TERATOMAS AND THEIR RELATION TO AGE H. E. HIMWICH

From Department of Pathology, C m e l l University Medical College, New York

Received for publication May 10, 1922

The great accumulation of reported cases of teratomas offers an excellent opportunity to review the data, with the object of investigating the relation of their frequency to the age of the host. In the course of the study, it has become apparent that this relationship is so definite as to assume the form of a gen- eral law.

The largest collections of teratomas were gathered by Taruffi and Ahlfeld. Both of these observers stressed the large con- genital forms which are situated in the head, the thoracic, the abdominal, or the sacral regions. Gonadal teratomas occur most frequently in early adult life (Wilms). Among others, Askanazy investigated the internal craniopagi, and Ekehorn, the internal thoracopagi. Lexer and Kakayama studied the abdominal inclusions and pygopagi.

Though many hypotheses have been advanced on the origin of teratomas, they may be resolved into two view points: The teratoma is either the offspring or the twin of its host. Stockard has recently produced experimental evidence in favor of the latter conception.

CRITERIA AND METHODS OF STUDY

Two precautions have been observed in compiling the present statistics: (1) Only growths of tridermal or bidermal origin have been considered. KO such case has been omitted. (2) Special effort has been exerted to determine the age at which the teratoma began its growth. The first increase in size of external growths may be accurat,ely observed. For those

26 1

262 H. E. HIMWICH

situated internally, the initial symptom was used as an indicator. Where the history was deficient, the age at which the operation took place or at which death occurred was taken as the closest approximation obtainable. The last criterium particularly applies to the teratomas of the aged. In this manner 895 cases have been studied. Sometimes a period of slow growth is followed by one of heightened activity. Such is the case of chorioma testis reported by Jackson, in which growth commenced at the age of twenty and slowly continued to twenty-three, after which the increase in size became extremely rapid. Since the relationship between the growth of the host and that of the teratoma is of interest, in such cases, the beginnings of both periods have been noted. A similar effort was made for internal teratomas, thus bringing the total number of growths tabulated to 975. In systematizing the results it was noted that though the

variation from year to year is considerable, there seems to be an orderly waxing and waning of the number of cases to an extent which justifies the drawing of a curve. An average has been drawn in order to minimize accidental variation. Six year periods have been chosen because they are the longest which correspond to actual changes throughout the length of the curve. The first period begins at fertilization and ends at five. In the curves which are drawn to a scale of one-half, the abscissae represent the age of the host when the tumor began its growth, the ordinates the number of cases in each year.

THE CURVE FOR ALL TERATOMAS

After an initial maximum rise, the curve falls and remains low from five to eleven years (fig. 1). At eleven it achieves a higher level, which is increased at seventeen and twenty-three years. The second maximum is found between twenty-three and twenty-nine years. The curve falls gradually at twenty-nine and thirty-five years, and then more rapidly at forty-one, after which it becomes progressively lower towards its end at seventy- six years. Eighty-seven per cent of the teratomas occur before forty-one years and 95 per cent before fifty-three.

TERATOMAS AND "HEIR RELATION TO AGE 263

.

Most congenital teratomas do not evince postnatal growth and since this study concerns only those which do grow, for the early maximal total may be substituted the smaller number of tumors, showing power for growth, represented by the low@ broken line in the graph. With this correction the highest point in the curve is found between twenty-three and twenty-nine years. This is borne out by Wilms who finds the period of greatest frequency for sex-gland teratomas to be between the ages of twenty and thhty years. His conclusion is to be expected because teratomas occur most frequently in aex glands.

..-. . I @ I I I I I I

r

Fro. 1. CURVE FOR ALL TERATOMAB The abscissae stand for the years of appearance of growths, the ordinates for

the number in each year. Both are drawn to a scale of one-half. The total number of congenital tumors is not shown. The dash line indicates the average for each six-year period. In the first six years there are two; the upper one stands for all cases, the lower for those which had power of postnatal growth. The mode is from twenty-three t o twenty-nine, the timo when growth stops.

