Beitr. Path. Bd. 157,301-306 (1976)
Rare and Unusual Cases
Department of Pathology, Bangour Hospital, West Lothian, U.K.
A Case of Unexplained Karyomegaly Fallbericht fiber eine ungeklarte Karyomegalie G.SCLARE With 3 Figures' Received October 8,1975 . Accepted December 31,1975
Key words: Karyomegaly - Cytomegaly - Nucleus - Cell- Dysplasia
This report concerns a case in which bizarre enlargement of nuclei occurred in many different organs and tissues, including epithelium, autonomic nerves and smooth muscle. Although there is no satisfactory explanation for this karyomegaly, the case is thought worthy of publication because of its exceptional nature.
Case report The patient was a labourer, first in a farm and later in a brickworks. He first attended hospital at the age of 45 with symptoms and signs of duodenal ulcer, and in later years returned repeatedly with similar symptoms. Four years after the first admission, the skin of the ears and nose was noted to be tight, and a clinical diagnosis of scleroderma was made. Skin biopsies were inconclusive, but consistent with this diagnosis. Later, dyspnoea became an important symptom, and chest x-ray suggested extensive pulmonary fibrosis. The E.S.R. was persistently high, but liver function tests and protein electrophoresis were normal, L.E. cells were absent, tests for antinuclear and rheumatoid factors were negative, and so also was the K veim test. Rectal biopsy revealed a mucosa which was normal except for the presence in the lamina propria of two or three unidentified cells with exceptionally large single nuclei. This finding was repeated in a fragment of duodenal mucosa which was obtained in an attempt at jejunal biopsy. The patient became increasingly breathless and emaciated. Treatment with steroids
302 . G. Sclare had little effect, and he died at the age of 55 after having been re-admitted to hospital in a moribund state. At necropsy, acute upper abdominal peritonitis was found to be due to perforation of a chronic duodenal ulcer. The only other macroscopic finding of importance was in the lungs, which were enlarged and unduly firm, with inter-lobar adhesions and a fibrinous pleural exudate. The brain, heart, liver, kidneys and other viscera were substantially normal, and there was little atheroma in the coronary, cerebral and other arteries. Microscopic examination confirmed the presence of a chronic duodenal ulcer, with perforation and consequent acute peritonitis. In the lungs, consolidation was active in some areas and unresolved in others, accompanied by fibrinous pleurisy. The bronchioles and smaller bronchi were infiltrated by chronic inflammatory cells. There was little collagenous fibrosis but many alveolar spaces were obliterated by histiocytes and fusiform cells resembling fibroblasts, intermingled with chronic inflammatory cells.
The most striking abnormality, and the one which is the occasion for this report, was grotesque enlargement of nuclei in many different organs and tissues. This abnormality is referred to here as karyomegaly, not as cytomegaly, since enlargement of the nucleus was not always accompanied by enlargement of the entire cell and indeed in some instances the cell had no stainable cytoplasm. The enlarged nuclei were always solitary, and they were not seen in mitosis. They did not resemble megakaryocytes or any other type of cell which might have reached the affected tissues from elsewhere; indeed it was clear that these were not infiltrating cells but the constituent cells of all the different organs affected. Nerves, smooth muscle, connective tissue and epithelium were all affected. Karyomegaly was not seen in the brain or in cartilage, bone and bone marrow, skeletal muscle or cardiac muscle. The Schwann cells in the autonomic nerves had enormous nuclei (Fig. I), which were of irregular outline but tended to remain spindleshaped. Virtually all the nuclei were affected in some degree, and the largest measured as much as 50 [lm in length. Each had a prominent nuclear membrane and irregularly distributed chromatin; nucleoli were inconspicuous. The example illustrated is from the epicardial autonomic nerves. Exactly the same abnormalities were seen in autonomic nerves in sections of lungs, alimentary tract, liver, pancreas and kidney. Karyomegaly was again prominent in the ganglion cells of the myenteric plexus. Major somatic nerves were not examined histologically, but the small branches seen in sections of skeletal muscle and skin showed the same abnormalities. The nuclei of smooth muscle were enlarged in sections of oesophagus,
A Case of Unexplained Karyomegaly . 30 3
Fig. I. Autonomic nerve in the epicardial fat. Enormous enlargement of the Schwann cell nuclei. HE; X 420.
