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Diffuse angiomatosis with hypersplenism
Diffuse
Angiomatosis
with Hypersplenism*
Splenectomy Followed
by Polycythemia
.JACK PINKHAS, M.D., MEIR DJALDETTI, s~.D., ANDRE DE VRIES, JI.D., PH.D., DORIS
SAFRA,
M.D.
and LEAH
DOLLBERG,
M.D.
Petah Tikca, Israel A patient with diffuse hemangiomatosis involving the spleen, liver, skin and conj unctivas, with pancytopenia due to hypersplenism, is described. Additional abnormalities were a mitral valve lesion, localized electroencephalographic disturbance and typical abortive coloboma of the retina. Splenectomy resulted in normalization of blood cell counts followed by polycythemia. The etiology of the combined congenital anomalies and of the postsplenectomy polycythemia is discussed. respond to iron and vitamin treatment. More recently the patient complained of shortness of breath on effort. The family history was noncontributory. Physical examination on the present admission revealed a well nourished, pale. slightly dyspneic man with jaundice of moderate degree, and a normal temperature. Slight engorgement of the jugular veins was seen. His pulse was 88 per minute and re,gular. his blood pressure 110/60 mm. Hg. ‘4 grade 2 presystolic murmur and an opening snap were heard over the apex of the heart. The second pulmonary sound was accentuated. Moist rales \vere heard over the bases of the lungs. The liver was palpated 9 cm. below the costal margin and the spleen reached the left iliac crest; both were firm and nontender. No enlarged lymph glands were palpated. There was pitting edema of the legs. Urine examination revealed bilirubin and increased amounts of urobilinogen. The hemoglobin concentration was 4.4 gm. per 100 ml., red blood cell count 1,400,OOO per cu. mm., white blood cell count 2,300 per cu. mm. with 57 per cent polymorphonuclear neutrophils, 5 per cent band forms, 1 per cent eosinophils and 37 per cent lymphocytes. The platelet count was 100,000 per cu. mm. and the reticulocyte count 4 per cent. The peripheral blood film showed anisocytosis, a few macrocytes and spherocytes. A sternal bone marrow aspirate showed erythronormoblastic hyperplasia and hyperplasia of the white blood cell series. A fair number of megakaryocytes with normal granulation was seen. Gaucher cells were not found. Blood urea, glucose and electrolyte levels were within normal limits. The serum total bilirubin was 2.2 mg. per 100 ml., of 12hich direct-reacting was 2.0 mg. per 100 ml. Cephalin flocculation and thymol
uLrrPr2 vascular malformations causing so-called multiple hemangiomatous syndromes [7], involving various organs, are well known. Hypersplenism due to angioma of the spleen has been described [Z-6], but its occurrence in multiple angiomatous organ involvement seems to be rare [4]. We recently observed a patient with hypersplenism in whom multiple diffuse angiomatosis was demonstrated in the spleen, liver, skin and conjunctivas. This patient is remarkable in two additional aspects: he had an additional congenital anomaly, coloboma of the retina and polycythemia following splenectomy.
M
CASE REPORT
A forty-three year old Polish-born Jewish male office worker (J.F.), the father of two healthy children, was admitted to the hospital on September 22, 1957, because of jaundice which appeared after a short period of malaise and slight fever. His mother had had infectious hepatitis three months previously. The patient informed us that at the age of six months his spleen and liver were found to be enlarged. i\t age fourtern he was admitted to another hospital; that time his liver was palpated 4 cm. below the costal and his spleen reached the level of the margin, umbilicus. Hemoglobin, red blood cell and white blood cell counts were within normal limits; the platelet count was 80,000 per cu. mm. Bone marrow examination was not performed, but the family was told that he suffered from Gaucher’s disease. As the years progressed an anemia developed which did not
* From the Department of Medicine D, The Department of Ophthalmology and The Department of Pathology, Tel-Aviv University Medical School, Beilinson Hospital, Petah Tikva, Israel. Requests for reprints should be addressed to Jack Pinkhas, M.D., Beilinson Hospital, P.O. Box 85, Pctah Tikva, Israel. Manuscript received December 11, 1967. VOL.
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796
Diffuse
Angiomatosis
with
FIG. 1. The bulbar conjunctiva, revealing irregularities in the caliber of blood vessels, dilatations and tortuosities of the veins, saccular and fusiform dilatations of the capillaries (microaneurysms) and sludging.
FIG. 2. Fundus photography, right eye. A large sector of choroidal thinning in the lower fundus, with the apex near the lower margin of the optic disc and extending to the fundus periphery. In the lower part of this area bone corpuscle-like pigmentations are seen.
Hypersplenism--Pinkhas
et al.
turbidity tests were strongly positive, the Weltman coagulation band was 8, alkaline phosphatase 8.8 Bodansky units, serum total protein 6.1 gm. per 100 ml., albumin 4.4 gm. per 100 ml., globulin 1.7 gm. per 100 ml., cholesterol 170 mg. per 100 ml., prothrombin (one-stage method) less than 10 per cent and serum iron 150 pg. per 100 ml. The Wassermann reaction and Coombs’ tests were negative. Blood cultures were sterile. Fecal stercobilinogen excretion in twenty-four hours was 984 mg. Infectious hepatitis, inactive rheumatic heart disease with mitral stenosis, congestive heart failure, hepatosplenomegaly of undefined nature, hypersplenism and a hemolytic process possibly related to the infectious hepatitis were diagnosed. Treatment consisted of the oral administration of digitalis, mercurial diuretics and vitamin K and the transfusion of 7 pints of packed red blood cells. The patient’s condition improved rapidly, the congestion of the jugular veins, the rales over the lungs and the pitting edema of the legs subsided, and the hemoglobin concentration rose to 10 gm. per 100 ml. The jaundice disappeared within fourteen days and the serum bilirubin became normal. The flocculation tests remained positive, the prothrombin concentration rose to 25 per cent, the white blood cell count was 2,900 per cu. mm. and the platelet count 90,000 per cu. mm. The patient opposed further investigation and was discharged at his own insistence. He did not reappear for six years. He was readmitted to our department on December 4, 1963, because of progressive weakness which had started a few months prior to hospitalization and compelled him to stop working. On examination he was thin and pale, but not icteric. The jugular veins were slightly engorged, the heart findings were as before. The liver was palpated 9 cm. below the costal margin and the spleen filled the entire left side of the abdomen, both were firm and nontender. There were no signs of ascites. Slight pitting edema of the legs was present. A roentgenogram of the chest was consistent with mitral stenosis. On biomicroscopic examination the bulbar conjunctivas showed irregularities in the caliber of the veins with dilatations and tortuosities, a large number of capillary saccular and fusiform angiectasies-microaneurysms around the limbus, and nludging of the blood columns (Fig. 1). The discs, maculas and blood vessels in the fundi were normal in appearance. In the lower part of both fundi was a large sector of choroidal thinning with its apex near the lower margin of the disc and extending to the periphery of the fundus. In the lower part of the sector near the periphery were a few bone-corpuscle like pigmentations, partly above and around the branches of the veins (Fig. 2). These findings were symmetrical in both eyegrounds and thought to be consistent with a typical abortive (minimal) coloboma. The electroretinogram was subnormal, central vision was 5/5 in both eyes, visual fields (Goldmann’s perimeter) were complete and color vision was AMERICAN
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IMuse
Angiornatosis
with
normal. Otolaryngologic and neurologic examinations 12’ere \Vithin normal limits. Examination of the urine disclosed traces of protein; an aminoacidogram was normal. The erythrocyte sedimentation rate (Westergren) was 22 mm. in rhr first hour. 42 mm. in the second. The hemoglobin concentration \