STUDY OF THE CORRECTED CURVE

There are three aspects of the described phenomenon: First, it is evident that the total number of teratomas at any age increases with the actual growth of the individual. As size

264 H. E. HIMWICH

increases, the total number of teratomas increases. But it must be remembered that while size is increasing, growth rate is falling. Therefore, second, teratomas become more frequent as growth slows down, at the time when growth potential be- comes smaller. Growth must be recognized as involving two elements: increasing actual proportions, and decreasing growth potential. Hence, third, the total number of teratomas at any age increases as growth potential diminishes.

When one recalls the fact that the changes in growth rate are not constant, the number of teratomas is seen to bear even a closer relationship to the growth of the hosts than has been indicated. Not only do these tumors appear as growth of the host slows, but during their time of appearance the teratomas are more frequent in the periods of slower growth of the host. Teratomas are common in early infancy following a space of the most rapid proliferation of all-fetal growth. They increase again when the comparatively rapid growth rate of earlychild- hood gives way to the slower one of pubescence and lastly they are found in greater numbers as active growth gradually ceases.

To explain the relative number of teratomas appearing in the several periods we must take into consideration an additional factor, the growth potential of the embryonal rest, for a teratoma by most theories arises in an embryonal rest of some kind. It is known that the great majority of embryonal rests do not grow; they either degenerate or remain dormant. Others achieve a more or less perfect adult growth, while a few develop into tumors. Tridermal rests act in a similar manner. Thus we have a few with high growth potential, many with less capacity for growth, and finally others which remain latent unless they are stirred to development by an external stimulus.

During the first six years of life the growth rate of the host declines rapidly, bis growth potential is greatly reduced, and the number of teratomas of relatively higher potential, capable of proliferation, is comparatively large. From five to eleven years the growth rate is fairly constant, the loss of potential is small, and the additional number of teratomas released is few. The next appreciable change takes place during the differentia-

TERATOXAS AND THEIR RELATION TO AGE 265

tion occurring a t puberty and accompanying the maturation of the sex organs. Here the number of teratomas begins to increase and continues to do so until growth finally stops, at which time the greatest number of teratomas make their pres- ence known. Although the loss of growth potential in the host becomes smaller, being least in the final period from twenty- three to twenty-nine years, yet just because growth itself is slow, there is an ever increasing number of embryonal rests of low potential, capable of expressing their latent growth energy. The very inactive rests even a t this period do not have suficient energy to start growth spontaneously and are therefore consid- ered in another group at a later time. However, they may serve as a nidus for neoplasms since many do commence development after the growth of the host has stopped.

Thus the number of teratomas appearing a t any given time depends upon the amount of loss in growth potential of the hosts during that time and the number of rests whose potential is large enough to proliferate under these conditions. Evidently the number of teratomas in any period varies inversely to the growth potential of the hosts and directly as that of the embryonal rests.

ANALYSIS OF CURVES OF AGE INCIDENCE OF TERATOMAS IN THE DIFFERENT LOCATIONS

The object of this study is to show the relation to the general law of the occurrence of teratomas in the various situations.

Ekehorn in his collection of teratomas of the anterior mediastinum finds fifteen cases occurring between the ages of twenty and thirty, four between thirty and forty years, and four more to sixty, thus agreeing with the present curve in showing the maximum occurrence from twenty-three years to twen ty-nine.

Abdominal inclusions. The abdominal tridermal growths are frequently discovered a t birth but continue to be found throughout life, with a second rise from twenty-three to twenty- nine years.

Craniopagi and pygopagi. There is not a sufficiently large number of head and sacral teratomas to yield reliable statistics.

Thoracopagi.

2G6 H e E. HIMWICH

4 3 10 8 12 14 10 11 8

10 6 3 1 2 2

103

Statistic8 of varioue authors. They ahow a cloee agreement with or@inul statwlkr here presented. Note increaaed number of dermoida during pubeSCeM8

