Education TUMORS of MUSCLE CHARLES I?

Education TUMORS OF MUSCLE CHARLES I?. QESCHICKTER, M.D.

(From the Surgioal Pathological Laboratory, Department 07 Surgery, Johns Hopbilcs Hoapital and Uniuereity)

INTRODU~TION: EMBRYOLOGY The muscular structures of the body appear very early in the embryo and are derived from mesoderm. Within the first month of embi:yonic life the mesoderm spreads out from the hind end of the embryo and separates into a paraxial mass, an intermediate cell mass, and sheets applied to the body wall and primitive digestive tube (Fig. 1). In the paraxial mesoderm and in the primitive body wall the seg-

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FIG. 1. nIAGRAMMATIC SECTION OF VERTmRATE EMBRYOSHOWING THE PARTS OF THE MESO- DERM (Modifled from Koith’s Human Embryology, Wm. Wood 5, Go., 1933) ment a1 voluntary muscles are developed. In the intermediate cell mass the musculature connected with the urogenital organs develops. In association with the splanchnopleure applied to the primitive gut, the muscles of the digestive tube, the heart, and the large blood vessels develop. Tumors are extremely rare in the spinal muscles of the body wall and limbs derived from the paraxial mesoderm. This rarity of tumor formation is probably dependent upon the extremely early differentiation of these structures. According to Keith no more new fibers are formed in skeletal muscle after birth, muscular growth henceforth being effected by enlargement of pre-existing fibers. On the other hand, tumors are very common in the smooth muscle of the genito- urinary organs developed from the intermediate cell mass, Here cle- 378 TUMORS OF MUSCLE 379 velopmental processes are delayed and modified in association with the sex physiology which necessitates fairly rapid changes in these structures. In the musculature of the digestive tube, heart, and large blood vessels derived from the splanchnopleure tumor incidence occu- pies a mid-position. New growths here are neither so rare as in the voluntary muscles nor so common as in the musculature of the gcnito- urinary organs.

TABLMI: Tumora of Smooth Muscle

Urogenital Digestive Vascular Tumor Musculature Musculature Musculature

Leiomyoma Uterus.. ... 5,900 G. I. tract., . , .128* Leiomyoma cutie Vagina. ...220* 2 Intestines. .... 45* 4 with involved Bladder.. .. 48* 1 Rectum ...... 27, 1 vessels...... 7* Prostate.. . 7* 7 Stomach...... 19 Kidney.. .. 4 Esophagus .... 28* Leiomyosarcoma Uterus.. ... 54 Digestive tract 20, Heart...... 40* Bladder.. .. 19* 6 Stomach...... 1 Ileum...... 1 Rectum...... 1 - Rhabdomyoma and Uterus.. ... 18* 1 Heart...... 42* Rhabdomyosarcoma Cervix.. ... 1 Vagina. ... 2 Bladder.. .. 13" 1 Testicle.. .. 14*

Myoblastoma Vagina. , . . 1

* Collected from the literature. Other numbers represent cases on file in t,he Johns Hopkins Hospital.

The individual muscle cells develop from a syncytial stage in the mesenchyme. These cells form fibers of smooth muscle, according to Carey, by the drawing out of their spongioplasm into longitudinal processes. Where voluntary muscle is formed there is a definite myoblastic stage in which the elongated cells become multinucleated and protoplasmic processes develop, in which striae appear. Between the third and fourth months of embryonic life the centrally arranged nuclei of these myoblasts migrate to the surface and both the nucleus and cytoplasm are encased in a sarcolemma sheath to form an adult fiber of voluntary muscle. According to Carey, the distinction between smooth and voluntary muscle is a matter of degree of differentiation in response to the laws of dynamics. Smooth muscle is formed from mesenchyme by a tension exerted on the muscle cells during growth. If this tension is much increased, smooth muscle is converted into voluntary muscle, Carey was able to convert smooth muscle of the bladder in the young dog into striated muscle by increasing the tension on the bladder wall with fluid pressure. Tumors of smooth muscle repeat the histogenesis of this structure. 380 CHARLES F. OESCEIOHTER

Myosarcoma and Rhabdomyosarcoma M yoblastoma Non-indigenous tumors Myoarcoma with giant Oral cavity...... 12*-1 Myoaitk ossificans ...... 32 mlls ...... 12 Tongue...... 22*-l Lipoma...... 1 Rhabdomyosarcoma. .... 2 Subcutaneous...... 7*-1 Fibroma...... 10 Extremities...... 2*-5 Angioma...... 3 Sacral (subcutaneous). ... 3 Mammary ...... 2

"Collected from the literature. Other numbers represent eases on file in the Johns Hopkins Hoepital.

Tumors of striated muscle and cardiac muscle repeat the more complicated histogenesis of these tissues. Benign tumors of striated muscle show cross striations in their elongated cytoplasmic processes (rhabdomyoma). More undifferentiated benign tumors composed of myoblasts with wavy, granular fibrils also occur. The sarcomas of striated muscle in certain cases may duplicate in structure the spindle-cell sarcomas of smooth muscle or may show the features of the multinucleated myoblastic stage in which the cells are large, elongated, and multinucleated. The histologic types of muscle tumors and their distribution in the muscular structures are indicated in Tables I and 11.

