Primary tumours of the valves of the heart

PRIMARY TUMOURS OF THE VALVES OF THE HEART.l

By GEORGE DEAN AND A. W. FALCONER, Aberdeen.

PRIMARY tumours of the heart are of interest partly on account of their comparative rarity, but more especially owing to the very divergent views which have been expressed as to their nature and origin.

Since Czapek (1891 6, first pointed out that many of the alleged primary tumours of the heart were in reality organised thrombi, there have appeared, more especially in German literature, numerous critical articles reviewing the recorded cases. Among these may be mentioned the papers of Ribbert (1 8 9 '7 28, 1 9 04 28, 1 9 10 30), Marchand (1 894 z5), Bostrom ( 1 8 9 5 2 ) , Leonhard t (1 9 0 5 22), Djewitzky (1 9 0 6 *), Bac- meister (1 9 0 6 I), Thorel (1 9 0 '7 34), Brenner ( 1 9 0 7 3), Hagedorn (1 9 0 8 l3), Koechliu ( 1 9 0 9 Is), Karrenstein (1 9 0 8 16), Link (1 9 0 9 23),

and Stahr (1910 33). In these papers the most divergent views are expressed, and the various cases are dogmatically placed in one or other compartment, frequently, it would seem, without any great justification.

As the case which we wish to place on record is one of a tumour situated on a pulmonary cusp, we will confine ourselves, as far as poss- ible, to a consideration of the recorded cases of tumours of the valves of the heart. We will not include a detailed reference to cases of alleged primary sarcomata of the valves, such as those recorded by Prud'homme (1 8 6 '7 26), Fuhrmann (1 8 9 9 9), and Crawford (1 8 9 8 '), or to the pedunculated growths described as valvular hrematomata by V. Kahlden (1 8 9 7 15), Gibson ( 1 8 7 9 11), and Gard (1 8 8 0 lo), but will confine ourselves to a brief review of the valvular tumours recorded under the terms myxoma, hyaline fibroma, hmnangioelasto-myxoma, papillary fibroma, etc.

The following tumour was discovered incidentally a t the autopsy of a male, Zt. 5 3 , who died as the result of the rupture of a small saccular aneurysm of the aorta. During life the sounds at the base of the heart were quite normal.

Rooeived March 6 , 1913.

PRIMARY TUMOURS OF CARDIAC VALVES. 65

Macroscopic appearances.-The aortic, tricnspid, and mitral valves were quite normal. Arising from the ventricular surface of the posterior cusp of the pulmonary artery was a pedunculated tumour about the size of, and very similar in shape, colour, and superfices to, a medium sized ripe raspberry. It had a gelatinous consistence, and was attached to the cusp by a central white pedicle. I n the fresh state the long axis of the growth was at a right angle to the cusp ; but after fixation, from pressure of the surrounding parts, it became parallel to the cusp. Apart from the presence of the tumour, the cusp was normal. The two anterior cusps were normal except for several fenestra- tions. After fixation in formalin the growth lost its colour and became much more wart-like in appearance (Fig. 1). The cusp measured 15 mm. in depth, and the pedicle of the growth, which was 2.5 mm. in thickness, arose 6 nim. from its free margin. The diameter of the growth after fixation was 14 mm. and its height 6 mm.

FIG. 1.

Nicroscopic appearances.-The cusp containing the tumour was excised, embedded, and sections stained with haematoxylin and eosin, hematoxylin and V. Gieson, orcein, thionin, polychrome methylene-blue and Gram-Weigert’s stain.

Although macroscopically no thickening of the cusp could be recognised, microscopic sections showed that in the upper half of the cusp there was, at parts, considerable thickening of the central layers. This thickening occurred irregularly, and in places gave an almost nodular appearance to the cup . It was particularly marked in the neighbourhood of the nodulus arantii. I n the thickened portions the differentiation into layers was largely lost, and the cusp presented an almost homogeneous appearance, staining a definite pink with thionin. With a higher power the thickened portions consisted of an almost homogeneous network staining pink with thionin, and containing moderately numerous cells. Some of these cells possessed a round nucleus

5-JJ4, OF PAT%-VOL. XVIII.