-- 0-5

6-17 18-24 25-29 30-34 35-39 40-44 45-40 50-59 80-75

--

5 0 16

11 11 7 3

2 2

61

-- 0-19

20-25 25-30 30-35 3540 40-45 45-60

4 6 0 - 6 0 80-63

--

46 1 1 4

2

279 33 70

114 144 118 94 45 30 10 10 8 6

OARCINOYAB - D v u p

11 26 48 19 20 21 10 10 14 14 1

-

- 207 -

- 1 19 7 2 2

- 31

- 1-5 6-10

10-15 15-20 20-25 26-30 30-35 36-40 40-46 4b-so 50-55 56-60 60-66 86-70 70 + -

I - 0 1 8 8

19 14 4 2 2

- 69

0-5 6-11

11-17 l.7-23 23-29 29-35 36-41 41-47 47-63 63-69 59-66 65-71

- -

2 2 1

12 29 30 34 27 10 8 1 1

- 167 -

10-20 20-30 30-40 40-50 so+

Incluiona according to age and situation. Those which are capable of growth appear in greater number from twenty-three yeara to twenty-nine years

?TQOPAOI I TOT'AL AOB .BDOYINAI P A B A I I T I B OVARIAN DRATOYAB rnOR*O- OPAQI RAMOPAQ 78 1 4 4 1

2

90

30 6

18 16 20 15 8 4 4 1 2 1 1

17 16 27 44 52 47 39 22 19 13 10 0 2

48 7 9

32 55 44 43 15 7

3 1

264

-5 6-11

11-17 17-23 23-29 29-36 35-41 41-47 47-53 53-69 69-65 66-71 71-77

Total. . . .

55 3

11 14 16 10 4 4 4 1 1

123 132 --

63 I 976 313

TERATOMAS AND THEIR RELATION TO AGE 267

Most are congenital. The internal craniopagi occur most frequently from eleven to twenty-seven years. The only year where there is more than one case is the nineteenth, where there are two. The last teratoma capable of spontaneous growth appeared at twenty-seven. The later examples of sacral tera- tomas are even rarer than those occurring in the head. There is one each at ten and thirteen years and four from nineteen to twenty-three.

Ovarian terakmas. Turning next to the gonadal teratomas and comparing the testicular and ovarian curves, we eee that the latter is less variable (fig. 3). This is due to the delayed diagnosis of so many of the ovarian teratomas, probably because of their slow growth, as their structure is often of the adult type. Their internal position further postpones their discovery, yet dermoids are sometimes found by accident. Nevertheless, the largest number of tumors occurs between the ages of twenty- three and twenty-nine. From a review of one hundred and three case8 Pauli fmds dermoids appearing most often from twenty to thirty years.

Another difference between the ovarian and testicular curves is the greater rise in the former in the two periods between eleven and twenty-three years. This phenomenon might be expected as a result of the growth differences since, in the male, postpubescent growth is more rapid than in the female.

Teratoma testis. The external situation of the male sex gland allows prompt discovery of its tumors. Although the greatest decline in rate of growth occurs early in life from birth to four years and the number of testicular teratomas at this time is large, the maximum number nevertheless occurs at a later period. This is probably due to the fact that growth under four years is comparatively very rapid in spite of its fast declining rate. The modal year of the curve is twenty-six, It is interesting to note that the last growth cartilage of the long bones ossifies at twenty-five.

Teratomas in the testes commence growth most frequently between the ages of twenty-three and twenty-nine years. Che- vassu finds the maximum between twenty and thirty years (fig. 2).

268 H. E. HIMWICH

TERATOMAB OF LATER LIFE

After establishing the time of greatest frequency of teratomas, it still remains to account for those of old age. Those diagnosed after the age of fifty-one may be divided into two groups. The first consists of neoplasms of adult structure which had reached the limits of their capacity for post-natal growth, while those of the second are more malignant. To the first group belong such tumors as the following:

Craniopagi. Beck reports a case in which a dermoid was found at autopsy in place of the hypophysis in a woman seventy- four years of age. Eberth reports a similar accidental finding beneath the dura in a woman of seventy-five.

Thoracopugi. There are two examples in Ekehorn’s collec- tion-Pinder’s case of a patient with bulbar paralysis, aged fifty- three, in whom the dermoid was discovered at autopsy; and Lebert’s of a man of sixty who had been dyspneic since his six- teenth year.

Abdominal inclusions. Rizzoli (Taruffi) reports two cases of late abdominal inclusions, one at sixty, the other at sixty-two. Symptoms had been present for a long time in both. In one of the cases they appeared first at the age of twenty.