I. TUMORSOF INVOLUNTARY~IUSCLE Leiomyoma Uterine Myomas: These muscular tumors, the most frequent of uterine neoplasms, occur during the period of active sex life. Approxi- mately 6,000 of these tumors have been surgically removed at the Johns Hopkins Hospital in the last forty years, They are more common in the colored than in the white race. The tumors are either single or multiple and may be (1) subserous, projecting from the wall of the uterus.toward its peritoneal surface, (2) intramural, within the uterine wall, or (3) submucous, directed toward the uterine cavity. The subserous and submucous varieties may be pedunculated and cause acute symptoms by twisting and strangulation of the pedicle. Necrosis, infection, and fibrosis are common changes in these growths. Myoma may caum increased menstrual bleeding through changes produced in the neighboring endometrium, or the submucous type of myoma may bleed into the uterine cavity through erosion of the vessels. Small myomas may produce no symptoms. Diagnosis can usually be made by palpation. The mass can be moved backward and forward with the uterus and has TUMORS OF MUSCLE 38 1 a characteristic nodularity or firmness. Under the microscope strands of smooth muscle and adult connective tissue predominate. These may be displaced by cysts, calcareous areas, or hemorrhage. Rarely marked proliferation occurs, and in about one per cent of these tumors malignant change in the form of spindle-cell sarcoma (leiomyosarcoma) is seen. (Figs. 2-6.)

FIG.2. BENIQNMYOMA OF THE UTERUS,SHOWING THE ENCAPSULATEDNATURE OF TEE GROWTH AND THE FIRM,INTERTWININQ BANDSOF MUSCLEAND FIBROUSTISSUE. PATH. NO. 37884

FIQ. 3. PHOTOMI('R0QRAPH OF A BENIQNMYOMA OF THE UTERUS, SHOWINQ INTERLACINO FIBERSOF SMOOTH MUSCLE. PATH.No. 44834

Myomas are treated by irradiation, myomectomy, or hysterectomy. Radiation is preferred in intramural growths of moderate size in women near the menopause, but is contraindicatcd in younger women in the childbearing period since the regression obtained is brought about by the effect of the radiation on the ovaries. In these younger patients, and where the uterine mass is larger than a three months' pregnancy, 382 OHARLES F. OESCHICKTER myomectomy should be performed. Necrotic and infected tumors pro- ducing marked symptoms in older women or undergoing malignant change are treated by hysterectomy. In all cases where conservative measures are contemplated diagnostic curettage is indicated to exclude malignancy. Myomas of Other Gewito-Urinary Organs: Myomas in the genito- urinary organs other than the uterus are not uncommon. Myomas of the broad ligament and of the cervix are usually associated with similar lesions of the uterus. Schilling was able to collect 220 cases of myomas of the vagina. The tumors are usually found in the anterior vaginal wall in patients between thirty and forty-five years of age. The larger krowths are pedunculated; they may press on the bladder or rectum

FIG. 4. RAPIDLY PEOLIFERATING MYOMAOF TEE Umus IN A WOMAN OF TWENTY-FOUB, REMOVEDBY HYSTE~ECTOMYIN 1928. PATH.No. 41514 The patient was reported well in July 1934, six yeare later. and are treated by excision. Kretschmer collected 48 leiomyomas of the bladder and found them equally divided between males and females. Hematuria, frequency, and dysuria were the common symptoms. The lesions can apparently appear at any age. From his study Kretschmer estimated that 10 per cent of all bladder tumors were mesothelial or embryonic in origin. Hinman and Sullivan collected six cases of leiomyoma of the prostate. The lesions occur in adults and are usually mistaken for prostatic hypertrophy (Fig. 7). In approximately 13,000 autopsies performed at the Johns Hopkins Hospital there are recorded one leiomyoma of the bladder, 4 in the kidney, and 6 in the prostate. In the cases surgically treated one myoma of the prostate, two of the vagina, and one attached to the ovary were observed. The majority of the lesions were small and definitely encapsulated. (Fig. 8.) Myomas of the Digestive Tube: Benign tumors of smooth muscle may occur in the wall of the digestive tract anywhere in its course from the esophagus to the rectum. Bouvier in 1924 collected a series of 128 leiomyomas occurring in the digestive tube. They are more common TUMORS OF MUSCLE 383 in the stomach. Raiford, reviewing the material from his laboratory and in the literature, was able to collect 45 myomas divided about evenly between the small and large intestine. The ages of the patients varied between thirteen and sixty-eight years, and males were affected more often than females, in the ratio of three to two. Myomas are more frequent in the ileum than in other portions of the intestinal tract and arise most frequently from the inner circular layer of muscles. The tumor may project as a polyp covered by mucosa or may form a sessile mass beneath the mucous membrane. Occasionally the layers of the mesentery are invaded. The tumors are firm in consistency and under the microscope show an interlacing of muscle fibers which re- semble those of uterine myomas (Figs. 9-11). The same regressive

Fro. 5. PHWMICROQRAPHFROM THE SPECIMENSHOWN IN FIQ.4 The tumor is composed of tightly packed immature muscle cells with poorly developed fibrils. It may be distinguishcd from sarcoiiia by thc absence of tumor giant cells aiid the scarcity of mitotic figures. changes may be noted histologically. The most common symptom is partial or complete obstruction. Bleeding with melena may occur. In such symptomatic growth resection of the affected portion of the bowel is employed. Nineteen cases of myoma of the stomach were found on routine autopsy examination at the Johns Hopkins Hospital (Figs. 12 and 13). All of these were small submucous nodules and produced no symptoms during life. The nodules occurred in adults, were multiple in two instances, and affected the pylorus, the cardiac end, and the body of the stomach with about equal frequency. Among the six females affected, two also had myomas of the uterus. In two males there was an accompanying hypertrophy of the musculature of the prostate. One large tumor of the stomach observed at operation was recorded in the series. 384 OHARLES F. QESUHIOETER In this instance bleeding and obstruction occurred. Morgan has reported a similar case of a gastric myoma, with death from hemorrhage. Myomas have been reported in the esophagus, appendix, rectum, and in Meckel’s diverticulum. Bezza collected 28 leiomyomas of the esophagus. Pape and Spitznagel described two cases of myoma of the esophagus, one with multiple myomas in the esophagus and stomach, and death from carcinoma of the bronchus, and another with a large solitary pedunculated myoma of the gullet and death due to asphyxia.