66 G E O R G E B E A N A N D A. W. FALCONXR.

and others an oval one. I n both types the cell body was scanty, and presented several branching processes. Stained with orcein the thickened portions of the cusp showed a very fine interlacing network of elastic fibres ; stained with hwmatoxylin and v. Gieson’s stain, they presented an almost homogeneous matrix staining brown, and a very fine network of fibrils staining pink. These appeared to correspond to the elastic fibrils shown by orcein.

The growth originated from the cusp some distance below, and had no connection with the nod ulus arantii. A very narrow pedicle arose at right angles to the ventricular surface of the cusp. The endothelium and elastic lamina were reflected on to the pedicle, and formed its periphery. The main mass of the pedicle arose from, and was continuous with, the central layers of the valve. After proceeding outwards for some distance, the pedicle became flattened out, so that on section it was T-shaped, and from the horizontal limb of the T numerous papilliform processes arose. Stained with haematoxylin and v. Gieson’s stain, the vertical portion of the pedicle was seen t o consist of longitudinally arranged fibrillz, among which were numerous cells. These were mostly spindle-shaped, hut there were also a few round cells. At parts the round cells were more numerous. Stained with thionin, the vertical portion of the pedicle did not give the myxomatous reaction. Staining with orcein showed that the ventricular elastic lamina seen at the periphery of the pedicle soon became lost as definite bands, hut several coarse elastic fibres could he seen in the central parts of the pedicle. The horizontal expansion of the pedicle differed from the vertical limb in the fact that, in addition to the longitudinally arranged fibrillw, there were considerable portions which stained pink with thionin and showed the typical branching cells of myxomatous tissue. Arising from this central stem were numerous papilliform processes of various sizes and shapes. The majority of these processes consisted of a central axis of longitudinally arranged fine fibrills staining pink with v. Gieson’s stain, and blue by the Gram-Weigert method. Occasionally a portion of this central axis was arranged in dense whorls. This hyaline tissue was almost without cells. Around this central axis was a more or less extensive area of myxomatous tissue showing characteristic myxomatous cells, taking a pink colour with thionin and polychrome methylene-blue, and remaining unstained with van Gieson. A certain number of the papilliform processes consisted entirely of myxornatous tissue, and a few of them entirely of the hyaline connective tissue. With orcein a small proportion of the papills showed the presence of fine elastic fibrils. The whoIe growth was covered by a layer of endothelium, and was without vessels.

We have here a tumour (Fig. l), the size of a raspberry, arising by a sharply circumscribed pedicle from the central layers of a pulmonary valve which was completely free from any evidence of inflammatory changes. The tuinour consists partly of typical myxomatous tissue, and partly of hyaline connective tissue.

The following is a brief review of the more or less similar cases which we have been able to find in the literature. DEBOVE (1 8 7 3 ’).

Female, zt. 64.-Pedunculated myxoma on the tyicuspid valve. No sign of other affection of the heart or of any similar tissue throughout the body. On microscopic examination the tumour was found to consist of purely mucoid tissue. No further details given. Debove considered it a genuine neoplasm. GUTH (1 8 9 8 ”).

A small tumour the size of a bean, situated on the tricuspid valve, to which It was covered by endothelium, and was it was attached by a broad base.

described as a papillary niyxoma. At parts it contained blood vessels.

PRIMARY TUMO URS OF CARDIA C VAL YES. 67

CURTIS (1871-72 Incidental discovery in a female, a t . 83. Myxoma, size of half a cherry,

smooth, glistening, and transparent. Situated on the auricular surface of the posterior mitral cusp. There were in addition signs of old endocarditis. Microscopically, the tumour consisted of papilla covered with endothelium. The papilla contained numerous round cells with a pale nucleus situated in a ground substance which was partly homogeneous and partly finely striated. Curtis considered the growth of inflammatory origin.

RIBBERT (1 8 9 7 29).

Situated on the tricuspid valve was a tumour 7 mm. wide and 3 to 4 mm. long. At the origin of the tumour the central layers of the cusp were thickened and showed slight myxomatous changes. The tumour was highly papilliform in structure. Most of the papilh consisted of a central axis of parallel longitudinal fibres surrounded by a transparent ground surface in which were large round spindle and star-shaped cells with long processes. The surface of the papills was covered by endothelium. I n some papillae, however, the central axis was more developed, and the myxomatous tissue was only present at the extreme periphery, and in others the whole papills consisted of parallel longitudinal fibrils.