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cells and increased numbers of capillarich: as well as hemosiderin deposits and slight inflammatory infiltration. Physical, ophthalmologic and laboratory examinations performed on the patient’s children, four and sixteen years of age, revealed no abnormalities. In the view of the eye and skin findings the possibility of a diffuse vascular anomaly> multiple hrmangiomatosis involving the spleen and liver, was entertained. Splenectomy was decided upon because of the abdominal discomfort caused by the large spleen, and also the severe anemia. On January 9. 1964, after the patient had received 5 units of packed red cells, laparotomy was performed; 3 units of packed red cells were given during operation. Thr spleen was reduced to haif its size after ligation of the splenic artery. The liver was enlarged and had a smooth surface. A liver biopsy specimen was taken and splenectomy performed. The spleen was dark red and firm and weighed 3,900 gm. Its surface and cut surface showed numerous discrete dark red nodules, a frw millimeters in diameter. A few larger paler nodules and a large round hemorrhagic area were seen. Microscopic examination of the spleen revealed congestion, reticular fibrosis of the pulp and recent as well as older peritrabecular hemorrhages (GamnaGandy bodies). The nodules proved to be areas of cavernous hemangiomas (Fig. 3) and areas rich in collagenous connective tissue containing vascular lumens, some of them compressed to slits (Fig. 41, as well as areas of proliferating endothelial cells in which only a few vascular lumens could be distinguished (Fig. 5). These angiomatous changes sometimes merged, and it seemed as if therv lvere transformations from one form into another. i.e., from dense endothelial proliferation to fibrotic areas without or with only a few vessels. It was often difllcult to determine whether the findings in the red pulp represented only chronic congestion or angiomatous changes. The surgical liver biopsy specimen revealed an abnormal structure. The liver lobuli were of various size; the central vein could not be distinguished. Proliferation of connective tissue was seen. sometimes in the form of bands. In some of these bands, as well as in some portal spaces, groups of fairly large vascular channels were found (Fig. 6j. Some small vascular lumens lined by swollen endothelial cells were seen. The postoperative course was uneventful. Within ten days after the operation the hemoglobin concentration rose 10 12.0 gm. per 100 ml., the white blood cell count to 20,000 per cu. mm. and the platelet count to 475,000 per cu. mm. Five weeks after splenectomy the hemoglobin level was 10.1 gm. per 100 ml., the red blood cell count 3,600,OOO per cu. mm., hematocrit 30 per cent, reticulocyte count 1 pel cent and platelet count 346,000 per cu. mm. The red blood cell half life estimated by Cr51-labeling was twenty-five days. The total blood volume was 81 ml. per kg. body weight, as determined by the red blood
Diffuse Angiomatosis
798
with Hypersplenism-Pinkhas
el al.
4
3 FIG.
3.
Spleen.
Area of cavernous
hemangioma.
Hematoxylin
FIG. 4. Spleen. Area rich in collagenous connective eosin stain, original magnification X 120.
tissue with few compressed
cell isotope dilution technic; the red blood cell mass was 28 ml. per kg., the plasma volume 53 ml. per kg. The patient was reexamined in the Hematology Clinic on December 9, 1964, i.e., eleven months after splenectomy. He felt well and had no signs of heart failure. The findings over the heart area were the same as those before the operation. The liver was palpated 5 cm. below the costal margin; there were no signs of ascites. The hemoglobin concentration was 16.2 gm. per 100 ml. ; the red blood cell count 5,500,000 per cu. mm., hematocrit 53 per cent, white blood cell count 8,500 per cu. mm. with 65 per cent polymorphonuclear neutrophils, 3 per cent band forms, 5 per cent monocytes, and 27 per cent lymphocytes. The platelet count was 210,000 per cu. mm. The peripheral blood film showed anisocytosis, target cells, Howell-Jolly bodies, a few macrocytes and spherocytes. The erythrocyte sedimentation rate (Westergren) was 3 mm. in the first hour and 6 mm. in the second. The serum iron was 86 pg. per 100 ml. The total blood volume was 85 ml. per kg. body weight,
of angiomatous
and eosin stain, original
magnification
vascular channels.
X 120.
Ilematoxylin
and
the total red cell mass 30 ml. per kg. and the plasma volume 55 ml. per kg. Ferrokinetic studies showed a plasma clearance with a half time of forty minutes, instead of the normal range of 60 to 120 minutes; 90 per cent of the radioactive iron appeared in the circulating red blood cells after seven days. Treatment with digitalis and thiazide diuretics was continued. On June 6, 1966, the patient complained of excruciating headache. The striking finding was his plethoric face with marked redness of the skin and mucosa. The liver was palpated 6 cm. below the costal margin. The hemoglobin level had risen to 18 gm. per 100 ml., the red blood cell count to 6,300,OOO per cu. mm. and the hematocrit to 59 per cent. The reticulocyte count was 0.7 per cent white blood cell count 8,700 per cu. mm. with 60 per cent polymorphonuclear neutrophils, 2 per cent band forms, 32 per cent lymphocytes, 6 per cent monocytes; the platelet count was 243,000 per cu. mm. The erythrocyte sedimentation rate (Westergren) was 2 mm. in the first hour and 4 mm. in the second. The total blood
FIG. 5.
Spleen. Active proliferation
FIG. 6. X 120.
Liver. Group of large vascular channels in a portal space. Hematoxylin
tissue. Hematoxylin
and eosin stain, original magnification
AMERICAN
X 456.
and eosin stain, original magnification
JOURNAL
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I >ifFuse Angiomatosis
with
volume gas 94.2 ml. per kg. body weight,
the total re(l wII mass 37.9 ml. per kg. and the plasma volume 50.i ml. per kg. Oxygen saturation of the arterial blood \vas 06 per cent. ‘I‘he intravenous pyelogram wa:, \virllin normal limits. Erythropoietin in blood and ur~nr~ t.stimated by thr method of Plzak et al. [7], MXS no1 increased. FoIlowing the withdrawal of 500 ml. of I)lood. the headache diminished. On December 1: 1966, following repeated phlebotomb-. the patient felt well, his hemoglobin concentration was 14.8 gm. per 100 ml., red blood cell count 4,800.OOO per cu. mm., hematocrit 49 per cent, reticulocyte count 0.7 per cent and white blood cell count 8,000 per cu. mm. with a normal differential. The platelet count was 179,000 per cu. mm. The sedimentation rate (Westergren) was 13 mm. in the first hour. 2 1 mm. in the second ; serum iron was 90 pg. per
100 ml. No occult blood was found in the feces. The feral stercohilinogen excretion was 215 mg. per twenty-four hours. the half life of CrVagged patient’s red Mood cells Lvas twenty-five days. COMMENTS
Angiomatous organ changes have been dehcmangio-endohemangioma, scribed as thelionla, hemangioblastoma and vascular hamartoma [ 7,8--70 ] ; the term hamartoma, refers to the designation by Albrecht of tumorlike lnalformations constituting an aberrant mixture of normal components of an organ [ 7 71, and more recently by Sweet and Warren [ 721 of a tumor composed of tissues in excess beyond normal requirements, possessing a limited capacity for aberrant growth. When affecting more than one organ, the abnormality is described as the multiple hemangiomatosis syndronle (I] including the Sturge-Weber and von Hippel-Lindau syndromes and Rendu-Osler’s disease. According to Willis [I] these vascular changes are generally benign, although malignant transformation may occur [8,73]; their multifocal development appears to have given rise to an exaggerated impression of the frequency of malignancy. Splenic hemangioma is not uncommon and has been reported as a single abnormality [4,8,!/,13-77) or in association with hemangiomas in other organs, such as the liver [70], skin, lung and stomach [78]. In many cases of splenic hemangioma the tumor was asymptomatic and discovered incidentally at autopsy or as an unsuspected finding during splenectomy performed for various indications [4,5,79]. The clinical manifestations of splenic hemangioma are various: fearer and weight loss, abdominal VOL.