FIO.6. PHOTOYICBoGEAPE OF A VASCUUR, INVASIVE MYOMAOF THE UTERUS OCCVBRINO IN A COLOW WOMAN OF FORTY-NINE.PATH. NO. 10438 The entire uterus was filled with myomatous growth. The patient died postoperatively following a panhysterectomy. At autopsy tumor nodules were found invading the pelvis, attached to the diaphragm, and surrounding the adrenal and kidney. The section shown was removed from the mass near the adrenal. It is extremely vascular and contains many immature muscle cells with myofibrils. Pohl has reported a myoma of the rectum and was able to collect 27 cases from the literature. Myomas of Vessels, Voluntary Muscles, and Subcutaneous Struc- tures: Benign myomas arising in smooth muscle are extremely rare outside of the genito-urinary and digestive tracts. In the heart and voluntary muscle non-striated tumors are potentially malignant and are usually undifferentiated rhabdomyomas. Ormsby was able to collect 44 cases of subcutaneous leiomyomas arising in most instances from the arrectores pilorum of the hair follicles. Seven of these cases were originally described as originating in the muscularis of the blood vessels. Clinically this condition, which is known as leiomyoma cutis, PIQ. 7. PHOTOMICBOOBAPH OF A BENIONLEIOMYOMA OF TEE PROSTATE.PATH. No. 53120 The patient was a man of seventy-five who suffered difficulty in voiding. Examination showed hypertrophy of the left lobe of the prostate. Buprapubic prostatectomy was done in December, 1933. The patient died one mouth later from pulmonary embolism. (Case of D. L. Dial.)

FIQ.8. LjMaLL MYOMATOUSNODULE OCCUB~INO IN THE CAPSULE OF THE KIDNEY,DISCOVERED AT AUTOPSY. GEN. PATE.8285

385 386 CHARLES F. GESCHICKTER is characterized by multiple elevated nodules of small size varying in color from pink to red or dull brown (Fig. 14). The number of nodules beneath the skin ranges from 20 to 100. They are painful and sensitive to pressure. The disease progresses slowly with increase in the size and number of the lesions. The condition is not radiosensitive and when treated by excision shows a tendency to recur in other areas. The tumors are characterized histologically by masses of smooth muscle fibers in disorderly arrangement. Leiomyosarcoma Uteriwe arzd Gewito-Urkary Leiomyosarcoma: One per cent of myomas of the uterus are complicated by the occurrence of sarcoma,

FIG. 9. MYOMAor PHI ILEIJXREMOVED BY RESECTIONFBOM A GIRL OF THIRTEEN. PATH. NO. 46281 The patient had been troubled with vomiting and nausea and vague gastric discomfort. The tumor mass could be palpated in the region of the appendix. The gross specimen shows a sessile mas8 projecting into the lumen of the intestine and a long pedunculated growth on the peritoneal surface. Fifty-four such cases were reported in the present series. The rela- tionship to previous benign myomas is indicated by the occurrence of a solitary malignant area in some cases with multiple benign myomatous lesions in the remaining portion of the uterus. Although the majority of the cases occur after the menopause, patients between the ages of thirty-five and forty-five are not uncommon. Bleeding from a large boggy uterus is one of the most common symptoms. The tumor may project into the cavity in the form of a large polyp, and rapid growth is the rule. Irradiation may fail to check the bleeding. The histology of the tumor tissue in myosarcoma of the uterus is variable. Usually a rapid proliferation of spindle cells with frequent mitotic figures and tumor giant cells is seen. The elongated spindle cells may be tightly packed or may be separated by a stroma of fibrous FIQ. 10. Low-POWERPHOTOMICROGRAPH OF A SECTIONTHROUGH A SMALLMYOMA OF THE ILEUM DISCOVEREDAT AUTOPSYIN A MAN OF SIXTY-EIQHT. GEN. PATH. 10584 The patient was suffering with an enlarged prostate with marked muscular hypertrophy in the stroma. The small sessile growth arose from the circular layer of the muscularis. (From Raiford, T. 8.: Tumors of the Small Tutestine, Arc.11. Burg. 25: 122, 321, 1932.)

FIQ. 11. PHOTOMICROGRAPHSHOWING THE INTERLACINGMUSCULAR FIBERS FORMING THE TUMORDEPICTED IN FIG.10 (From Raiford, T. 8.: Tumors of the Small Intestine, Arch. Burg. 25: 122, 321, 1932.)

387 FIG. 12. LOW-POWER PHOTOMICROQRAPH OF A SECTION THBOUQH A SMALL MYOMAOF THE STOMACH The growth resembles the tumor shown in Figs. 10 and 11.