A second case, also situated on the tricuspid valve, although somewhat smaller, was of exactly similar formation. In addition to the pedunculated tumour a few similar papills passed directly from the cusp.

I n a third case the tumour was situated on the ventricular surface of a pulmonary cusp. It was much smaller than the first two, and was only 1 mm. broad and 1 mm. high. I n the neighbourhood of the growth a few papilla passed directly from the cusp. There was considerable thickening of the central layers of the cusp. The growth was covered by endothelium and was without vessels.

A fourth case was situated on the tricuspid valve, and was about the size of a pea. It differed from his other cases in being less transparent and more fibrillated and in containing numerous capillaries.

It was attached to the cusp by a pedicle 1 mm. thick.

The whole growth was without vessels.

REITMANN (1 9 0 5 27). Incidental discovery in a male, at. 74. Attached to the nodulus arantii

of an anterior semilunar cusp of the pulmonary valve was a pedunculated growth about the size of a pea, egg-shaped, reddish-yellow in colour, wau-like in appearance, and slightly translucent. Otherwise the heart showed nothing abnormal. Sections were stained with hamalum and eosin. Sections were also stained to show fibrin, elastic fibres, glycogen, and amyloid with negative results. On microscopic examination the growth consisted of a central stem, arising from and continuous with the framework of the cusp. Aris- ing from this stem were numerous papillomatous branches covered with endothelium continuous with that of the CUSP. At parts this endothelium differed from that of the cusp in a marked increase in height, its nuclei being frequently longer and irregular in shape. At places the endothelial covering consisted of two or more layers. The groundwork of the growth consisted of a peculiar hyaline-like substance, poor in nuclei, and presenting, according to Reitmann, the signs of commencing hyaline degeneration of connective tissue. This degeneration was present in various stages, as was shown by its different colour reactions to the stain. There was no typical arrangement of the connective-tissue bundles, but whorls and circles were frequently present. The whole growth was without vessels. Reitmann suggests the name hyalo-fibroma.

68 GEORGE DEAN AND A. W. FALCONER.

DJEWITZKY (1 9 0 6 Attached to the

ventricular surface of an aortic cusp to the left of the nodulus arantii was a small pedunculated warty tumour the size of a pea. Apart from the tumour the aortic cusps were normal. On niicroscopic examination the tumour showed a highly papillary arrangement, and was covered by an uninterrupted layer of endothelium continuous with that of the cusp. The ground substance of the papilla consisted of a fine network in which were cells of two types. The cells of the first type presented oval, faintly staining nuclei, a small amount of protoplasm and branching processes. Those of the second type were large round cells with deeply staining nuclei and abundant protoplasm. I n the central parts of the papilla there were connective-tissue bundles with corresponding nuclei. The periphery took no colour, the central part staining red with van Gieson’s stain. At parts among the connective tissue, elastic fibres were demonstrated, and these were more numerous in the pedicle, which ran directly into the subendothelial layer of the cusp, which was distinctly thickened.

Incidental discovery in the body of a patient, Zt. 38.

The growth and the cusp were without vessels. HAGEDORN (1 9 0 9 13).

Middle-aged maze.-On the free margin of the posterior cusp of the aortic valve was a transparent raspberry jelly-like growth about the size of a cherry. It was attached to the side of the nodulus arantii by a thin pedicle. The tumour had a highly papillary form, and was covered by a single layer of endothelium continuous with the endothelium of the cusp. The groundwork of the growth consisted of coarse and fine bundles of connective tissue, poor, or wanting, in nuclei, staining a rose red with haeniatoxylin and eosin. In parts the fibres were arranged in concentric layers. Elastic fibres were present, chiefly in the central parts of the papillae, and in places were so numerous that the fibrous character of the growth could be detected with difficulty. The growth was without vessels.

SIMMONDS (I 9 0 8 31).

Incidentttl discovery in a zvomun, st. 62. A pednnculated tumour attached by a slender pedicle to the inner side of an aortic cusp. It was rather larger than a pea, and highly papillary in form. On microscopic examination it showed a poorly nucleated fibrous ground substance covered by a single layer of endothelial cells. It was without blood vessels.