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distention, pain in the left hypochrondriunr sometimes accompanied by gastrointestinal disturbances such as anorexia, dysphagia, ronstipation or diarrhea [ d>5,/7], and s~~~JI~ltm~‘o~ls [!I, 75,20,2/l or traumatic i&2/] splrnir rupture with intraperitoneal bleeding. The maxirnul!l weight of a spleen containing heltlan+onla hitherto reported was 13,130 ~III. j Ifi]. The youngest patient in whom splen;c lic~~~an~iorria was found was four lllonths old [h’]. In our patient the angiomatous in\olvernent of the spleen was associated with an idcntical vascular anomaly in the liver and the skin and with vascular changes in the ronjuncti\.as. Since the hepatosplenomegaly was discovered at the age of six months, a congenital \.ascular anomaly ma)- be presumed. The irregularities in the conjunctival vessels, i.e., the tortuosities and aneurysms are silnilar to those found in Rendu-Osler’s disease [22] and ataxiateleangiectasia [23,24], both classifiable with the group of multiple hemangiomatous syndromes. The conjunctival findings, however, arc not specific for such congenital anomalies and may be found in various other conditions such as sickle cell disease [25], diabetes [Zri] and in apparently normal subjects [27]. The absence of these conditions and the association of the vascular conjunctival changes with the diffuse angiomatosis in other organs makes it highly probable that in this patient they were all of the same nature. Whether the electroencephalographic finding is due to a vascular anomaly is speculative; brain involvement in diffuse cavernous hemangiomatosis has been described [28]. The question may also be raised whether the heart abnormality in this patient with physical and roentgenographic findings typical of mitral stenosis may be related to the angiomatous process. The patient with diffuse hernangionlatosis described by Wood et al. [28J had an angioma in the left auricular appendage, bllt no signs of any valvular lesion. In a few documented cases /.i- (i,17,29] hemangioma of the spleen has led to hypersplenism, i.e., pancytopenia associated with splenic enlargement and disappearing following splenectomy. To our knowledge, in only one of the reports on hypersplenism associated with splenic hemangioma, that of a thirty-nine year old woman who had additional hemangiomas in the liver [4], was angiomatous involvement of other organs mentioned. In our patient with
800
Diffuse Angiomatosis
with Hypersplenism-Pinkhas
diffuse multiple organ angiomatosis it is reasonable to assume that the pancytopenia, which disappeared following splenectomy, was causally related to the splenic vascular hamartoma since no other abnormality in the spleen was found. The mechanism by which the splenic process caused the anemia has not been elucidated. A red blood cell life span determination was not made prior to splenectomy and thus hemolysis was not proved. Yet the spherocytosis, reticulocytosis and markedly increased fecal stercobilinogen excretion indicate a hemolytic process, possibly aggravated by the viral hepatitis on the first admission. The pathogenesis of this hemolytic process is not known. No anti-red demonstrated. blood cell antibodies were Hemolysis of the microangiopathic type seems improbable in view of the normal red blood cell life span after splenectomy, in the presence in other organs. of multiple angiomatosis Thrombocytopenia associated with hemangioma is well known and the platelet count may rise and even return to normal following radiation treatment or excision of the tumor [30]. The moderate thrombocytopenia in our patient prior to splenectomy may have been due to platelet pooling in the large splenic vascular bed [31]. after The development of polycythemia splenectomy appears to be rare, and according to Crosby [32], has been described only in hereditary spherocytosis [33] in which the spherocytes may be functionally deficient as to oxygen release [34]. No evidence for a primary red cell disturbance in our patient was obtained; an oxygen dissociation curve, however, was not obtained. Polycythemia has been described in Rendu-Osler-Weber’s disease, one of the multiple hemangiomatosis syndromes but, to our knowledge, only in association with pulmonary arteriovenous fistula [35-381. The patient described herein had a normal arterial oxygen saturation and no roentgenologic evidence of arteriovenous fistula in the lungs. Pulmonary angiography, however, was not carried out. In view of the known association of polycythemia with cerebellar hemangioblastoma [39,&l, it is an attractive hypothesis to relate the polycythemia in our patient to an angiomatous process in the brain possibly evidenced by the electroencephalographic abnormality. Another possibility is that the polycythemia is related to angiomatosis of the kidney, which, however, was not documented in our patient. Lack of increase
et al.