FIG. 33. PHOTOMICBOQBAPH FEOM THE SPECIMEN SHOWN IN FIG. 12 TUMORS OF MUSCLE 389 material. Areas of necrosis and hemorrhage are frequent. In the less malignant growth there is a tendency for the cells to retain an orderly alignment. In the more rapidly growing tumors the cells, with much larger and irregular nuclei, are scattered in a disorderly fashion. There is general agreement that the majority of these spindle-cell sarcomas of the uterus are derived from smooth muscle rather than from the surrounding connective tissue, and that the majority of them develop in previously benign myomas. A small percentage of benign myomas show a transition to sarcoma in the form of a rapid prolifera-

FIff. 14. PHOTOMICROQRAPH OF ONE OF MULTIPLE SMALL NODULESBENEATH THE SKIN IN A CASEOF LEIOMYOMACUTIS The iuterlaciiig fibers of smootli niuscle can be seen just beneath the epidermis. tion of elongated cells difficult to distinguish from the frankly malignant sarcoma (Figs. 4-6). Ewing is of the opinion that many of these sarcomas are malignant from the start. The tumors are best treated by radical hysterectomy. Sarcoma of smooth muscle in genito-urinary organs is relatively rare outside of the uterus. The bladder and kidney are most commonly the seat of such extra-uterine growths. Four tumors of this type occurring in the bladder and two in the kidney are recorded in the Surgical Pathological Laboratory at Johns Hopkins (Figs. 15-18). Krauskopf has reported a tumor in the blGdddr of a woman of sixty years who had a mass above the symphysis with frequency of urination and loss of weight. The tumor was definitely encapsulated. He was able to collect 19 similar cases in the literature. 390 CHARLES F. GESUHICKTER

Leiomyosarcoma of the Digestive Tract :Myosarcomas of the digestive tract are most common in the stomach and small intestine. In the series of this laboratory there was one case each in the stomach, ileum, and rectum (Figs. 19-22). In a review of 335 gastric sarcomas D’Aunoy and Zoeller found that myosarcoma constituted 6 per cent of the entire series. According to Klages, who refers to 128 cases of benign and malignant myogenic tumors of the gastro-intestinal tract in the literature, malignant lesions of this type are extremely rare. He could find only 20 myosarcomas in the series studied. He found only one myosarcoma of the rectum besides that observed by himself,

FIG. 15. LEIOMYOSARCO~IAOF THE BLADDE~(PATH. No. 45450) The patient was a colored man of thirtyone years, who complained of pain on urination and cramps in the lower abdomen. Ten days previously he had passed blood in the urine, followed three days later by severe hemorrhage. The tumor was pdunculated. It was excised in 1931, the pedicle fulgurated and radium implanted. The patient was reported well six months later. and none in the colon, Recently Mornet and Delarue reported such a tumor in the rectum and Neugebauer a myosarcoma of the cecum in a woman of forty-eight years. Dvorak in a review of esophageal sarcoma quotes Simon’s statement that only 30 acceptable cases are on record. Only three of these cases were histologically described as containing fibers of smooth muscle, although more than twice this number were described as spindle-cell sarcoma. Leiomyosarcoma of the digestive tract, as of the genito-urinary tract, may be encapsulated or infiltrative. The lesions metastasize late to the lung and to the liver. They tend to recur and to kill by invasion. Isolated cases of permanent cures have been recorded. The tumors are radio-resistant. Leiomyosarcoma of the Heart: Whereas the majority of benign neo- Fro. 16. PHOTOMICROOROHOF A LEIOMYOSARCOMA OCCURRING IN THE LEFTKIDNEY OF A MAN OF SIXTY-SEVEN YEARS. GEN. PATH.8577 The patient had been suffcring from prostatic hypertrophy and anemia, and complained of a mass in the lower abdomen. Clinically, the diagnosis of Banti’s disease had been con sidered. The patient had had numerous vomiting spells and had passed blood in both the urine and stools. He died following operation for removal of the prostate. At autopsy the left kidney was displaced by a large tumor mass weighing 3700 grams and measuring 22 cm. in its longest diameter. Its cut surface showed dense white tissue arranged in whorls. The tumor had invaded the pancreas and the renal vein.

FIQ.17. PHoTOXICRWEAPH OF A LEIOMYOSARCOMAARIBING IN THE KIDNEY. PATH. NO. 47170 This tumor was found at autopsy in a man of sixty-five. According to his physician his death had been due to cardiac failure. Thc tumor measured 9 x 7 x 4 em., and occupied the lower pole of the left kidney. Tumor nodules had collapsed the right lung. 391 392 UHARLES F. QESUHTCETER plasms primary in the heart are rhabdomyomas, the majority of the sarcomas arising in that organ are of spindle-cell type, approaching leiomyosarcoma in structure (Fig. 23). Goldstein was able to collect 40 cases of primary malignant tumors of the heart arising in the muscle. This represents a rather large series in the heart, where involvement by any form of neoplasm is rare. Leriche and Bauer were able to collect only 150 neoplasms of the heart of all types and Morris estimated that only 0.38 per cent of carcinoma and 0.7 per cent of sarcoma metastasized to that organ.

FIG. 18. PHOTOMIC~QRAPHOP A MEJPASTATIC NODULEIN THE LUNQ PWM THE CASE OP LEIOMYOSARCOMABHOWN IN FIQ.17

Rhabdomyorna and Rhabdomyosarcoma Muscular tumors containing fibers with cross striations occur in the genito-urinary tract, in the upper portion of the alimentary tract, in the skeletal muscles, and in the heart. The incidence of these tumors is greatest in the heart. Cardiac rhabdomyomas are benign congenital lesions which terminate fatally because of the local changes produced. Elsewhere rhabdomyomas show a uniform tendency to undergo malignant change. Neoplasms of this group, therefore, have a grave prog- nosis, either because of location or because of their pathological char- acter. Rhabdomyomas of the Heart: Farber was able to collect 42 rhabdomyomas of the heart, 34 of which showed multiple nodules and 8 of which were solitary. One case of cardiac rhabdomyoma is recorded in the present series. The tumors apparently have their origin before FIG. 19. LEIOMYOSARCOMAOF THE STOMACH,REMOVED AT AUTOPSYFEOX A MAN OF TEIRTY- THREE YENLS. PATH. NO. 30095 The patient had been seen twice, previously, for fulluese in the abdomen, pain, and diarrhea. A liver abscess had beeii drained and a tuberculous tumor was found in the sigmoid. Ten years later because of blood in the stools, diarrhea, and abdominal pain, the abdomen was explored under a diagiiosis of duodeiial ulcer. A retroperitoiieal growth was found ulcerating through the posterior stomach wall. A gastro-eiiterostomy was done. Death was due to extension of the abdominal mass.