The tumors mentioned thus far were benign, though some produced symptoms because of their size and position.

In the second group of neoplasms the element of trauma be- comes important in the etiology. There is Bonney’s report of a retroperitoneal chorioma of a man of sixty-seven, and Goebell’s of an abdominal teratoma that became malignant a t fifty-four, twenty-seven years after a mass had been diagnosed. Djewitski reports a chorioma of the bladder which first gave symptoms at the age of seventy-three. The same irritation which produces a papilloma of the bladder may transform an otherwise benign embryonal rest.

Pygopagi. Hudson describes a sacral teratoma which began growth at the age of fifty-two; the history shows that a nodule had existed in that region since the birth of the patient. The histological picture is one of a tridermal rest with cancerous degeneration of mucous glands. It is similar to an old age

TERATOMAS AND THEIR RELATION TO AGE 269

cancer arising in previously normal tissue. Evidently in the last four cases it is not growth potential of the embryonal rest but an extrinsic traumatic influence, to which every part of the body is subject, that caused the proliferation of cells. A case of Briddon’s beautifully illustrates both these factors occurring in the same growth but independently and at different times. It concerns a sacral dermoid which appeared externally a t the age of twenty-two and then ceased growth till the fifty-second year, when it underwent epitheliomatous change.

Teratoma testis. There are three examples of late teratoma testis. Lexer quotes one from v. Bergmann’s clinic in a man of sixty. On section the growth was of adult structure.

Ewing and Pepere report cases which first showed growth a t the ages of sixty-one and sixty-three, respectively. The micro- scopic examination in both instances showed carcinomatous change of one element in rt totipotent rest.

Ovarian teratmnas. Of thirty-two dermoids, thirteen exhibited malignant transformation of a carcinomatous, sarcomatous, or endotheliomatous type. Four showed thyroid structure, of which three were rapidly growing tumors. In six reports de- tails were lacking. However, since the growths were called dermoids, their structure must have been of the adult type, like that of the remaining nine inclusions.

To summarize, the late appearance of stationary teratomas is due to their delayed discovery, while that of growing teratomas is caused by their injury.

Carcinoma testis is discussed in this place not only for its possible teratomatous origin, but because trau- matic etiology links it with the tumors of later life. In many cases of teratoma testis in young people the transformation of a slowly into a more rapidly growing tumor is caused by trauma. In older people the growth is rapid from the start. The same se- quence of events obtains for carcinoma testis. The cell of many cases of carcinoma testis is characteristic, with a large nucleus and clear cytoplasm. Sometimes the growth is called a sarcoma; the difference in opinion is due to the fact that no analogous cell is found in the human body. This same cell is

,

Carcinoma testis.

270 H. E. HIMWICH

often found with teratoma testis. There are only two probable interpretations: (1) The irritation caused by some extrinsic factor, in this special case, by the teratoma on the tubule cells, is the cause of carcinoma. (2) The unique type of cell is of teratomatous origin. Chevassu takes the position that it develops from the adult spermatogonia, putting the tumor in the class of acquired carcinomas. The final convincing link in the chain of evidence has not been produced, for he has not been able to trace the steps of anaplastic change from the sperma- togonia to the carcinoma cell.

It has been definitely established that the cell which is of more rapid growth will often overrun and may finally crowd out alto- gether the other constituents of the tumor. Thus arise the rhabdomyomas, the chondromas-the simple tumors of the sex glands. In this uncontrolled competition the most embryonal type of cell would have a decided advantage. Therefore Ewing concludes that carcinoma testis is a one-sided teratoma. In the light of the foregoing it is interesting to see to which of these two theories the carcinoma curve lends itself.

According to Chevassu’s statistics embryomas occur with greatest frequency from twenty-five to thirty years and semino- mas from thirty-five to forty (fig. 2). The writer’s review of a larger number of cases coincides with the data of Chevassu, the modes occuring from twenty-three to twenty-nine years in the teratomas and thirty-five to forty-one years in the carcinomas.

Comparing the carcinoma testis curve with that of all cancer (Hoffmanl), of which the congenital cases are too small a propor-

Mortality from cancer throughout the United States Registration Area. All organs and all parte. 1903-1912. (Hoffman, The Mortality from Cancer.)