KOECIILIN (1 9 0 9 18).

Fe7nuZe, at. 19.-On the right cusp of the otherwise normal pulmonary valve was a tumour 8 mm. long and 7 mm. broad. It was attached to the cusp 3 mm. from the nodulus arantii by x pedicle 1 to 2 mm. thick and about 2 mm. long. On microscopic examination the tumour had a highly papillary form, arose from the ventricular connective tissue layer of the cusp, was covered by a layer of endothelium, and was without vessels. The pedicle and main part of the growth consisted of a fine fibrillary connective tissue arranged in many different forms. I n the ground substance were many spindle and star-shaped cells with fine branching processes. Thionin gave a negative myxomatous reaction, but Koechlin considered there could be no doubt as to the myxomatous character of the ground substance. Elastic fibres were numerous. The pedicle went straight into the connective-tissue layer of the valve. The valve itself was completely normal; a t no part were there signs of any acute or chronic inflammation.

LEONHARDT (1 9 0 5 22).

orifice no longer admitted a finger. Female, at. 26.-The mitral cusps were thickened and adherent and the

Situated on the auricular surface of the

PRIMAR Y TUMO URS OF CARDIAC VAL YES. 69

posterior cusp was a tumour the size of a cherry. It was irregularly rounded in shape, and was attached by a short pedicle close to the insertion of the cusp 9 mm. from its free margin. The superficies was smooth and glistening, without a trace of fibrin deposit. The other valves of the heart were normal. Microscopically, the tumour arose from the subendothelial layers of the valve, which were thickened throughout and contained blood vessels. These vessels were continued into the tumour and formed a framework, in the meshes of which was an almost homogeneous tissue containing spindle- and star-shaped cells. This tissue gave the characteristic mucin reaction with thionin, polychrome methylene-blue and muci-carmine. Here and there were cells re- sembling lymphocytes, and at parts a considerable amount of blood pigment. The growth was covered by endothelium and was rich in elastic fibres.

This list includes all the recorded cases of valvular tumours of this type which we have been able to find. With the exception of the cases of Curtis (1 871 6 , and Koechlin (1 909 Is), all of them have been regarded by their discoverers as undoubted neoplasms. Although complete details are lacking in some of the earlier records, the cases fall naturally into two groups : -

1. Those without, or practically without, vessels. 2. Those with a more or less highly organised system of vessels. Both types have given rise to much discussion as to their true

nature, but the various views may be summed up under three headings :--

1. That they are true blastomata of the connective-tissue class. (a) True niyxomata. (b ) Connective-tissue tumours showing hyaline or myxo-

niatous degeneration. 2. That they are organised thrombi. 3. That they are of similar nature to Lambl’s (1 8 5 6 ”) excrescences. 1. (a) That they are, true myxomata.-By those who, like Ribbert

(1 9 10 30) and Leonhardt (1 9 0 5 22), hold that true mucin occurs only in genuine blastomata and cannot result from degeneration or cedematous changes in inflammatory products, a, ready means of differentiation of these growths is found in the histological characters and the various chemical and colour reactions characteristic of mucin. Ribbert holds that the myxomata represent a distinct type of neoplasm which can originate only from isolated rests of embryonic mucoid tissue. Such tuinours differ from the embryonic tissue in that there is a relative increase of mucin. Just as both ordinary connective tissue and fatty tissue are developed from the embryonic mucoid tissue, so may a similar development take place in myxomatous tumours. Thus myxomata of the valves of the heart may consist in parts of pure myxomatous tissue and in parts of fully formed fibrous tissue, or should the whole of the mucoid tissue have fulfilled its ultimate developmental intention, the growth will consist entirely of fibrous tissue. Hagedorn’s case, described as a fibroma, Ribbert considers to be of this nature. Thorel (1 9 0 7 34) and Veraguth (1 8 9 5 ”) also refer the origin of these tumours to isolated rests of the embryonic mucoid

GEORGE B E A N ANB A. lZ FALCONER.