FIG. 20. PHOTOMICROGRAPHOF TUMOR SHOWN IN FIG. 19

393 394 CHARLES F. GESCHICKTER birth and only 12 patients are reported as living beyond the age of three years. One tumor was reported in a patient of thirty-five years. The patients usually show some abnormality of the central nervous system (tuberous sclerosis of the brain) and die of early cardiac failure. Cardiac rhabdomyomas show a characteristic microscopic picture (Fig. 24). The cells are large and contain numerous protoplasmic processes which surround vacuolated spaces. The diagnostic features lie in the protoplasmic processes. These are supposed to form typical

FIQ.21. AUTOPSYSPECIMEN OF A LAMELEIOMYOSARCOMA ARISING IN THE JEJUNALWALL AND METASTASIZINQTO THE Lwm. PATH.No. 44558 (From Raiford, T. S.: Tumors of the Small Intestine 25: 122, 321, 1932.) sarcous elements and have a sheath of Krause. Bead-like granules which, according to Wolbach, arise from the centrioles occur, and definite striations can be found. The tumors do not metastasize. Rhabdomyomas of the Gennito-Urinary Tract: These potentially malignant tumors with striated fibers have been reported in the ovary, testicle, kidney, bladder, prostate, and uterus (Mallory, Ewing). In the series studied in this laboratory the rhabdomyomas had the following distribution: uterus, 1; cervix, 1; vagina, 2; bladder, 1 (Figs. 25 and 26). Petersen was able to collect 18 cases of rhabdomyoma of the uterus in 1923. Several recent reports have appeared in the literature (Shaw, Shapiro, Lista, Cook County Hospital). Colombino reported a rhabdomyoma of the bladder in a boy of seventeen years and collected TUMORS 0% MUSCLE 395 13 cases from the literature. Lockwood reported a case in the vulva of a child and Hirsch collected 13 cases, adding one of his own, of rhabdomyoma of the spermatic cord. All of these growths produce fleshy infiltrating masses which rapidly invade the surrounding tissues and eventually give rise to metastases. The tumors are characterized histologically by large nuclear structures, elongated protoplasmic processes with and without striation, numerous tumor giant cells, and smaller cells with peculiar spider-like processes.

FIG. 22. PHOTOMICROGRAPHOF TUMOR SHOWN IN FIG. 21 (From Raiford, T. 8.: Tumors of the Small Intestine, Arch. Burg. 25: 122, 321, 1932.) Many of the growths are extremely vascular. They are not radio-sensitive and show a great tendency to recur after excision. The tendency for rhabdomyomas of the genito-urinary tract to be associated with smooth muscle fibers and with occasional areas of spindle-cell sarcoma suggests a mesenchymal origin and a metaplasia of voluntary muscle from smooth non-striated forms. Many authors, however, have disputed such an origin. In the gonads the striated fibers quite frequently are of teratological origin and can be traced to mesodermal structures. On the other hand, the experiments of Carey, cited above, suggest a metaplasia of voluntary fibers from the mesenchyme. FIQ.23 A. MYOSARCOMAOF TEE HEARTOCCURRING IN A WOMANOF THIRTY-NINEYEARS. PATE.No. 53394 The patient had complained of dyspnea and cough and had recurrent cardiac attacks with marked cyanosis and edema of the face and upper extremities for five months prior to death. There was fluid in the chest and increased mediastinal dullness. At autopsy a mass tho size of a grapefruit was found distending the right auricle and arising from the interauricular septum. (Case of Dr. L. Keasbey.)

FIQ.23 B. PHOTOMICROGRAPHOF TUMOR SHOWN IN FIQ.23 A

396 TUMORS OF MUSCLE 397

Summary Tumors of smooth muscle can be conveniently summarized on the basis of the cases collected from the various services of the Johns Hopkins Hospital and studied in the Surgical Pathological Laboratory. The benign smooth muscle tumors found in the genito-urinary tract included, beside those of the uterus, 2 of the kidney, 6 of the prostate, one of the ovary, and 2 in the vagina. These tumors were small and encapsulated lesions, firm in consistency and sometimes pedunculated. The symptoms were never pronounced. The 25 benign myomas of the gastro-intestinal tract included 20 myomas of the stomach, 4 of the small intestine, and one of the rectum.

