytoplasmic), insulin, and islet cell stimulating antibodies.22 These stimulating antibodies have been found in patients with spontaneous hyperinsulinaemic hypoglycaemia and in some cases of insulin-dependent diabetes mellitus, and were identified by the ability of IgG fractions to stimulate insulin release both in islet cell cultures and in vivo in rats. The endogenous ligand for the receptor has not been identified and blocking antibodies have not yet been described. 1. Burman KD, Baker JR. Immune mechanisms in Graves’ disease. Endocr Rev 1985; 6: 183-232. 2. Rees Smith B, McLachlan SM, Furmaniak J. Autoantibodies to the
thyrotropin receptor. Endocr Rev 1989; 9: 106-21. SM, Peg CAS, Atherton MC, et al. TSH receptor antibody synthesis by thyroid lymphocytes. Clin Endocrinol 1986; 24: 223-30. 4. Hashim FA, Creagh FM, El Hawrani A, et al Characterization of TSH antagonist activity in the serum of patients with thyroid disease. Clin 3. McLachlan
Endocrinol 1986; 25: 275-81. 5. Bech K, Bliddal H, Siersbaek-Nielsen K, Friis T. Production of non-stimulatory immunoglobulins that inhibit TSH binding in Graves’ disease after radioiodine administration. Clin Endocrinol 1982; 17: 395-402. 6. Konishi J, Iida Y, Endo K, et al. Inhibition of thyrotropin-induced adenosine 3’, 5’-monophosphate increase by immunoglobulins from patients with primary myxedema. J Clin Endocrinol Metab 1983; 57: 544-49. 7. Steel NR, Weightman DR, Taylor JJ, Kendall-Taylor P. Blocking activity to action of thyroid stimulating hormone in serum from patients with primary hypothyroidism. Br Med J 1984; 288: 1559-62. 8. Arikawa K, Ichikawa Y, Yioshida T, et al. Blocking type antithyrotropin receptor antibody in patients with nongoitrous hypothyroidism: its incidence and characteristics of action. J Clin Endocrinol Metab 1985; 60: 953-59.
9. Endo K, Kasagi K, Konishi J, et al. Detection and properties of TSH-binding inhibitor immunoglobulins in patients with Graves’ disease and Hashimoto’s thyroiditis. J Clin Endocrinol Metab 1978; 46: 734-39. 10. Zakarija M, McKenzie JM, Munro DS. Immunoglobulin G inhibitor of thyroid-stimulating antibody is a cause of delay in the onset of neonatal Graves’ disease. J Clin Invest 1983; 72: 1352-58. 11. Matsuura N, Yamada Y, Nohara Y, et al. Familial neonatal transient hypothyroidism due to maternal TSH-binding inhibitor immunoglobulins. N Engl J Med 1980; 303: 738-41. 12. Iseki M, Shimizu M, Oikawa T, et al. Sequential serum measurement of thyrotropin binding inhibitor immunoglobulin G in transient familial neonatal hypothyroidism. J Clin Endocrinol Metab 1983; 57: 384-87. 13. Takasu N, Mori T, Koizumi Y, et al. Transient neonatal hypothyroidism due to maternal immunoglobulins that inhibit thyrotropin-binding and post-receptor processes. J Clin Endocrinol Metab 1984; 59: 142-46. 14. Jones DE, Hashim FA, Creagh FM, et al. The interaction between the TSH receptor and Graves’ sera with TSH agonist or antagonist properties. Mol Cell Endocrinol 1985; 41: 257-63. 15. Valente WA, Yavin Z, Yavin E, et al. Graves monoclonal antibodies to the thyrotropin receptor: stimulating and blocking antibodies derived from the lymphocytes of patients. Proc Natl Acad Sci USA 1982; 79: 6680-84. 16. Boyages SC, Halpern J-P, Maberly GF, et al. Endemic cretinism: possible role for thyroid autoimmunity. Lancet 1989; ii: 529-32. 17. Van der Gaag RD, Drexhage HA, Dussault JH. Role of maternal immunoglobulins blocking TSH-induced thyroid growth in sporadic forms of congenital hypothyroidism. Lancet 1985; i: 246-50. 18. Dumont JE, Roger PP, Ludgate M. Assays for thyroid growth immunoglobulin and their clinical implications: methods, concepts, and misconceptions. Endocr Rev 1987; 8: 448-52. 19. Parmentier M, Libert F, Maenhaut C, et al. Molecular cloning of the thyrotropin receptor. Science 1989; 246: 1620-22. 20. Kendall-Taylor P, Lambert A, Mitchell R, Robertson WR. Antibody that blocks stimulation of cortisol secretion by adrenocorticotrophic hormone in Addison’s disease. Br Med J 1988; 296: 1489-91. 21. Wulffraat NM, Drexhage HA, Bottazzo G-F, et al. Immunoglobulins of patients with idiopathic Addison’s disease block the in vitro action of adrenocorticotropin. J Clin Endocrinol Metab 1989; 69: 231-38. 22. Wilkin TJ, Hammonds P, Mirza I, Bone AJ, Webster K. Graves’ disease of the &bgr; cell: glucose dysregulation due to islet-cell stimulating antibodies. Lancet 1988; ii: 1155-58.