of urinary erythropoietin does not exclude such a mechanism. To our knowledge, polycythemia associated with hemangioma of the kidney has not been reported. If the patient’s polycythemia was at all related to an angiomatous process in the brain, kidney or other organ, it may be assumed that the splenic process had prevented its development. Thus, although the tendency to develop polycythemia may have been present for a long time it did not become manifest prior to splenectomy. of an additional congenital The presence malformation, typical abortive coloboma of the retina, in this patient with diffuse angiomatosis is of interest because of a possible connection between the two anomalies. Coloboma is due to interference with the normal closure of the fetal cleft in the embryonic secondary optic vesicle, normally occurring in the fifth to seventh week of gestation [41]. Its cause may be genetic with irregular dominant heredity, or environmental acting in early embryonic life. Association of coloboma with other congenital deformities apart from the eye is known but joint occurrence with vascular hamartoma has to our knowledge not been reported. Still, the timing of the development of the blood vessels at the third to fourth week of embryonal life [42] prompts consideration of a possible joint etiology. Whereas vascular anomalies are of mesenchymal origin, coloboma is generally considered to be due to a disturbance in the ectoderm, the primary aberration lying in the epiblast of the optic cup [41]. A mesoblastic theory, ascribing formation of coloboma to overdevelopment of mesoblastic tissue preventing the lips of the tissue from closing, had been proposed by von Hippel early in this century [43], and more recently a failure in the development of the blood vessels of the mesoblast surrounding the secondary optic vesicle was held responsible by Collins [&I. Whether the coloboma was due to a disturbance in the epiblast or in the mesoblast, an environmental factor active early in pregnancy may have caused both anomalies, angiomatosis and coloboma. Intensive questioning of the patient’s mother did not bring out any febrile disease or ingestion of a specific drug during pregnancy. There was no evidence for a genetic cause ; no hemangiomas, colobomas or other malformations were found in the patient’s family as far as they could be examined. Chromosornc analysis in the patient was normal. AMERICAN
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Diffuse
Angiornatosis
with
Hyperspleniwn--~--Pinkha.r
Pathology of Tumors, p. 702. London, 1’148. Rutterworth 8 Co. .I. Hypersplrnisln associated with 2. ~IIW.I3AM:K, h;llllartoina of thr spleen. SC/~mrd. scandinao., 146: 2-6, 1953. .>. ~~CHKlJVtK, 14. and VBKDONK, G. J. Hamartoma of tllr spl~cn with inhibition of thr bone marrow. :lcta med. scandimw., 158: 235, 1957. 4. M-\(:LF.~N, N., MACPHERSON, A. 1. and ROBB, P. M. I)iffuse hemangiomata of the spleen. J. Roy. Coil. .Sii,,<~rvz.~, 3: 218, 1958. 5. I~IT~NI,E. A. The clinical course of splenic hemangiollla. Arch. Surg., 83: 681, 1961. o ~JARDMEIER, T’H. Hypersplenismus bei einem Hamartom der Milz (Splenom). Schweiz. med. Wchnschr., 07: 1270, 1962. 7. PI./.u, L. F., FRIED, \V., JACOBSON, L. 0. and BETHARD, I\‘. F. Demonstration of stimulation of vrythropoiesis by plasma from anemic rats using Fc59. J. Lab. & Clin. Med., 46: 671, 1955. 8. PIKES, R. and RABINOWITCH, J. Hemangioma of the spleen. Arch. Path., 33: 487, 1942. ‘I S I ECVART: E. H., JK. Cavernous hemangioma of the spleen. Am. J. Surg., 71: 536, 1946. 10. '~‘ASKEK, K. G. Hemangioma-endothelioma of the spleen and liver. J. Clin. Path., 11 : 142, 1958. 11, AI.BR~.CH r. Ucber Hamartoma. Verhandl. deutsch. path. Gesellsrh., 7: 153, 1904. 12. SM~I~.ET,I(. H. and \TARREN, S. Hamartoma of the spleen : report of a case. Xeuew England J. Med., 226: 7.57,1942. 13. DOWD, C:. N. Cavernous angioma of the spleen. :11~n.Surg., 62: 177, 1915. 14. AK(:.A~COYUNL.U, I. Capillary and cavernous hemancionla of the spleen (trlnngiolna). Am. J. Surg., 41: 519, 1938. 15. C‘OTt. F. L. and FORSEE, J. H. Cavernous hemanyiollla of the spleen. Surgery. 8: 639, 1940. 16. I IOIXE, G. B. and WILSON, D. A. Benign cavernous hc~~llan+oma of the spleen. Surgrry, 21 : 343, 1947. 17. HENJAMIK, B. I., MOHL~R, D. N. and SANDUSKY, 11’. 1~. Hemangioma of the spleen. Arch. Znt. Med., 115: 280, 1965. 18. I’HL.,II.E. Gber Angioma und sarkomatdse Angiome cJcr Milz. Arch. path. iinat., 178: 296, 1904. 1’1. Bosrrc, \\‘. I,. Spleen tumors: primary neoplasms. /lm. J. Path., 21: 1243, 1945. 20. I~AINL.S, C. E. and MCII.LROY, P. T. Spontaneous rupture of hemangioma. J.A.M.A., 100: 1862, 1933. 21. INGIIAM, 'r. R. and THOMSON, J. A. Apparent spontaneous rupture of spleen from hemangioma. .\‘or/hwst Med., 59: 914, 1960. 22. \VINTROBE, M. M. Clinical Hematology, 4th ed., p. 1185. Philadelphia, 1956. Lea & Febiger. 27. BOIXR, E. and SEDWICK, R. P. Ataxia-telangiectasia. Prdmtrics, 21 : 526, 1958. D. D. Ataxia-telangiectasia. Henry 34. \ZTO~CESTER, ITwd Hosp. .\I. Bull., 14: 429, 1966. 21. FUN~HASIII, I., FINK, .A., ROBINSON, M. and WAT1
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26.
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SON, .I. Conjunctiva in sickle-celL d~sr~~rv.Anr. .J. O,bhth., 57: 713, 1964. DITZEL, J., \VHI.TE, P. and DUCKERS, .I. (:hangrs in the pattern of the smaller blood vessels in the bulbar conjunctiva in children of diabetic mothers. Diabetes, 3: 99, 1954. DUKE-ELDER, S. I. Diseases of the corljunctiva and associated diseasrs of the corncal cpithelium. Diseases of the outer eye. In: System of Ophthalmology. vol. 8, p. 28. London, 19h5. Henry Kimpton. WOOD, FT. \V., WHI.I.I<, R. J. and KEKNU~IAN.I. \I’. Cavernous hemangiomatosis involving the brain, spinal cord, heart, skin and kidney: report of case. Pm. Staff Meet. Mayo Clin., 32: 249, 1957. FLOREN.I.IN, P., CHALNOT, P. and MICI~N, 1~. Diffuse angiomatosis of spleen with pancytopenia, favorable result of splenectomy. F&v. Wrfq Path., 24: 501, 1955. DARGEON, 1-I. W., ADIAO, A. C. and P.ACK, G. 'I'. IIcmangioma with thrombocytopcnia. J. Prdiat.. 54: 285, 1959. ASTEZ, R. H. Pooling of platelets in the spleen: role in the pathogenesis of “hypersplenic” thrornbocytopenia. J. Clin. Iwest., 45: 645. 1966. CROSSU, W. H. Hyposplenism: an inquiry into normal functions of the spleen. Ann. Rw. .&fed.. 14: 349, 1963. MEULENGRACH.~, E. Chronic hereditary hrinolytic jaundice. In: Handbook of Hematology, vol. 3, p. 2283. Edited by Downey, H. New York, 1938. Paul B. Hoeber, Inc. VALTIS, D. J. and BAIKIE, A. G. The influence of redcell thickness on oxygen dissociation rurve of blood. Brit. J. Haemat., 1: 146, 1955. SAUNDERS, W. H. Hereditary hemorrhagic telangiectasia. Arch. Otolaryng,, 76: 245, 1962. WEISS, E. and GASUL, B. M. Pulmonary arteriovenous fistula and telangiectasia. Ann. Int. Jled., 41 : 989, 1954. BRINK, .A. J. Telangiectasis of the lungs, with two case reports of hereditary hemorrhagic telangiectasis with cyanosis. Quart. J. Med., 19: 239, 1950. HALES, M. R. Multiple small arteriovenous fistulae of the lungs. Am. J. Path., 32: 927, 1956. CARPENTER, G., SCHWARTZ, I-I. G. and \VAL.~ER, A. E. Neurogenic polycythemia. Ann. I&. .\fed., 19: 470,1943. BRODY, J. I. and RODRIGUEZ, F. Cerebellar hemangioblastoma and polycythemia (erythrocythrmia ). Am. J. M. SC., 242: 579, 1961. DUKE-ELDER, S. and COOK, CH. System of Ophthalmology, vol. 3, p. 38. I. Embryology. Normal and Abnormal Development. London, 1963. Henry Kimpton. PA.I.TEN, B. M. Human Embryology, p. 776. Philadelphia, 1946. Blakiston Co. VON HIPPEL, E. Embryologische Untersuchungen iiber die Entstehungsweise der typischen angeborenen Spaltbildungen (Coloboma) des Aiigapfels. Graefes Arch. Ophth., 55: 507, 1903. COLLINS, P. R. S. Cited by Duke-Elder, S. and Cook, <:h. [17].