FIU.24. CONOENITALRHABDOMYOMA OF THE HFARTIN AN INFANTDYINQ FORTY-EIUHT HOURS AFTER BIRTH. PATH.No. 53118 The photomicrograph shows large myoblasts with a vacuolated or granular cytoplasm with numerous fibrillar processes. Small spider-like cells are seen in the stroma. Under oil im- mersion the processes of the myoblasts were seen to contain definite striations. (Case of Dr. John Gray.) With one exception all of the lesions in the stomach were symptomless and were found at autopsy. This exception and the myomas elsewhere in the digestive tube produced symptoms of obstruction and bleeding. Most of the growths were intramural ; rarely they were pedunculated (Fig. 9). While invasive myomas in the genito-urinary or gastro- intestinal tract are prone to be vascular, and cannot be related to the musculature of the enclosed vessels, two instances of encapsulated muscular nodules (Fig. 27) m7ere recorded, the size of a walnut, one in the musculature of the thigh, the other subcutaneous and apparently arising from the muscular wall of vessels. Only one case of leiomyoma eutis, arising from the smooth muscle of the hair follicles, occurred in this series (Fig. 14). FIQ.25. RHABDOMYOSARCOMAOF THE CERVIX OCCIJRRINQ IN A WOMAN OF THIRTY-NINEYEARB. PATH.No. 52680 The patient had suffered from intermittent bleeding and on examination a large mass was found infiltrating the vagina, arising from the cervix. The characteristic large myoblasts with coarse aiid fine myoflbrils are seen in the ~iliotoniicrograpli. Compare with Figure 24.

FIG. 26. RHABDOMYOSARCOMAOF THE BLADDERIN A BOY OF SEVEN. PATH.NO. 6798 The patieiit hail difficulty iii uriiiating, progressing to inability, and a cystostoiiiy had bcru done elsewhere to relieve his symptoms. At examination the abdomeii was distended aiid a purulent discharge of urine drained from a fungating wound. The rectum was obstructed. Death followed a suprnpultie cystostoniy. At autopsy the entire pelvis was Alled with a gelatinous, mucoid mass. Both ureters were obstructed aiid multiple abscesses were found iii both kidneys. There were no denioiistr:rble metastases. The characteristic large myoblasts with myofibrils are shown. Mesciicliyinal areas of stellate cells were also characteristic of the sections.

398 TUMORS OF MUSCLE 399 In addition to the 54 leiomyosarcomas of the uterus, the following sarcomas of smooth muscle in unusual locations in the genito-urinary tract were studied: 4 in the bladder, oiic in the cervix, and 3 in the kidney. Two of the bladder tumors were pedunculated; 2 were sessile. All recurred or metastasized. The lesions of the kidney were invasive and killed by transplantation, extension, or metastasis. One patient with sarcoma of the cervix has remained well following excision and irradiation. In the gastro-intestinal tract, there was one myosarcoma of the stomach, one of the small intestine, and one of the rectum. All proved

FIo. 27. ENCAPSUL.lTED MYOMAHENE.ZTI3 TIIE FAS(’1A OF TIiE THIGHIN A MAN OF FORTY- THREE, APPARENTLYARISING FROM TIIE WALL OF Rl.OOD VESSELS. PATH. NO. 52766 The mass was Ii:~rd, not adlicwwt, and about 3 WII. in iliatneter. Tlie section shows the proliferation of large niuscular fibers about tlic \\~:rllsof siiiall blood vessels. fatal. They were large growths, mctastasiziiig to the regional lymph nodes or to the liver. In the vascular tree there was one spindle-cell sarcoma of the heart with characteristic muscular structure, arising from the iiiterauricular septum, It was a large invasivc growth about the size of a small grapefruit. A review of the smooth muscle tumors seems to indicate that those growths outside of the uterus are more vascular and more prone to maligiiant change than the wry common uterine myoma. Striated tumors were rare in this series. One rhabdomyoma was observed in the heart, one in the cervix, one in the bladder, and two in the vagina. The tumors outside of the heart were definitely malignant. The details of these striated muscular growths are presented in Part, 11, under the discussion of tumors of voluntary muscle. 400 OHARLES F. OESCHICKTER

11. TUMORSOF VOLUNTARYMUSCLE Tumors of voluntary muscle are extremely rare. In the present series, rhabdomyomas were observed in the heart, cervix, vagina, and bladder. It is questionable whether the term rhabdomyoma should be used in describing tumors of voluntary muscle, because of their un- doubted malignant tendencies. According to Klinge, only 9 accepttible cases of rhabdomyoma of the body musculature had been described up to 1926. There were two additional rhabdomyomas of the voluntary muscles in the present series, one observed in the cervical region of a child, the other in the leg. With the exception of the case occurring

FIQ.28. RHABDOYPOSARCOYAOCCURRINQ IN THE CERVICALREQION OB A CHILD OF SIX. PATH. No. 49689 To the right is shown a mass of large myoblasts. In the center myofibrils are depicted, and to the left a syncytium of mesenchyme. The tumor was in the region of the parotid gland, which is indicated to the extreme left.

in the heart all these lesions were malignant. Twelve myoblastomas, chiefly subcutaneous, and 12 myosarcomas of the musculature of the extremities were studied. Taken as a group these 30 tumors of striated muscle represent every phase in the histogenesis of voluntary muscle, Voluntary muscle passes from a syncytial stage in mesenchyme to a myoblastic stage and thence to a myofibrillar stage in which the developing muscle fibers show first beading and then cross striations. In this latter stage multinucleated cells are common. In benign rhabdomyomas of the heart nearly all the enlarged myoblasts show proto- TUMORS OF MUSCLE 401 plasmic processes which have developed myofibrillae, many with bead- like nodes and others with cross striations. The coarse fibrils containing granules have been described as arising from nuclear chromatin and are seen in normal histogenesis. Benign myoblastomas of voluntary muscle are composed of cells with a large amount of granular cytoplasm and a small nucleus with occasional protoplasmic processes or fibrils. Rhabdomyosarcomas-or myosarcoma, as the more undifferentiated tumors are called-show more completely all phases of histogenesis. Areas of small spindle cells represent the mesenchymal condensation from which the muscle tissue arises. Where such areas cannot be found separately, these cells may be made out in the stroma