Until 10 10-24 25-34 35-41 45-54 65-04 65-74

75 and over

1,170 2,028 3,767

10,750 24,431 35,327 33,745 i a , ~

984 1,844 7,891

26,779 46,669 62,393 43,010 24,801

TERATOMAS AND THEIR RELATION TO AGE 271

tion materially to alter the general outline, we see that the former has no resemblance to the latter, for in that case it would have a continuous rise to some time after sixty. In brief, the carcinoma testis curve is the teratoma testis curve with themode slightly shifted.

Since the histogenesis of carcinoma testis has not been traced from either embryonal or adult tubule cells, it is probable that carcinoma testis is of nontesticular origin, and since there is no reason why misplaced cells should so often be of the same type or occur so frequently with teratomas, unless they are of tera-

Fro. 2. TESTICWLAR TERATOMAS The lower two curves are reproduced from Chevassu’s paper. The con-

tinuous line represents the teratomas; the dash line, the carcinomas. In order better to compare the new curves with those of Chevassu, the number of tera- tomas in each year was divided by four, and that of carcinomas by two. Both curves are plotted on a basis of ten-year periods.

tomatous origin, we are forced to this conclusion towards which the study of the curve gives additional evidence. Similarly to teratoma test,is, carcinoma may show a congenital increase in the size of the organ. Morestin (Chevassu) reports such a tumor, which assumed malignancy at the age of thirty-seven. Like-

272 H. E. HIMWICH

wise carcinoma occurs more often in undescended testicles. It begins its growth in the rete and, like teratoma testis, is occa- sionally observed in pseudohermaphrodites.

The origin of primary tumors of the ovary is so undecided that any data in reference to them is of particular interest. Here we shall mention a few facts in regard to one of these tumors which may be of teratomatous origin, i.e., the sarcoma.

Ewing divides these sarcomas into three main types: (1) spindle cell; (2) round cell; (3) myxoma cell. This classification is of special significance since just such types of sarcomatous de- generation of dermoids have been observed (Debucy).

Ovarian tumors.

FIG. 3. OVARIAN TERATOMAS These curves are averages for six year periods drawn to a scale of one-half.

The continuous line represents the teratomas with the mode from twenty-three to twenty-nine years; the dash line the carcinomas with the mode from eleven to seventeen years, the period of pubescence.

Desurmont finds that the different primary tumors are bilateral to varying degrees. However, sarcomas, 25 per cent, and der- moids, 20 per cent (Pauli), approximate each other quite closely.

Finally, the most common tumor of infancy is the sarcoma, which is most frequent at fifteen years (Donhauser). Cordier and Zangemeister give fifteen and twenty years, respectively, as the age of most common occurrence of sarcomas. They are found from fifteen years to twenty-five and from forty years to fifty (Desurmont), both periods of physiological stimulation, The writer finds the mode of the combined carcinoma and sar- coma curve at fifteen years (fig. 3). Comparing the mode of this curve with that of ovarian teratomas, we find that it has been shifted forward to the time of pubescence. Hence there is a group of embryonal cell tumors having an age incidence simi- lar to teratomas, and becoming malignant under the stimulation of puberty.

TERATOMAS AND THEIR RELATION TO AGE 273

FACTORS I N T H E ETIOLOGY O F TERATOMAS

The growth of the earlier teratomas may be adequately ex- plained on the basis of a growth competition between the host and the embryonal rest. But even in the teratomas of infancy another factor, trauma, may be present. It becomes increasingly important later on.

Growth potential. The growth of the host inhibits that of the teratoma.

The growth of the embryonal rest may be divided into two parts: its prenatal development, or growth which continues until stopped by the inhibition produced by the excessive growth of the host; and the growth of which it is still capable (growth potential) after that of the host slows down or ceases. These two parts are in reciprocal relation to each other. The earlier the prenatal inhibition, the smaller and less differentiated will be the inhibited rest but the greater will be the remaining growth potential. Small embryonal rests may develop proliferative powers while large ones, which achieve a certain intrauterine development, seldom if ever show further capacity for spontaneous growth.