CALCIUM IN BREAST BIOPSY SPECIMENS Focal calcification in an ostensibly normal breast is commonly seen in mammograms undertaken as part of screening programmes. Evaluation of such changes requires accurate radiological localisation and tissue sampling. Investigations with permutations of electron microscopy, microprobe analysis, and X-ray diffraction1-3 have shown that calcium in breast tissues is present mainly as phosphates in the crystalline form of hydroxyapatite; a smaller proportion occurs as oxalates in the form of weddellite crystals. These findings are important for two reasons. First, birefringent weddellite crystals do not stain with conventional reagents and are difficult to see unless the sections are viewed in polarised light, so there may be discrepancies between calcification observed in mammograms and in biopsy specimens. Secondly, there is evidence that phosphates and oxalate tend to be associated with different kinds of breast lesions. Both topics have now been investigated in two studies.4,5 Radi in Florida4 studied 127 randomly selected mammographic biopsy specimens, obtained from 118 women aged 28-77 years (mean 545). Preoperative radiographic localisation was repeated in the excised specimen and the tissues were extensively sampled. 78 of the biopsies (61-4%) were undertaken because of calcification on mammograms and the remainder because of "suspicious masses" without calcification. Among these 78 specimens, 9 contained oxalate crystals, 9 oxalate and phosphates, and 48 phosphates. No calcium was found in the remaining 12. The
764
overall figure for the occurrence of calcium oxalate crystals in the series was 23-1%. Deposits of calcium oxalate were identified in benign epithelial cysts, in which they were thought to represent secretory activity. Calcium phosphates were found in or near in-situ and invasive ductal carcinomas, zones of typical and atypical epithelial hyperplasia, fibroadenomas, sclerosing adenosis, and lobular atrophy; they were often associated with cellular degeneration and necrosis. In the second study, reported jointly from Edinburgh and London,s weddellite crystals were identified in needle localisation biopsy specimens from 18 of 246 women aged 39-62 years who presented with impalpable microcalcified lesions detected by mammography. Weddellite and hydroxyapatite crystals were detected in different parts of the same specimen in 13 cases. Weddellite calcification was almost always identified among parenchymal rather than stromal elements and was seen most commonly in apocrine cysts (10 cases). Occasional crystals lay within ducts or near inflammatory lesions. No direct association was found between the presence of weddellite and contiguous dysplasia or carcinoma, although incidental atypical lobular hyperplasia and lobular carcinoma-in-situ were present, each in 1 case. Electron probe microanalysis confirmed the identity of calcium oxalate in histological sections from 8 specimens and distinguished weddellite (the dihydrate form) from monohydrate whewellite. Results from both these investigations confirm the view3 that deposition of weddellite crystals is a feature of benign rather than malignant processes within the breast. Calcium oxalate crystals have occasionally been identified in breast tissue which also contained in-situ lobular carcinoma,2 but the association, if any, appears to be tenuous. The practical message that emerges from this work is that calcium oxalate (weddellite) crystals should be sought in mammographically derived biopsy specimens when there is an apparent hiatus between radiological and pathological
findings. 1. Ahmed A. Calcification in human breast carcinomas: ultrastructural observations. J Pathol 1975; 117: 247-51. 2. Busing CM, Keppler U, Menges V. Differences in microcalcification in breast tumours. Virchows Arch (Pathol Anat) 1981; 393: 307-13. 3. Frappart L, Boudeulle M, Boumendil J, Lin HC, Martinon I, et al. Structure and composition of microcalcifications in benign and malignant lesions of the breast. Hum Pathol 1984; 15: 880-89. 4. Radi MJ. Calcium oxalate crystals in breast biopsies. Arch Pathol Lab Med 1989; 113: 1367-69. 5. Going JJ, Anderson TJ, Crocker PR, Levison DA. Weddellite calcification in the breast: 18 cases with implications for breast cancer
screening. Histopathology 1990; 16: 119-24.