Angiomatosis
with Hypersplenism*
Splenectomy Followed
by Polycythemia
.JACK PINKHAS, M.D., MEIR DJALDETTI, s~.D., ANDRE DE VRIES, JI.D., PH.D., DORIS
SAFRA,
M.D.
and LEAH
DOLLBERG,
M.D.
Petah Tikca, Israel A patient with diffuse hemangiomatosis involving the spleen, liver, skin and conj unctivas, with pancytopenia due to hypersplenism, is described. Additional abnormalities were a mitral valve lesion, localized electroencephalographic disturbance and typical abortive coloboma of the retina. Splenectomy resulted in normalization of blood cell counts followed by polycythemia. The etiology of the combined congenital anomalies and of the postsplenectomy polycythemia is discussed. respond to iron and vitamin treatment. More recently the patient complained of shortness of breath on effort. The family history was noncontributory. Physical examination on the present admission revealed a well nourished, pale. slightly dyspneic man with jaundice of moderate degree, and a normal temperature. Slight engorgement of the jugular veins was seen. His pulse was 88 per minute and re,gular. his blood pressure 110/60 mm. Hg. ‘4 grade 2 presystolic murmur and an opening snap were heard over the apex of the heart. The second pulmonary sound was accentuated. Moist rales \vere heard over the bases of the lungs. The liver was palpated 9 cm. below the costal margin and the spleen reached the left iliac crest; both were firm and nontender. No enlarged lymph glands were palpated. There was pitting edema of the legs. Urine examination revealed bilirubin and increased amounts of urobilinogen. The hemoglobin concentration was 4.4 gm. per 100 ml., red blood cell count 1,400,OOO per cu. mm., white blood cell count 2,300 per cu. mm. with 57 per cent polymorphonuclear neutrophils, 5 per cent band forms, 1 per cent eosinophils and 37 per cent lymphocytes. The platelet count was 100,000 per cu. mm. and the reticulocyte count 4 per cent. The peripheral blood film showed anisocytosis, a few macrocytes and spherocytes. A sternal bone marrow aspirate showed erythronormoblastic hyperplasia and hyperplasia of the white blood cell series. A fair number of megakaryocytes with normal granulation was seen. Gaucher cells were not found. Blood urea, glucose and electrolyte levels were within normal limits. The serum total bilirubin was 2.2 mg. per 100 ml., of 12hich direct-reacting was 2.0 mg. per 100 ml. Cephalin flocculation and thymol
uLrrPr2 vascular malformations causing so-called multiple hemangiomatous syndromes [7], involving various organs, are well known. Hypersplenism due to angioma of the spleen has been described [Z-6], but its occurrence in multiple angiomatous organ involvement seems to be rare [4]. We recently observed a patient with hypersplenism in whom multiple diffuse angiomatosis was demonstrated in the spleen, liver, skin and conjunctivas. This patient is remarkable in two additional aspects: he had an additional congenital anomaly, coloboma of the retina and polycythemia following splenectomy.
M
CASE REPORT
A forty-three year old Polish-born Jewish male office worker (J.F.), the father of two healthy children, was admitted to the hospital on September 22, 1957, because of jaundice which appeared after a short period of malaise and slight fever. His mother had had infectious hepatitis three months previously. The patient informed us that at the age of six months his spleen and liver were found to be enlarged. i\t age fourtern he was admitted to another hospital; that time his liver was palpated 4 cm. below the costal and his spleen reached the level of the margin, umbilicus. Hemoglobin, red blood cell and white blood cell counts were within normal limits; the platelet count was 80,000 per cu. mm. Bone marrow examination was not performed, but the family was told that he suffered from Gaucher’s disease. As the years progressed an anemia developed which did not
* From the Department of Medicine D, The Department of Ophthalmology and The Department of Pathology, Tel-Aviv University Medical School, Beilinson Hospital, Petah Tikva, Israel. Requests for reprints should be addressed to Jack Pinkhas, M.D., Beilinson Hospital, P.O. Box 85, Pctah Tikva, Israel. Manuscript received December 11, 1967. VOL.
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Diffuse
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FIG. 1. The bulbar conjunctiva, revealing irregularities in the caliber of blood vessels, dilatations and tortuosities of the veins, saccular and fusiform dilatations of the capillaries (microaneurysms) and sludging.
FIG. 2. Fundus photography, right eye. A large sector of choroidal thinning in the lower fundus, with the apex near the lower margin of the optic disc and extending to the fundus periphery. In the lower part of this area bone corpuscle-like pigmentations are seen.
Hypersplenism--Pinkhas
et al.
turbidity tests were strongly positive, the Weltman coagulation band was 8, alkaline phosphatase 8.8 Bodansky units, serum total protein 6.1 gm. per 100 ml., albumin 4.4 gm. per 100 ml., globulin 1.7 gm. per 100 ml., cholesterol 170 mg. per 100 ml., prothrombin (one-stage method) less than 10 per cent and serum iron 150 pg. per 100 ml. The Wassermann reaction and Coombs’ tests were negative. Blood cultures were sterile. Fecal stercobilinogen excretion in twenty-four hours was 984 mg. Infectious hepatitis, inactive rheumatic heart disease with mitral stenosis, congestive heart failure, hepatosplenomegaly of undefined nature, hypersplenism and a hemolytic process possibly related to the infectious hepatitis were diagnosed. Treatment consisted of the oral administration of digitalis, mercurial diuretics and vitamin K and the transfusion of 7 pints of packed red blood cells. The patient’s condition improved rapidly, the congestion of the jugular veins, the rales over the lungs and the pitting edema of the legs subsided, and the hemoglobin concentration rose to 10 gm. per 100 ml. The jaundice disappeared within fourteen days and the serum bilirubin became normal. The flocculation tests remained positive, the prothrombin concentration rose to 25 per cent, the white blood cell count was 2,900 per cu. mm. and the platelet count 90,000 per cu. mm. The patient opposed further investigation and was discharged at his own insistence. He did not reappear for six years. He was readmitted to our department on December 4, 1963, because of progressive weakness which had started a few months prior to hospitalization and compelled him to stop working. On examination he was thin and pale, but not icteric. The jugular veins were slightly engorged, the heart findings were as before. The liver was palpated 9 cm. below the costal margin and the spleen filled the entire left side of the abdomen, both were firm and nontender. There were no signs of ascites. Slight pitting edema of the legs was present. A roentgenogram of the chest was consistent with mitral stenosis. On biomicroscopic examination the bulbar conjunctivas showed irregularities in the caliber of the veins with dilatations and tortuosities, a large number of capillary saccular and fusiform angiectasies-microaneurysms around the limbus, and nludging of the blood columns (Fig. 1). The discs, maculas and blood vessels in the fundi were normal in appearance. In the lower part of both fundi was a large sector of choroidal thinning with its apex near the lower margin of the disc and extending to the periphery of the fundus. In the lower part of the sector near the periphery were a few bone-corpuscle like pigmentations, partly above and around the branches of the veins (Fig. 2). These findings were symmetrical in both eyegrounds and thought to be consistent with a typical abortive (minimal) coloboma. The electroretinogram was subnormal, central vision was 5/5 in both eyes, visual fields (Goldmann’s perimeter) were complete and color vision was AMERICAN
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normal. Otolaryngologic and neurologic examinations 12’ere \Vithin normal limits. Examination of the urine disclosed traces of protein; an aminoacidogram was normal. The erythrocyte sedimentation rate (Westergren) was 22 mm. in rhr first hour. 42 mm. in the second. The hemoglobin concentration \