The shift in the mode of the curve of carcinoma testis from twenty-three to twenty-nine years to thirty-five to forty-one years is due to an external stimulus.

In spite of the larger growth potential of the smaller testicular rests many do not achieve malignancy until their immediate region is traumatized. This is illustrated on comparing these tumors in the testicle and the ovary. A larger proportion of the latter are benign, forming adult structures. The chief difference in their histories is due to their locations; the testicle is exposed to injury, the ovary is not. It is generally admitted that teratomas do not become malignant much oftener than do normal tissues.

In the case of carcinoma testis we should expect with a history of injury to a small undifferentiated rest and the resulting pro- liferation of an embryonal cell, a shift in the mode of the cwve towards that of old age cancer.

Trauma.

TED JOURNAL 01 CANCER nmmutx, VOL. VI, NO. 4

274 H. El. H M I C H

SUMMARY AND CONCLUSIONS

i. Growth potential and teratomas

1. Parasite. Teratomas are tridermal embryonal rests en- dowed with a certain amount of possible growth, i.e., growt,h potential. When the rest is comparatively large it has necessarily consumed considerable growth energy before birth, while in the small teratoma, the growth period may be divided into two parts, a slight early growth soon followed by an inhibition, and a later, or post-natal growth, should conditions permit.

2. Host. The total number of teratomas in a population, up to any given age, increases while growth potential of the hosts decreases. As the Iarger increases in the number of tera- tomas occur in periods when growth of the host is slowed most, the growth of the host must inhibit that of the embryonal rest.

3. The number of teratomas appearing in any given time varies inversely with the growth potential of the host and directly as that of the embryonal rest. The tumors which begin their postnatal growth before that of the host stops are of highest potential, but are not necessarily more malignant, for they must overcome a still present inhibition. Since most teratomas have a low growth potential, they appear most commonly at the time the growth of the host stops-from twenty-three to twenty- nine years.

I I . Trauma and autono?nous growths

1. Teratomas which start growth as a result of injury are malignant more frequently than those which proliferate solely under t,he influence of growth potential.

2. When trauma precipitates growth, the teratoma is fre- quently monodermal. If the inclusion is still in an undifferen- tiated condition the cell is often of an embryonal type. If a developed inclusion is traumatized the cell in many instances is like that of acquired cancer.

3. The curve of carcinoma testis rises and falls in a manner similar to that of teratoma testis and not like that of old age

TERATOMAS AND THEIR RELATION TO AQE 275

cancer. This is another fact which may be adduced in support of the theory that carcinoma testis is a one-sided teratoma. In the female, a similar neoplasm might be expected to arise as the result of the physiologic stimulations of puberty, This is what actually takes place, hence the growth, in all probability, is of teratomatous origin.

4. Trauma is followed by proliferation of cells, and any pre- cipitant of regeneration may be important in the etiology of acquired cancer. I n the old the inhibition of the organism is almost negligible. Hence trauma at that time may readily be followed by an uncontrolled and therefore excessive growth. Thus, loss of growth restraint may be almost as important a factor in the etiology of acquired cancer as in that of congenital inclusions.

REFERENCES

BARRON: Teratomata of the brain, Jour. Cancer Res., 1916, i, 311. CIIRI~TIAN: Dermoid cysts and teratomata of the anterior mediastinum, Jour.

Med. Ree., 1902, vii, 54. DE~URMONT: Etude anatomo-clinique des tumeurs solides bilateralea des ovares,

These de Paris, 1911-1912. EWING: Neoplastic Diseases, Philadelphia, 1919. EWING: Teratoma testis and its derivatives, Surg., Gynec. & Obst., 1911, xii, 230. LEXER: Ueber teratoide Geschwulste in der Bauchhohle und deren Operation,

NAKAYAMA : Ueber Congenitale Sacraltumoren, Arch. f. Entwcklngsmechn. d.

STOCKARD: Developmental rate and structural expression, Am. Jour. Anat.,

TARUPPI : Storia della Teratologia, 1S61-1694.

Arch. f . klin. Chir., 1900, lxi, 646.

Organ., 1905, xix, 475.

1920-1921, xxviii, 115.

These references were chosen out of over one hundred and sixty; they contain extensive reviews of the literature consulted.