HOW FAR SHOULD INDICATIONS FOR GROWTH HORMONE TREATMENT EXPAND? For many years the therapeutic use of growth hormone (GH) was limited by the quantities available. Criteria were therefore devised to determine which children had sufficient hormone deficiency to warrant treatment.1 The introduction of biosynthetic GH in 1985 has encouraged a reappraisal of the indications for therapy. Whilst no-one would deny that children with GH deficiency should receive the hormone, or that those with minor disorders of GH secretion may benefit from such treatment, should GH be given to short children without GH insufficiency? Short non-GH-deficient children will grow faster when given exogenous GH,2-5 but in most of these groups of children it
is not yet known whether final adult height can be improved. Girls with Turner syndrome respond well, although the dose needs to be higher than that in GH deficiency, and in these individuals at least it seems increasingly likely that final height can be augmented.6 In the excitement of assessing new applications for GH many children with various types of short stature have been treated.7 In the interpretation of the results, it is necessary to distinguish between the demonstration of a growth response to GH and the suitability of GH as a therapeutic agent for the condition. In children with short stature due to chronic diseases such as chronic renal failure, treatment of the underlying disorder is of prime importance and GH to improve height should be used only as an adjunct to optimum therapy for that condition. Spadoni and colleagues8 lately reported the growth response to GH of 4 children with short stature associated with sporadic microcephaly. They comment that all the children had retarded mental development but do not indicate the severity of retardation. These patients, like other short children with normal GH responses to pharmacological stimulation, showed an increase in growth velocity after 6-12 months of GH treatment. Spadoni et al are unable to assess whether or not a greater final height will be achieved, and they do not discuss their views about the role of GH as a therapeutic agent in non-GH-deficient mentally handicapped children. No effective medication is risk free, and the possibility of a higher frequency of leukaemia among GH recipients is worrying.9 GH is an expensive tool for increasing height and its long-term benefits and side-effects are unknown. The assumption that an increase in height improves the psychological wellbeing of the child and will make him or her a more useful and productive member of society when full grown has been given as justification for use of the hormone. This is almost entirely speculation. GH can make almost any short child grow faster in the short term, but how long this effect lasts is unknown, nor is it clear whether final height can be increased. Even if this goal is attainable, what will be the cost per centimetre of extra height in financial terms and with respect to side-effects for the recipient? These issues cannot be ignored. Is it right to spend many thousands of pounds to make an otherwise healthy child a few centimetres taller, or would it ultimately be preferable to persuade society that bigger is not necessarily better. RDG, Burns EC. Investigation of suspected growth hormone deficiency. Arch Dis Child 1982; 57: 944-47. 2. Ackland FM, Jones J, Buckler JMH, Dunger DB, Rayner PHW, Preece MA. Growth hormone treatment in non-growth hormone deficient children: effects of stopping treatment. Acta Paediatr Scand (in press). 1. Milner
3. Albertsson-Wikland K. Growth hormone treatment in short children. Acta Paediatr Scand 1986; 325 (suppl) 64-70. 4. Hindmarsh PC, Brook CGD. Effect of growth hormone on short normal children. Br Med J 1987; 295: 573-77. 5. Rudman D, Kumer MH, Blackston RD, Cushman RA, Bain RP, Patterson JH. Children with normal variant short stature: treatment with human growth hormone for six months. N Engl J Med 1981; 305: 123-31. 6. Rosenfeld RG, Hintz RL, Johanson AJ, et al. Three-year results of a randomised prospective trial of methionyl human growth hormone and oxandrolone in Turner syndrome. J Pediatr 1988; 113: 393-400. 7. Tonshoff B, Shauer A, Ranke RM, Blum W, Heinrich U, Mehls O. Improvement of growth by recombinant human growth hormone in uraemic children. Acta Paediatr Scand 1989; 349 (suppl): 160. 8. Spadoni GL, Cianfarini S, Bernardini S, Fabrizio V, Galasso C, Boscherini B. Growth hormone treatment in children with sporadic primary microcephaly. Am J Dis Child 1989; 143: 1282-83. 9. Watanabe S, Tsunematsu Y, Fujimoto J, Komiyama A. Leukaemia in patients treated with growth hormone. Lancet 1988; i 1159.