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cells and increased numbers of capillarich: as well as hemosiderin deposits and slight inflammatory infiltration. Physical, ophthalmologic and laboratory examinations performed on the patient’s children, four and sixteen years of age, revealed no abnormalities. In the view of the eye and skin findings the possibility of a diffuse vascular anomaly> multiple hrmangiomatosis involving the spleen and liver, was entertained. Splenectomy was decided upon because of the abdominal discomfort caused by the large spleen, and also the severe anemia. On January 9. 1964, after the patient had received 5 units of packed red cells, laparotomy was performed; 3 units of packed red cells were given during operation. Thr spleen was reduced to haif its size after ligation of the splenic artery. The liver was enlarged and had a smooth surface. A liver biopsy specimen was taken and splenectomy performed. The spleen was dark red and firm and weighed 3,900 gm. Its surface and cut surface showed numerous discrete dark red nodules, a frw millimeters in diameter. A few larger paler nodules and a large round hemorrhagic area were seen. Microscopic examination of the spleen revealed congestion, reticular fibrosis of the pulp and recent as well as older peritrabecular hemorrhages (GamnaGandy bodies). The nodules proved to be areas of cavernous hemangiomas (Fig. 3) and areas rich in collagenous connective tissue containing vascular lumens, some of them compressed to slits (Fig. 41, as well as areas of proliferating endothelial cells in which only a few vascular lumens could be distinguished (Fig. 5). These angiomatous changes sometimes merged, and it seemed as if therv lvere transformations from one form into another. i.e., from dense endothelial proliferation to fibrotic areas without or with only a few vessels. It was often difllcult to determine whether the findings in the red pulp represented only chronic congestion or angiomatous changes. The surgical liver biopsy specimen revealed an abnormal structure. The liver lobuli were of various size; the central vein could not be distinguished. Proliferation of connective tissue was seen. sometimes in the form of bands. In some of these bands, as well as in some portal spaces, groups of fairly large vascular channels were found (Fig. 6j. Some small vascular lumens lined by swollen endothelial cells were seen. The postoperative course was uneventful. Within ten days after the operation the hemoglobin concentration rose 10 12.0 gm. per 100 ml., the white blood cell count to 20,000 per cu. mm. and the platelet count to 475,000 per cu. mm. Five weeks after splenectomy the hemoglobin level was 10.1 gm. per 100 ml., the red blood cell count 3,600,OOO per cu. mm., hematocrit 30 per cent, reticulocyte count 1 pel cent and platelet count 346,000 per cu. mm. The red blood cell half life estimated by Cr51-labeling was twenty-five days. The total blood volume was 81 ml. per kg. body weight, as determined by the red blood
Diffuse Angiomatosis
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4
3 FIG.
3.
Spleen.
Area of cavernous
hemangioma.
Hematoxylin
FIG. 4. Spleen. Area rich in collagenous connective eosin stain, original magnification X 120.
tissue with few compressed
cell isotope dilution technic; the red blood cell mass was 28 ml. per kg., the plasma volume 53 ml. per kg. The patient was reexamined in the Hematology Clinic on December 9, 1964, i.e., eleven months after splenectomy. He felt well and had no signs of heart failure. The findings over the heart area were the same as those before the operation. The liver was palpated 5 cm. below the costal margin; there were no signs of ascites. The hemoglobin concentration was 16.2 gm. per 100 ml. ; the red blood cell count 5,500,000 per cu. mm., hematocrit 53 per cent, white blood cell count 8,500 per cu. mm. with 65 per cent polymorphonuclear neutrophils, 3 per cent band forms, 5 per cent monocytes, and 27 per cent lymphocytes. The platelet count was 210,000 per cu. mm. The peripheral blood film showed anisocytosis, target cells, Howell-Jolly bodies, a few macrocytes and spherocytes. The erythrocyte sedimentation rate (Westergren) was 3 mm. in the first hour and 6 mm. in the second. The serum iron was 86 pg. per 100 ml. The total blood volume was 85 ml. per kg. body weight,
of angiomatous
and eosin stain, original
magnification
vascular channels.
X 120.
Ilematoxylin
and
the total red cell mass 30 ml. per kg. and the plasma volume 55 ml. per kg. Ferrokinetic studies showed a plasma clearance with a half time of forty minutes, instead of the normal range of 60 to 120 minutes; 90 per cent of the radioactive iron appeared in the circulating red blood cells after seven days. Treatment with digitalis and thiazide diuretics was continued. On June 6, 1966, the patient complained of excruciating headache. The striking finding was his plethoric face with marked redness of the skin and mucosa. The liver was palpated 6 cm. below the costal margin. The hemoglobin level had risen to 18 gm. per 100 ml., the red blood cell count to 6,300,OOO per cu. mm. and the hematocrit to 59 per cent. The reticulocyte count was 0.7 per cent white blood cell count 8,700 per cu. mm. with 60 per cent polymorphonuclear neutrophils, 2 per cent band forms, 32 per cent lymphocytes, 6 per cent monocytes; the platelet count was 243,000 per cu. mm. The erythrocyte sedimentation rate (Westergren) was 2 mm. in the first hour and 4 mm. in the second. The total blood
FIG. 5.
Spleen. Active proliferation
FIG. 6. X 120.
Liver. Group of large vascular channels in a portal space. Hematoxylin
tissue. Hematoxylin
and eosin stain, original magnification
AMERICAN
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and eosin stain, original magnification
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volume gas 94.2 ml. per kg. body weight,
the total re(l wII mass 37.9 ml. per kg. and the plasma volume 50.i ml. per kg. Oxygen saturation of the arterial blood \vas 06 per cent. ‘I‘he intravenous pyelogram wa:, \virllin normal limits. Erythropoietin in blood and ur~nr~ t.stimated by thr method of Plzak et al. [7], MXS no1 increased. FoIlowing the withdrawal of 500 ml. of I)lood. the headache diminished. On December 1: 1966, following repeated phlebotomb-. the patient felt well, his hemoglobin concentration was 14.8 gm. per 100 ml., red blood cell count 4,800.OOO per cu. mm., hematocrit 49 per cent, reticulocyte count 0.7 per cent and white blood cell count 8,000 per cu. mm. with a normal differential. The platelet count was 179,000 per cu. mm. The sedimentation rate (Westergren) was 13 mm. in the first hour. 2 1 mm. in the second ; serum iron was 90 pg. per
100 ml. No occult blood was found in the feces. The feral stercohilinogen excretion was 215 mg. per twenty-four hours. the half life of CrVagged patient’s red Mood cells Lvas twenty-five days. COMMENTS
Angiomatous organ changes have been dehcmangio-endohemangioma, scribed as thelionla, hemangioblastoma and vascular hamartoma [ 7,8--70 ] ; the term hamartoma, refers to the designation by Albrecht of tumorlike lnalformations constituting an aberrant mixture of normal components of an organ [ 7 71, and more recently by Sweet and Warren [ 721 of a tumor composed of tissues in excess beyond normal requirements, possessing a limited capacity for aberrant growth. When affecting more than one organ, the abnormality is described as the multiple hemangiomatosis syndronle (I] including the Sturge-Weber and von Hippel-Lindau syndromes and Rendu-Osler’s disease. According to Willis [I] these vascular changes are generally benign, although malignant transformation may occur [8,73]; their multifocal development appears to have given rise to an exaggerated impression of the frequency of malignancy. Splenic hemangioma is not uncommon and has been reported as a single abnormality [4,8,!/,13-77) or in association with hemangiomas in other organs, such as the liver [70], skin, lung and stomach [78]. In many cases of splenic hemangioma the tumor was asymptomatic and discovered incidentally at autopsy or as an unsuspected finding during splenectomy performed for various indications [4,5,79]. The clinical manifestations of splenic hemangioma are various: fearer and weight loss, abdominal VOL.