tissue of the fetal valves. Leonhardt accepts as undoubted blastomata only those cases in which a positive niucin reaction has been demonstrated. Djewitzky (1906 s), on the other hand, states that he has found a myxomatous reaction in an undoubted thrombus. Koniger (1903 19) also has described a myxomatous tissue in several cases O P thickening of the subendothelial layer of the mitral valve associated with defects in the endothelial layer and fibrinous deposits. Honegger (1882 14) has found myxomatous tissue in thickenings of the nodules arantii of the semi-lunar valves arid in the deeper layers of thickened mitral valves. Brenner (1 9 0 7 3, considers a negative mucin reaction is sufficient to exclude myxoma, but that a positive reaction is not pathognomonic. Stahr also believes that too much weight has been laid on the presence of m u c h Hagedorn (1908 13) and Koechlin (1909 have found lhese stains untrustworthy. Brenner lays most stress on the presence of a highly developed system of blood vessels and elastic fibres. The only tumours limited to the cardiac valves which he unreservedly accepts as genuine neoplasms are Ribbert’s fourth case and Leonhardt’s case.

1. (6 ) That they are conncetive-tissue tunzours undergoing various degenerations-The majority of the cases have been recorded by their authors under this heading, Reitmann designated his case “ a hyalo- fibroma.” Djewitzky considered his own case similar to Ribbert’s (30), Curtis, Guth and Reitmann’s cases, and regarded them as fibroniata, which on account of their unfavourable site were prone to undergo various forms of degeneration. These observers found their diagnosis of blastoma on the gross anatoniical characters of the growths and on their microscopical features. They emphasise the presence of such a growth in an otherwise unaltered valve, the highly papillary structure, and the tense shining superficies. Microscopically, they lay stress on the homogeneous structure, the absence of pigment or other sign of an organising thrombus, and the presence of a continuous layer of endothelium passing from the endocardium over the tumour. They admit that it has been shown by Krumbholtz (189320) and many others that undoubted thrombi may show an endothelial covering, but they question whether such a covering would show such a highly developed papillary type as is met with in these growths.

2. That they are organised thrombi.-Although this suggestion has been brought more prominently forward in connection with the cases of alleged neoplasms arising from the left auricle than in those tumours situated on the cardiac valves, the same criticisni has been applied to the vascular tumours recorded by Ribbert, Leonhardt, and Guth. Koechlin also includes Steinhaus’s (1 8 9 9 32) case, which he erroneously places on an aortic cusp, but which arose from the right ventricle below the attachment of the pulmonary valve. Koechlin considers that Guth’s case must be regarded as the result of a circumscribed endocarditis, and believes Leonhardt’s to be undoubtedly an

PRIMARY T U M O URS OP CARDIAC VAL YES. 71

endocardial formation. He adduces in support of his view the presence, in addition to the tumour, of endocardial changes in the cusps. Ribbert's fourth case he includes in the same category. Stahr (19 1 0 33) agrees with Koechlin. Djewitzky unhesitatingly rejects Leonhardt's case, and considers the other's description both of the macro- and microscopic characters a beautiful description of an organising thrombus.

On the other hand, Thorel (1907 14) accepts Leonhardt's case on the strength of a positive mucin reaction. Brenner also unhesitatingly accepts Ribbert's fourth case and Leonhardt's case, but lays more stress on the presence of a highly developed system of blood vessels and of numerous elastic fibres than on the positive mucin reaction. He considers that thrombi and true tumours may show the same macroscopic characters, including the gelatinous consistence and the external form and attachment. Microscopically, however, he considers that the neoplasms differ completely from organised thrombi. The ground substance of the true tumours consists of a pure myxomatous tissue with elastic tissue and without any sign of organisation. The vessels show a highly developed formation, which is not usual in thrombi. They do not lie in the form characteristic of organised thrombi, and stand in no close relation to the elastic tissue net. In no part is there fibrin or fibroblasts, and nowhere a stratification of the tissues. Throughout the growth the vessels and cells of the outer and inner parts are similar. The presence of blood and blood pigment, he points out, is in no way against the diagnosis of neoplasm, as in most neoplasms of such vascularity, haemorrhages and pigment in all stages of absorption are frequent.