shown to inhibit corticotropin-induced cortisol secretion from guineapig adrenal cells in vitro.2O Inhibition preceded cAMP generation and therefore was probably due to a receptor antibody. Without a receptor binding assay for corticotropin, direct interaction of IgG with the receptor could not be shown. In a more extensive study, IgG preparations from 23 of 25 patients with idiopathic Addison’s disease blocked the in-vitro effects of corticotropin.21 Guineapig adrenal segments in organ culture were exposed to corticotropin and graded concentrations of patient IgG. Biological effects were assessed by radioimmunoassay of cortisol in the culture fluid, and DNA synthesis was determined by Feulgen densitometry on frozen sections of cultured adrenal segments. 19 of the 25 patients had antiadrenal cytoplasmic antibodies. However, the specificity of these antibodies is unclear, because they were also present in some patients with Cushing’s disease or primary hypothyroidism who had no evidence of adrenal insufficiency. Nevertheless, it seems reasonable to conclude that Addison’s disease in some patients is another example of a receptor-blocking-antibody disease. The list of disorders in which blocking antibodies have a pathogenic role continues to grow and now includes insulin-resistant diabetes with acanthosis nigricans (insulin receptor), premature ovarian failure (follicle-stimulating
hormone
receptor), myasthenia gravis (acetylcholine receptor), and pernicious anaemia (gastrin receptor). Receptor antibodies are not the only antibodies found in autoimmune endocrine disease and it has been suggested that a triad of autoantibodies exists for many, if not all, the endocrine organs 22 The best characterised autoantibody system is in the thyroid gland, for which there are well-documented cytoplasmic (microsomal/ lactoperoxidase), receptor (thyrotropin), and product (thyroglobulin, thyroid hormone) antibodies. The pancreatic &bgr; cell has islet cell (cytoplasmic), insulin, and islet cell stimulating antibodies.22 These stimulating antibodies have been found in patients with spontaneous hyperinsulinaemic hypoglycaemia and in some cases of insulin-dependent diabetes mellitus, and were identified by the ability of IgG fractions to stimulate insulin release both in islet cell cultures and in vivo in rats. The endogenous ligand for the receptor has not been identified and blocking antibodies have not yet been described. 1. Burman KD, Baker JR. Immune mechanisms in Graves’ disease. Endocr Rev 1985; 6: 183-232. 2. Rees Smith B, McLachlan SM, Furmaniak J. Autoantibodies to the
thyrotropin receptor. Endocr Rev 1989; 9: 106-21. SM, Peg CAS, Atherton MC, et al. TSH receptor antibody synthesis by thyroid lymphocytes. Clin Endocrinol 1986; 24: 223-30. 4. Hashim FA, Creagh FM, El Hawrani A, et al Characterization of TSH antagonist activity in the serum of patients with thyroid disease. Clin 3. McLachlan
Endocrinol 1986; 25: 275-81. 5. Bech K, Bliddal H, Siersbaek-Nielsen K, Friis T. Production of non-stimulatory immunoglobulins that inhibit TSH binding in Graves’ disease after radioiodine administration. Clin Endocrinol 1982; 17: 395-402. 6. Konishi J, Iida Y, Endo K, et al. Inhibition of thyrotropin-induced adenosine 3’, 5’-monophosphate increase by immunoglobulins from patients with primary myxedema. J Clin Endocrinol Metab 1983; 57: 544-49. 7. Steel NR, Weightman DR, Taylor JJ, Kendall-Taylor P. Blocking activity to action of thyroid stimulating hormone in serum from patients with primary hypothyroidism. Br Med J 1984; 288: 1559-62. 8. Arikawa K, Ichikawa Y, Yioshida T, et al. Blocking type antithyrotropin receptor antibody in patients with nongoitrous hypothyroidism: its incidence and characteristics of action. J Clin Endocrinol Metab 1985; 60: 953-59.