FIO.29. SARCOMA OF VOLUNTARY MUSCLEOCCURRING IN THE FOREARMOF A MAN OF SIXTY- THREE YEARS. PATH. ?JO. 47680 The tumor recurred after excision three years previously. The photomicrograph shows numerous tumor giant cells surrounded by coarse niyofibrils. Under high power numerous of these fibers call be traced directly to the large myoblasts. Cross striations were not seen in the tumor. of the tumor. Myoblasts of varying sizes are prominent in rhabdomyosarcomas. In these tumors and in the undifferentiated myosarcomas all forms of myofibrils of the fine, coarse, and beaded types may be found, accompanied by clumping of nuclei and the formation of tumor giant cells. Rhabdomyosarcoma and Myosarcorna: Two rhabdomyosarcomas in which cross striations were visible on microscopic study are shown in the accompanying illustrations (Figs. 26 and 28). One of these was in the cervical region of a child, another in the bladder of a boy aged seven. In both of these tumors areas of spindle-cell sarcoma, repre- senting a condensation of mesenchyme, were prominent. The spindle cells showed a tendency to grow in strands alternating with loose myx- FIQ. 30. MYOSARCOMAOCCURRING IN THE LEQ OF A BOY AQED SEVENTEEN. PATH. NO. 28117 The tumor had developed six weeks after a trauma received in a baseball game. Ampu- tation was done through the upper third of the thigh following a dissection of the lymph nodes about the femoral vessels. The patient was reported well eleven years later. The large myoblasts shown in the photomicrograph are giving rise to coarse aud fine myofibrils.

FIQ.31. PHOTOHICROQRAPH OF THE CASEILLUSTRATED IN FIG. 30, SHOWINGAN ACCUMULATION OF MYOBLASTSIN ONE AREAOF THE TUMOR

402 TUMORS OF MUSCLE 403 omatous areas. In other regions the tumor was composed largely of large myoblasts with a granular or foamy cytoplasm arid a nucleus of variable size. In places these myoblasts were tightly packed. Else- where the cells were loose with elongated cytoplasmic processes and numerous myofibrils. Only rarely did the fibrils show cross striations. One rhabdomyosarcoma of the cervix and one in the upper arm re- sembled closely the rhabdomyoma of the heart recorded in this laboratory but showed no well developed myofibrils with cross striations. Twelve cases were placed in the category of myosarcoma. These showed numerous tumor giant cells, large degenerating myoblasts, and a disorderly arrangement of myofibrils. Two of these cases are illus- trated in Figs. 29-31. In general these tumors were iiivasive and recurred promptly after local excision whether or not they were treated by interstitial or exteriial irradiation. Similar cases have been reported in the literature by Touriienx and Gouzi.

FIQ.32. GROSS SPECIMENOF A MYOBLASTOMAOF THE BREAST,SHOWINQ THE FIRMENCAPSU- LATED CIIARACTEROF THE GROWTH. PATH.No. 39034 Myoblasfoma: In 1926 Abrikossoff described five cases of a muscle tumor which he termed myohlastic myoma. Three of these were lo- cated on the tongue, one on the upper lip, and one on the leg. Klem- perer has recently tabulated 44 cases, including 6 cases of his own. Twenty-one were in the tongue, 7 subcutaneous, 12 in the oral cavity or about the jaws, 2 in the breast, 2 in the leg. The present series includes 5 myoblastomas in the muscles of the extremities; 3 in the breast; 3, subcutaneous, in the sacral region; one beneath the skin of the ear, one in the lip, and one in the tongue. The tumors, which include both encapsulated and non-encapsulated growths, are composed of cells with granular cytoplasm, small dense nuclei, and ribbon-like bands of muscular fibers. The cells are believed to arise from the embryonal ancestors of voluntary muscle. These tumors occur most commonly in the third and fourth decades of life. A few have been described as congenital. Death may occur through erosion of blood vessels, and the tumor may recur after excision. The lesions previously reported have not contained cross striations FIQ. 33. LOW-POWERPHOTOMICR~RllpH SHOWINQ THE MICROSCOPICSTRUCTU~ OF THE TUMORSEEN IN FIG.32 The large granular myoblasts are separated by coarse myofibrils.

FIQ.34. HIQH-POWER PHOTOMICRWRAPH OF THE TUMORSHOWN IN FIQS.33 AND 33

404 TUMORS OF MUSCLE 405 and have not metastasized. However, in our series of myoblastomas there was one case, in a woman of forty-four, with metastases to both groins from the region of the sacrum (Fig. 35). Five and one half years after excision of the primary lesion there was an ulcer of the back at the site of the original growth and masses in both groins, the larger on the left. The growth on the right was well encapsulated and was removed. On the left the growth infiltrated the surrounding tissues and was adherent to the femoral artery. Some tumor tissue was left behind along the artery and 4 radon seeds of one millicurie each