small intestine, large intestine, bronchi, and even in the arrectores pilorum in the skin. The abnormality was most pronounced in the muscle coat of the duodenum and jejunum, where some nuclei were exceptionally large and mis-shapen while many others were normal. The muscularis mucosae was similarly affected. Elsewhere in the alimentary tract, the picture was more like that of ordinary hypertrophy, in that there was a mild uniform enlargement of nuclei without alteration in their shape. Bizarre enlarged nuclei also occurred in the tunica media of small arteries and veins in many different organs, but the aorta and other major vessels were scarcely affected. Karyomegaly in epithelial cells was especially conspicuous in the kidneys (Fig. 2), where examples were numerous in the convoluted tubules and rather less so in the collecting tubules. In some groups of tubules all the cells were affected, while in others the cells were entirely normal. The nuclei, which measured up to 20 /Am in diameter, were moderately pleomorphic and varied greatly in their staining characters. Some of the affected cells also had an excessive amount of cytoplasm. Extremely few enlarged nuclei occurred in the glomeruli. Examples of karyomegaly were sparse in other epithelial tissues. A few occurred in solid glandular organs such as the thyroid, the exocrine pan-
30 4 . G. Sclare
Kidney. Karyomegaly and cytomegaly
Myocardium. Two huge nuclei
the renal tubules. HE; X
a narrow band of fibrous tissue. HE; X
A Case of Unexplained Karyomegaly . 3 0 5
creas, the islets of Langerhans and the lacrimal glands. In the parenchymal epithelium of the liver, where some variation in nuclear size is usual, extremely few nuclei were considered to be beyond the normal limits, and the same was true of the adrenal cortex and medulla. There was little or no karyomegaly in the epidermis, the respiratory and alimentary epithelium, and the epithelial lining of the intra-hepatic bile ducts and renal pelvis. Other tissues. Karyomegaly also occurred in the fibrous capsule and trabeculae of the spleen, and in other septa and connective tissues, most commonly in close relation to small blood vessels (Fig. 3). Vascular endothelium was affected in some degree. A few examples were also found among the cells which obliterated the pulmonary alveoli. Isolated enlarged nuclei, without stainable cytoplasm, were in some instances so situated that the nature of the affected cell could not be determined. Such sites were the intestinal lamina propria and the pulp of the spleen. The pituitary, the testis and the bladder were not examined histologically.
Discussion The widespread enlargement of nuclei, occurring in nerves, smooth muscle and epithelium, remains unexplained. Detailed enquiry into the patient's medical, occupational and social history revealed no causative factor, and since it was identified in biopsies of alimentary tract three years and one-and-a-half years before death it was evidently not merely a terminal phenomenon. Karyomegaly is known to occur after radiotherapy and after the administration of a variety of therapeutic and other substances which inhibit mitosis. Such changes when due to radiotherapy affect epithelial cells and fibroblasts in particular, and are confined to the irradiated site. Carbimazole and related anti-thyroid substances induce karyomegaly only in the thyroid epithelium. A case has been reported in which karyomegaly confined to the distal nephron was attributed to lithium (Lindop and Padfield, 1975). Of the therapeutic agents which produce more widespread karyomegaly, the best documented is busulphan ("Myleran"), used in the treatment of chronic myeloid leukaemia; karyomegaly occurs especially in the alveolar epithelium of the lungs (Heard and Cooke, 1968), but also occurs in a wide variety of other tissues, even including Schwann cells (Feingold and Koss, I969).
306 . G. Sclare
Extreme dysplasia of the renal epithelium and carcinoma of the liver have been described in a young woman who had no history of medication, poisoning or any other factor which could have inhibited mitotic activity (Burry, 1974). The development of malignancy in the liver was thought to represent a consequence of the abnormalities in the liver nuclei. The present case is another example in which no causative agent was known, with a much more widespread distribution of the abnormal nuclei but without the development of malignancy. If one were to postulate the effects of an unknown mitotic inhibitor, then an unexpected feature is the absence of karyomegaly in the hepatic nuclei, since experimentally the administration of aflatoxin (Deo et aI., 1970) and pyrrolizidine alkaloids (Peterson et aI., 1972; Van der Watt, 1972) conspicuously affects the hepatic as well as the renal epithelium. However, it may be noted that in several recorded cases of karyomegaly induced by busulphan, there has been little or no involvement of the liver nuclei. One such case, an infant whose mother had been treated with busulphan during pregnancy (Diamond et aI., 1960), has close similarities to the present case in that widespread karyomegaly conspicuously affected nerves, also affected smooth muscle and many other tissues but scarcely affected the liver.
References Burry, A. F.: Extreme dysplasia in renal epithelium of a young woman dying from hepatocarcinoma.]. Path. IIJ, 147-I50 (1974) Deo, M. G., Dayal, Y., and Ramalingaswami, V.: Aflatoxins and liver injury in the rhesus monkey. J. Path. 101,47-5 6 (1970) Diamond, I., Anderson, M. M., and McCreadie, S. R.: Transplacental transmission of busulphan (Myleran) in a mother with leukemia. Pediatrics 25, 85-90 (1960) Feingold, M. 1., and Koss, 1. G.: Effects of long-term administration of busulphan. Arch. intern. Med. 124,66-71 (1969) Heard, B. E., and Cooke, R. A.: Busulphan lung. Thorax 2J, 187-193 (1968) Lindop, G. B. M., and Padfield, P. 1.: The renal pathology in a case of lithium-induced diabetes insipidus. ]. din. Path. 28, 472-475 (1975) Peterson, J. E., Samuel, A., and ]ago, M. V.: Pathological effects of dehydroheliotridine, a metabolite of heliotridine-based pyrrolizidine alkaloids, in the young rat. ]. Path. 107, 175- 189 (197 2 )
Van der Watt, J. ]., Purchase, 1. F. H ., and Tustin, R. C.: The chronic toxicity of retrorsine, a pyrrolizidine alkaloid, in vervet monkeys. J. Path. 107, 279-287 (1972) G. Sclare, M.D., F. R. C. Path., Department of Pathology, Bangour Hospital, West Lothian, U.K.