9. Endo K, Kasagi K, Konishi J, et al. Detection and properties of TSH-binding inhibitor immunoglobulins in patients with Graves’ disease and Hashimoto’s thyroiditis. J Clin Endocrinol Metab 1978; 46: 734-39. 10. Zakarija M, McKenzie JM, Munro DS. Immunoglobulin G inhibitor of thyroid-stimulating antibody is a cause of delay in the onset of neonatal Graves’ disease. J Clin Invest 1983; 72: 1352-58. 11. Matsuura N, Yamada Y, Nohara Y, et al. Familial neonatal transient hypothyroidism due to maternal TSH-binding inhibitor immunoglobulins. N Engl J Med 1980; 303: 738-41. 12. Iseki M, Shimizu M, Oikawa T, et al. Sequential serum measurement of thyrotropin binding inhibitor immunoglobulin G in transient familial neonatal hypothyroidism. J Clin Endocrinol Metab 1983; 57: 384-87. 13. Takasu N, Mori T, Koizumi Y, et al. Transient neonatal hypothyroidism due to maternal immunoglobulins that inhibit thyrotropin-binding and post-receptor processes. J Clin Endocrinol Metab 1984; 59: 142-46. 14. Jones DE, Hashim FA, Creagh FM, et al. The interaction between the TSH receptor and Graves’ sera with TSH agonist or antagonist properties. Mol Cell Endocrinol 1985; 41: 257-63. 15. Valente WA, Yavin Z, Yavin E, et al. Graves monoclonal antibodies to the thyrotropin receptor: stimulating and blocking antibodies derived from the lymphocytes of patients. Proc Natl Acad Sci USA 1982; 79: 6680-84. 16. Boyages SC, Halpern J-P, Maberly GF, et al. Endemic cretinism: possible role for thyroid autoimmunity. Lancet 1989; ii: 529-32. 17. Van der Gaag RD, Drexhage HA, Dussault JH. Role of maternal immunoglobulins blocking TSH-induced thyroid growth in sporadic forms of congenital hypothyroidism. Lancet 1985; i: 246-50. 18. Dumont JE, Roger PP, Ludgate M. Assays for thyroid growth immunoglobulin and their clinical implications: methods, concepts, and misconceptions. Endocr Rev 1987; 8: 448-52. 19. Parmentier M, Libert F, Maenhaut C, et al. Molecular cloning of the thyrotropin receptor. Science 1989; 246: 1620-22. 20. Kendall-Taylor P, Lambert A, Mitchell R, Robertson WR. Antibody that blocks stimulation of cortisol secretion by adrenocorticotrophic hormone in Addison’s disease. Br Med J 1988; 296: 1489-91. 21. Wulffraat NM, Drexhage HA, Bottazzo G-F, et al. Immunoglobulins of patients with idiopathic Addison’s disease block the in vitro action of adrenocorticotropin. J Clin Endocrinol Metab 1989; 69: 231-38. 22. Wilkin TJ, Hammonds P, Mirza I, Bone AJ, Webster K. Graves’ disease of the &bgr; cell: glucose dysregulation due to islet-cell stimulating antibodies. Lancet 1988; ii: 1155-58.