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distention, pain in the left hypochrondriunr sometimes accompanied by gastrointestinal disturbances such as anorexia, dysphagia, ronstipation or diarrhea [ d>5,/7], and s~~~JI~ltm~‘o~ls [!I, 75,20,2/l or traumatic i&2/] splrnir rupture with intraperitoneal bleeding. The maxirnul!l weight of a spleen containing heltlan+onla hitherto reported was 13,130 ~III. j Ifi]. The youngest patient in whom splen;c lic~~~an~iorria was found was four lllonths old [h’]. In our patient the angiomatous in\olvernent of the spleen was associated with an idcntical vascular anomaly in the liver and the skin and with vascular changes in the ronjuncti\.as. Since the hepatosplenomegaly was discovered at the age of six months, a congenital \.ascular anomaly ma)- be presumed. The irregularities in the conjunctival vessels, i.e., the tortuosities and aneurysms are silnilar to those found in Rendu-Osler’s disease [22] and ataxiateleangiectasia [23,24], both classifiable with the group of multiple hemangiomatous syndromes. The conjunctival findings, however, arc not specific for such congenital anomalies and may be found in various other conditions such as sickle cell disease [25], diabetes [Zri] and in apparently normal subjects [27]. The absence of these conditions and the association of the vascular conjunctival changes with the diffuse angiomatosis in other organs makes it highly probable that in this patient they were all of the same nature. Whether the electroencephalographic finding is due to a vascular anomaly is speculative; brain involvement in diffuse cavernous hemangiomatosis has been described [28]. The question may also be raised whether the heart abnormality in this patient with physical and roentgenographic findings typical of mitral stenosis may be related to the angiomatous process. The patient with diffuse hernangionlatosis described by Wood et al. [28J had an angioma in the left auricular appendage, bllt no signs of any valvular lesion. In a few documented cases /.i- (i,17,29] hemangioma of the spleen has led to hypersplenism, i.e., pancytopenia associated with splenic enlargement and disappearing following splenectomy. To our knowledge, in only one of the reports on hypersplenism associated with splenic hemangioma, that of a thirty-nine year old woman who had additional hemangiomas in the liver [4], was angiomatous involvement of other organs mentioned. In our patient with
800
Diffuse Angiomatosis
with Hypersplenism-Pinkhas
diffuse multiple organ angiomatosis it is reasonable to assume that the pancytopenia, which disappeared following splenectomy, was causally related to the splenic vascular hamartoma since no other abnormality in the spleen was found. The mechanism by which the splenic process caused the anemia has not been elucidated. A red blood cell life span determination was not made prior to splenectomy and thus hemolysis was not proved. Yet the spherocytosis, reticulocytosis and markedly increased fecal stercobilinogen excretion indicate a hemolytic process, possibly aggravated by the viral hepatitis on the first admission. The pathogenesis of this hemolytic process is not known. No anti-red demonstrated. blood cell antibodies were Hemolysis of the microangiopathic type seems improbable in view of the normal red blood cell life span after splenectomy, in the presence in other organs. of multiple angiomatosis Thrombocytopenia associated with hemangioma is well known and the platelet count may rise and even return to normal following radiation treatment or excision of the tumor [30]. The moderate thrombocytopenia in our patient prior to splenectomy may have been due to platelet pooling in the large splenic vascular bed [31]. after The development of polycythemia splenectomy appears to be rare, and according to Crosby [32], has been described only in hereditary spherocytosis [33] in which the spherocytes may be functionally deficient as to oxygen release [34]. No evidence for a primary red cell disturbance in our patient was obtained; an oxygen dissociation curve, however, was not obtained. Polycythemia has been described in Rendu-Osler-Weber’s disease, one of the multiple hemangiomatosis syndromes but, to our knowledge, only in association with pulmonary arteriovenous fistula [35-381. The patient described herein had a normal arterial oxygen saturation and no roentgenologic evidence of arteriovenous fistula in the lungs. Pulmonary angiography, however, was not carried out. In view of the known association of polycythemia with cerebellar hemangioblastoma [39,&l, it is an attractive hypothesis to relate the polycythemia in our patient to an angiomatous process in the brain possibly evidenced by the electroencephalographic abnormality. Another possibility is that the polycythemia is related to angiomatosis of the kidney, which, however, was not documented in our patient. Lack of increase
et al.