FIQ.35. MYOBLASTOMAOCCURRINQ IN THE REQION OF THE SACRUMAND METASTASIZINQ TO BOTHGROINS. PATH. No. 49128 The lesions occurred in a woman of forty-four. The initial lesion had been excised five and a half years previously. The patieut was reported well following excision of the two massea in the groin and ratloii implantation. (Case of Dr. J. SIielton Horsley.) were implanted. The patient was reported well twenty months later. In a large encapsulated myoblastoma occurring on the ear of a colored girl of seven years, measuring 6 x 4 x 3 em., definite striations were observed. The findings in these two cases must be exceedingly rare in myoblastoma. The majority of the myoblastomas reported have been observed in the tongue or lip immediately beneath the mucous membrane. In the present series these tumors showed a tendency to extend to the epidermis. The sacral region appears to be another site of predilection. Two of the three cases studied in this location were originally inter- preted as chordomas. In the oral cavity the initial microscopic im- pression has sometimes been xanthoma or xantholipoma, or liposar- coma. While the large vacuolated cells in myoblastoma may be confused with those of chordoma, and the cells with granular cytoplasm with 406 CHARLES F. QESCHICKTER those of xantholipoma, the ribbon-like fibers in the stroma, which are myofibrils, are characteristic, since they may be traced on careful study to the myoblasts. Masson’s trichrome stain is valuable in differen- tiating these cells from those of lipoid, chromaffin, and chordal tumors. The myoblasts and myofibrils stain red in contrast to the green connective-tissue fibers and are more readily studied. Non-iwndigertous Tumors of Muscle: Tumors composed of bone, cartilage, fat, fibrous, or vascular tissue are not rare in voluntary muscle. The most common neoplastic process of this type is traumatic myositis ossificans.

FIG. 36. MYOSITISOSSIFICANS WITH RECURRENCEAND METASTASIS. PATH.No. 36014 A. The roentgenograrn before the recurrence. B. The amputated epeeimen following recurrence. The diffuse, progressive form of myositis ossificans is a rare disease, occurring in children, beginning in the tendinous attachments of muscle about the spine and spreading gradually throughout most of the muscles of the body. It progresses slowly over a period of many years, the patient ultimately dying of intercurrent infection, Histologically this form of myositis ossificans, which produces benign, well formed spicules of adult bone, differs from the more common traumatic form by showing ossification via cartilage and a tendericy to begin in the tendinous insertions. Traumatic myositis ossificans of the circumscribed type is most frequent following a severe injury. Among the 30 cases of this form FIG. 37. ROENTQENOQRAN SHOWINGMETASTASIS TO THE CHEST IN THE CASESnowN IN FIQ.36

FIQ.38. PHOTOMICROQRAPH OF THE RECURRENTTUMOR IN CASE SHOWN IN FIQS. 36 AND 37, SHOWINGPROLIFERATION OF MALIQNANT OSSIFYING FIBROBLASTS

407 408 UHARLES F. QESUHICKTER recorded in our laboratory, involvement of the quadriceps f emoris and brachialis anticus is most common. The majority of the patients are young adults in whom a circumscribed indurated mass develops within a period of six weeks following trauma. The roentgenograms show a wedge-shaped mass of laminated bone separated by a narrow space from the shaft of the neighboring bone. Excision should not be performed in the active stage of ossification. Many of these growths re- gress without interference. Those that have been repeatedly excised or which have recurred following incomplete surgical procedures show a definite tendency to undergo malignant change and to metastasize. Intramuscular angiomas are recorded in five instances in the present series. These occurred in the buttocks, arm, and in the leg. Jenkins and Delaney have reviewed 256 cases of benign angiomatous tumors of the skeletal muscle and believe that, with the exception of 17 per cent of the cases, which appeared to be related to trauma, congenital factors play the dominant etiological r61e. The tumors produce swell- ing, pain, tenderness, and impairment of function. Aspiration of blood from the tumor and phleboliths in the roentgenogram are the two most valuable aids in diagnosis. The authors cited favor complete excision of these lesions. Lipomas, chondromas, and fibromas of the intramuscular septa have been recorded. The intramuscular chondromas and lipomas are most often associated with the tendon sheaths. One intramuscular lipoma is reported in the laboratory, in the brachial biceps. Muller reported a similar case. In the literature he found three lipomas in the crural triceps and two in the brachial biceps. Intramuscular lipomas in the muscles of the tongue have been reported more frequently. Some of these were undoubtedly unrecognized myoblastomas. Fibromas in relation to the muscular fascia are most common in the abdominal wall. These tumors, usually described under the term desmoid, are supposedly derived from the tendinous inscriptions of the rectus abdominis muscle. Ten of these tumors have been recorded in our laboratory. Mason has reviewed the literature and reported a series of 50 cases observed at the Mayo Clinic. The tumors may occur subcutaneously on the posterior surface of the rectus muscle. There is no definite line of cleavage between the tumor and the adjoining muscle. While the tumors do not metastasize, recurrence was observed four times in 35 cases surgically removed. Irradiation is the less suc- cessful method of treatment. The tumor is composed of fibers and bands of adult connective tissue and blends with the surrounding fascia1 elements. Summary: Thirty tumors derived from myoblastic tissue in the voluntary muscles are recorded in the Surgical Pathological Labora- tory of Johns Hopkins. Two rhabdomyosarcomas of voluntary muscle and rhabdomyomas of the heart, cervix, vagina, and bladder were studied. Twelve undifferentiated tumors of the voluntary muscles classed as myosarcoma were observed. With the exception of the lesion of the heart, all of these tumors were malignant, rapidly invading the TUMORS OF MUSCLE 409 surrounding tissue and recurring promptly after excision. The tumors are radio-resistant. Twelve myoblastomas, mostly sub-epidermal, were included in this grouping. The majority of these were benign encapsulated growths. One in the ear showed definite striations and ono over the sacrum metastasized to both groins. Non-indigenous tumors of the voluntary muscles derived from connective tissue or blood vessels included 32 cases of myositis ossificans, 3 angiomas, a lipoma, and 10 fibromas of the abdominal muscles, commonly referred to as desmoids.

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