CALCIUM IN BREAST BIOPSY SPECIMENS Focal calcification in an ostensibly normal breast is commonly seen in mammograms undertaken as part of screening programmes. Evaluation of such changes requires accurate radiological localisation and tissue sampling. Investigations with permutations of electron microscopy, microprobe analysis, and X-ray diffraction1-3 have shown that calcium in breast tissues is present mainly as phosphates in the crystalline form of hydroxyapatite; a smaller proportion occurs as oxalates in the form of weddellite crystals. These findings are important for two reasons. First, birefringent weddellite crystals do not stain with conventional reagents and are difficult to see unless the sections are viewed in polarised light, so there may be discrepancies between calcification observed in mammograms and in biopsy specimens. Secondly, there is evidence that phosphates and oxalate tend to be associated with different kinds of breast lesions. Both topics have now been investigated in two studies.4,5 Radi in Florida4 studied 127 randomly selected mammographic biopsy specimens, obtained from 118 women aged 28-77 years (mean 545). Preoperative radiographic localisation was repeated in the excised specimen and the tissues were extensively sampled. 78 of the biopsies (61-4%) were undertaken because of calcification on mammograms and the remainder because of "suspicious masses" without calcification. Among these 78 specimens, 9 contained oxalate crystals, 9 oxalate and phosphates, and 48 phosphates. No calcium was found in the remaining 12. The
764
overall figure for the occurrence of calcium oxalate crystals in the series was 23-1%. Deposits of calcium oxalate were identified in benign epithelial cysts, in which they were thought to represent secretory activity. Calcium phosphates were found in or near in-situ and invasive ductal carcinomas, zones of typical and atypical epithelial hyperplasia, fibroadenomas, sclerosing adenosis, and lobular atrophy; they were often associated with cellular degeneration and necrosis. In the second study, reported jointly from Edinburgh and London,s weddellite crystals were identified in needle localisation biopsy specimens from 18 of 246 women aged 39-62 years who presented with impalpable microcalcified lesions detected by mammography. Weddellite and hydroxyapatite crystals were detected in different parts of the same specimen in 13 cases. Weddellite calcification was almost always identified among parenchymal rather than stromal elements and was seen most commonly in apocrine cysts (10 cases). Occasional crystals lay within ducts or near inflammatory lesions. No direct association was found between the presence of weddellite and contiguous dysplasia or carcinoma, although incidental atypical lobular hyperplasia and lobular carcinoma-in-situ were present, each in 1 case. Electron probe microanalysis confirmed the identity of calcium oxalate in histological sections from 8 specimens and distinguished weddellite (the dihydrate form) from monohydrate whewellite. Results from both these investigations confirm the view3 that deposition of weddellite crystals is a feature of benign rather than malignant processes within the breast. Calcium oxalate crystals have occasionally been identified in breast tissue which also contained in-situ lobular carcinoma,2 but the association, if any, appears to be tenuous. The practical message that emerges from this work is that calcium oxalate (weddellite) crystals should be sought in mammographically derived biopsy specimens when there is an apparent hiatus between radiological and pathological
findings. 1. Ahmed A. Calcification in human breast carcinomas: ultrastructural observations. J Pathol 1975; 117: 247-51. 2. Busing CM, Keppler U, Menges V. Differences in microcalcification in breast tumours. Virchows Arch (Pathol Anat) 1981; 393: 307-13. 3. Frappart L, Boudeulle M, Boumendil J, Lin HC, Martinon I, et al. Structure and composition of microcalcifications in benign and malignant lesions of the breast. Hum Pathol 1984; 15: 880-89. 4. Radi MJ. Calcium oxalate crystals in breast biopsies. Arch Pathol Lab Med 1989; 113: 1367-69. 5. Going JJ, Anderson TJ, Crocker PR, Levison DA. Weddellite calcification in the breast: 18 cases with implications for breast cancer
screening. Histopathology 1990; 16: 119-24.