of urinary erythropoietin does not exclude such a mechanism. To our knowledge, polycythemia associated with hemangioma of the kidney has not been reported. If the patient’s polycythemia was at all related to an angiomatous process in the brain, kidney or other organ, it may be assumed that the splenic process had prevented its development. Thus, although the tendency to develop polycythemia may have been present for a long time it did not become manifest prior to splenectomy. of an additional congenital The presence malformation, typical abortive coloboma of the retina, in this patient with diffuse angiomatosis is of interest because of a possible connection between the two anomalies. Coloboma is due to interference with the normal closure of the fetal cleft in the embryonic secondary optic vesicle, normally occurring in the fifth to seventh week of gestation [41]. Its cause may be genetic with irregular dominant heredity, or environmental acting in early embryonic life. Association of coloboma with other congenital deformities apart from the eye is known but joint occurrence with vascular hamartoma has to our knowledge not been reported. Still, the timing of the development of the blood vessels at the third to fourth week of embryonal life [42] prompts consideration of a possible joint etiology. Whereas vascular anomalies are of mesenchymal origin, coloboma is generally considered to be due to a disturbance in the ectoderm, the primary aberration lying in the epiblast of the optic cup [41]. A mesoblastic theory, ascribing formation of coloboma to overdevelopment of mesoblastic tissue preventing the lips of the tissue from closing, had been proposed by von Hippel early in this century [43], and more recently a failure in the development of the blood vessels of the mesoblast surrounding the secondary optic vesicle was held responsible by Collins [&I. Whether the coloboma was due to a disturbance in the epiblast or in the mesoblast, an environmental factor active early in pregnancy may have caused both anomalies, angiomatosis and coloboma. Intensive questioning of the patient’s mother did not bring out any febrile disease or ingestion of a specific drug during pregnancy. There was no evidence for a genetic cause ; no hemangiomas, colobomas or other malformations were found in the patient’s family as far as they could be examined. Chromosornc analysis in the patient was normal. AMERICAN
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Pathology of Tumors, p. 702. London, 1’148. Rutterworth 8 Co. .I. Hypersplrnisln associated with 2. ~IIW.I3AM:K, h;llllartoina of thr spleen. SC/~mrd. scandinao., 146: 2-6, 1953. .>. ~~CHKlJVtK, 14. and VBKDONK, G. J. Hamartoma of tllr spl~cn with inhibition of thr bone marrow. :lcta med. scandimw., 158: 235, 1957. 4. M-\(:LF.~N, N., MACPHERSON, A. 1. and ROBB, P. M. I)iffuse hemangiomata of the spleen. J. Roy. Coil. .Sii,,<~rvz.~, 3: 218, 1958. 5. I~IT~NI,E. A. The clinical course of splenic hemangiollla. Arch. Surg., 83: 681, 1961. o ~JARDMEIER, T’H. Hypersplenismus bei einem Hamartom der Milz (Splenom). Schweiz. med. Wchnschr., 07: 1270, 1962. 7. PI./.u, L. F., FRIED, \V., JACOBSON, L. 0. and BETHARD, I\‘. F. Demonstration of stimulation of vrythropoiesis by plasma from anemic rats using Fc59. J. Lab. & Clin. Med., 46: 671, 1955. 8. PIKES, R. and RABINOWITCH, J. Hemangioma of the spleen. Arch. Path., 33: 487, 1942. ‘I S I ECVART: E. H., JK. Cavernous hemangioma of the spleen. Am. J. Surg., 71: 536, 1946. 10. '~‘ASKEK, K. G. Hemangioma-endothelioma of the spleen and liver. J. Clin. Path., 11 : 142, 1958. 11, AI.BR~.CH r. Ucber Hamartoma. Verhandl. deutsch. path. Gesellsrh., 7: 153, 1904. 12. SM~I~.ET,I(. H. and \TARREN, S. Hamartoma of the spleen : report of a case. Xeuew England J. Med., 226: 7.57,1942. 13. DOWD, C:. N. Cavernous angioma of the spleen. :11~n.Surg., 62: 177, 1915. 14. AK(:.A~COYUNL.U, I. Capillary and cavernous hemancionla of the spleen (trlnngiolna). Am. J. Surg., 41: 519, 1938. 15. C‘OTt. F. L. and FORSEE, J. H. Cavernous hemanyiollla of the spleen. Surgery. 8: 639, 1940. 16. I IOIXE, G. B. and WILSON, D. A. Benign cavernous hc~~llan+oma of the spleen. Surgrry, 21 : 343, 1947. 17. HENJAMIK, B. I., MOHL~R, D. N. and SANDUSKY, 11’. 1~. Hemangioma of the spleen. Arch. Znt. Med., 115: 280, 1965. 18. I’HL.,II.E. Gber Angioma und sarkomatdse Angiome cJcr Milz. Arch. path. iinat., 178: 296, 1904. 1’1. Bosrrc, \\‘. I,. Spleen tumors: primary neoplasms. /lm. J. Path., 21: 1243, 1945. 20. I~AINL.S, C. E. and MCII.LROY, P. T. Spontaneous rupture of hemangioma. J.A.M.A., 100: 1862, 1933. 21. INGIIAM, 'r. R. and THOMSON, J. A. Apparent spontaneous rupture of spleen from hemangioma. .\‘or/hwst Med., 59: 914, 1960. 22. \VINTROBE, M. M. Clinical Hematology, 4th ed., p. 1185. Philadelphia, 1956. Lea & Febiger. 27. BOIXR, E. and SEDWICK, R. P. Ataxia-telangiectasia. Prdmtrics, 21 : 526, 1958. D. D. Ataxia-telangiectasia. Henry 34. \ZTO~CESTER, ITwd Hosp. .\I. Bull., 14: 429, 1966. 21. FUN~HASIII, I., FINK, .A., ROBINSON, M. and WAT1
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SON, .I. Conjunctiva in sickle-celL d~sr~~rv.Anr. .J. O,bhth., 57: 713, 1964. DITZEL, J., \VHI.TE, P. and DUCKERS, .I. (:hangrs in the pattern of the smaller blood vessels in the bulbar conjunctiva in children of diabetic mothers. Diabetes, 3: 99, 1954. DUKE-ELDER, S. I. Diseases of the corljunctiva and associated diseasrs of the corncal cpithelium. Diseases of the outer eye. In: System of Ophthalmology. vol. 8, p. 28. London, 19h5. Henry Kimpton. WOOD, FT. \V., WHI.I.I<, R. J. and KEKNU~IAN.I. \I’. Cavernous hemangiomatosis involving the brain, spinal cord, heart, skin and kidney: report of case. Pm. Staff Meet. Mayo Clin., 32: 249, 1957. FLOREN.I.IN, P., CHALNOT, P. and MICI~N, 1~. Diffuse angiomatosis of spleen with pancytopenia, favorable result of splenectomy. F&v. Wrfq Path., 24: 501, 1955. DARGEON, 1-I. W., ADIAO, A. C. and P.ACK, G. 'I'. IIcmangioma with thrombocytopcnia. J. Prdiat.. 54: 285, 1959. ASTEZ, R. H. Pooling of platelets in the spleen: role in the pathogenesis of “hypersplenic” thrornbocytopenia. J. Clin. Iwest., 45: 645. 1966. CROSSU, W. H. Hyposplenism: an inquiry into normal functions of the spleen. Ann. Rw. .&fed.. 14: 349, 1963. MEULENGRACH.~, E. Chronic hereditary hrinolytic jaundice. In: Handbook of Hematology, vol. 3, p. 2283. Edited by Downey, H. New York, 1938. Paul B. Hoeber, Inc. VALTIS, D. J. and BAIKIE, A. G. The influence of redcell thickness on oxygen dissociation rurve of blood. Brit. J. Haemat., 1: 146, 1955. SAUNDERS, W. H. Hereditary hemorrhagic telangiectasia. Arch. Otolaryng,, 76: 245, 1962. WEISS, E. and GASUL, B. M. Pulmonary arteriovenous fistula and telangiectasia. Ann. Int. Jled., 41 : 989, 1954. BRINK, .A. J. Telangiectasis of the lungs, with two case reports of hereditary hemorrhagic telangiectasis with cyanosis. Quart. J. Med., 19: 239, 1950. HALES, M. R. Multiple small arteriovenous fistulae of the lungs. Am. J. Path., 32: 927, 1956. CARPENTER, G., SCHWARTZ, I-I. G. and \VAL.~ER, A. E. Neurogenic polycythemia. Ann. I&. .\fed., 19: 470,1943. BRODY, J. I. and RODRIGUEZ, F. Cerebellar hemangioblastoma and polycythemia (erythrocythrmia ). Am. J. M. SC., 242: 579, 1961. DUKE-ELDER, S. and COOK, CH. System of Ophthalmology, vol. 3, p. 38. I. Embryology. Normal and Abnormal Development. London, 1963. Henry Kimpton. PA.I.TEN, B. M. Human Embryology, p. 776. Philadelphia, 1946. Blakiston Co. VON HIPPEL, E. Embryologische Untersuchungen iiber die Entstehungsweise der typischen angeborenen Spaltbildungen (Coloboma) des Aiigapfels. Graefes Arch. Ophth., 55: 507, 1903. COLLINS, P. R. S. Cited by Duke-Elder, S. and Cook, <:h. [17].