3. That they are similar in origin to Lambl's excrescences.- Lamb1 (1 8 5 6 ") described fine thread-like structures situated on the aortic cusps. These occurred singly or in small clusters, and were attached either to the free margin of the cusp, to the line of closure, or to the nodulus arantii. On microsopic examination they consisted of tufts covered by a single layer of endothelium, and contained a homogeneous hyaline central axis. Lanibl found such excrescences on the aortic cusps in a t least 2 per cent. of the thousand cases examined. Luschka (1 8 57 ") also described these structures on the aortic valve, and recorded a similar condition on a pulmonary cusp, which he said was rare. Koniger (1903 le) likewise noticed these bodies, and described an excrescence attached to the nodulus arantii of an aortic cusp, which was 4 mm. in diameter. Koechlin examined 150 bodies for these structures, and found them more or less marked in about 20 per cent. of the cases. He describes in detail thirty-seven cases. In thirty-five the growths were situated on the aortic cusps; four showed excrescences both on the aortic and mitral valves, one on the mitral and one on the pulmonary valves done. Many of the cases showed, in addition to the excrescence, fatty degeneration in the

7 2 GEORGE DEAN AND A. W; FALCONER.

central layers of the valve, and most of them were associated with a thickening of the nodulus arantii and of the free margin of the cusp. It was only very rarely that such an excrescence passed directly into a normal valve. All cases which showed such excrescences on the mitral valves showed in addition distinct evidence of endocarditis. The excrescences varied in size from a macroscopically scarcely visible thread-like structure to definite tumour-like bodies of several inillimetres in length and breadth. The majority of the larger structures were attached by a broad base; in a few there was a definite pedicle. Several of the larger pedunculated growths were shown on serial section to consist not; of a single growth, but of two adjacent ones. Microscopically, the excrescences were found to present an appearance very similar to that of the so-called neoplasms. Both structures arose from the ventricular connective-tissue layer of the cusp, both showed the sanie highly papillary structure, both were without vessels, and both were covered by a single layer of endothelium. On both, the ground substance consisted of a homogeneous poorly nucleated tissue with numerous elastic fibres.

Koechlin admits that his case of a growth on the pulmonary valve differs from the usual excrescence, in its sharply circumscribed origin from an unaltered valve and in the presence of niyxomatous tissue, but considers that there are so many similarities, that, although i t may be impossible to absolutely deny its neoplastic nature, it is equally impossible to affirm it. He concludes that no undoubted case of primary valvular neoplasm has yet been recorded, and that all the aIleged cases may be expIained either as Lambl's excrescences or as endocarditic formations.

Although it must be admitted that Lambl's excrescences present, in many of their microscopical features, a structure very similar to that of the alleged tumours, there appear to us, in the present uncertain state of our knowledge as to the exact significance of myxomatous tissue, to be several cogent reasons for not regarding the majority of the recorded cases of tumour as unusually developed excrescences. As these excrescences occur more or less developed in the aortic cusps in a considerable proportion of all adults, one would expect, if there was any close relationship between the two conditions, that; cases of apparent tumour would be of considerable frequency instead of extreme rarity. Furt<her, one would certainly expect that the enormous majority of apparent tuniours would be situated on the aortic valves. In Koechlin's thirty-seven cases of excrescences, in thirty-five the growths were situated on the aortic valves, and in only five were they found on the mitral valve. In all the mitral cases there was undoubted evidence of endocarditis. Excluding, on account of the insufficiency of the report, the cases of Debove (1875 '> and Curtis (1871-72 5>, one of which was situated on the tricuspid and one on the mitral valve, and excluding Ribbert's third case, which was

PRIMARY TUMOURS OF CARDIAC VALVES. 73

situated on the pulmonary valve, but which was of minute size and was associated with several papille passing directly into the cusp, we find that of the remaining eight tumours without vessels, three were situated .on the pulmonary valve, three on the aortic, and two on the tricuspid. Again, it would certainly be remarkable if the largest excrescences should arise by narrow pedicles from cusps which are either completely normal as in Koechlin’s case, or present only some thickening of the central layers of the cusp.

Granted that these growths represent true neoplasms, the answer to the question whether they are to be regarded as myxomata in the aense of Ribbert, or whether they are to be considered as fibrous tissue tumours undergoing various degenerations, must depend not on the consideration of these growths alone, but on the myxomata as a group.

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74 PRIMARY TUMO URS OF CARDIAC VAL YES.

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Primary tumours of the valves of the heart