HOW FAR SHOULD INDICATIONS FOR GROWTH HORMONE TREATMENT EXPAND? For many years the therapeutic use of growth hormone (GH) was limited by the quantities available. Criteria were therefore devised to determine which children had sufficient hormone deficiency to warrant treatment.1 The introduction of biosynthetic GH in 1985 has encouraged a reappraisal of the indications for therapy. Whilst no-one would deny that children with GH deficiency should receive the hormone, or that those with minor disorders of GH secretion may benefit from such treatment, should GH be given to short children without GH insufficiency? Short non-GH-deficient children will grow faster when given exogenous GH,2-5 but in most of these groups of children it
is not yet known whether final adult height can be improved. Girls with Turner syndrome respond well, although the dose needs to be higher than that in GH deficiency, and in these individuals at least it seems increasingly likely that final height can be augmented.6 In the excitement of assessing new applications for GH many children with various types of short stature have been treated.7 In the interpretation of the results, it is necessary to distinguish between the demonstration of a growth response to GH and the suitability of GH as a therapeutic agent for the condition. In children with short stature due to chronic diseases such as chronic renal failure, treatment of the underlying disorder is of prime importance and GH to improve height should be used only as an adjunct to optimum therapy for that condition. Spadoni and colleagues8 lately reported the growth response to GH of 4 children with short stature associated with sporadic microcephaly. They comment that all the children had retarded mental development but do not indicate the severity of retardation. These patients, like other short children with normal GH responses to pharmacological stimulation, showed an increase in growth velocity after 6-12 months of GH treatment. Spadoni et al are unable to assess whether or not a greater final height will be achieved, and they do not discuss their views about the role of GH as a therapeutic agent in non-GH-deficient mentally handicapped children. No effective medication is risk free, and the possibility of a higher frequency of leukaemia among GH recipients is worrying.9 GH is an expensive tool for increasing height and its long-term benefits and side-effects are unknown. The assumption that an increase in height improves the psychological wellbeing of the child and will make him or her a more useful and productive member of society when full grown has been given as justification for use of the hormone. This is almost entirely speculation. GH can make almost any short child grow faster in the short term, but how long this effect lasts is unknown, nor is it clear whether final height can be increased. Even if this goal is attainable, what will be the cost per centimetre of extra height in financial terms and with respect to side-effects for the recipient? These issues cannot be ignored. Is it right to spend many thousands of pounds to make an otherwise healthy child a few centimetres taller, or would it ultimately be preferable to persuade society that bigger is not necessarily better. RDG, Burns EC. Investigation of suspected growth hormone deficiency. Arch Dis Child 1982; 57: 944-47. 2. Ackland FM, Jones J, Buckler JMH, Dunger DB, Rayner PHW, Preece MA. Growth hormone treatment in non-growth hormone deficient children: effects of stopping treatment. Acta Paediatr Scand (in press). 1. Milner
3. Albertsson-Wikland K. Growth hormone treatment in short children. Acta Paediatr Scand 1986; 325 (suppl) 64-70. 4. Hindmarsh PC, Brook CGD. Effect of growth hormone on short normal children. Br Med J 1987; 295: 573-77. 5. Rudman D, Kumer MH, Blackston RD, Cushman RA, Bain RP, Patterson JH. Children with normal variant short stature: treatment with human growth hormone for six months. N Engl J Med 1981; 305: 123-31. 6. Rosenfeld RG, Hintz RL, Johanson AJ, et al. Three-year results of a randomised prospective trial of methionyl human growth hormone and oxandrolone in Turner syndrome. J Pediatr 1988; 113: 393-400. 7. Tonshoff B, Shauer A, Ranke RM, Blum W, Heinrich U, Mehls O. Improvement of growth by recombinant human growth hormone in uraemic children. Acta Paediatr Scand 1989; 349 (suppl): 160. 8. Spadoni GL, Cianfarini S, Bernardini S, Fabrizio V, Galasso C, Boscherini B. Growth hormone treatment in children with sporadic primary microcephaly. Am J Dis Child 1989; 143: 1282-83. 9. Watanabe S, Tsunematsu Y, Fujimoto J, Komiyama A. Leukaemia in patients treated with growth hormone. Lancet 1988; i 1159.