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MULTIPLE OSTEOGENIC SARCOMATA- METASTATIC OR MULTICENTRIC? Report of Two Cases and Review of Literature

HARLANC. AMSTUTZ,MD"

almost

simultaneously arising tumors suggesting the possibility of multiple de novo growths. However, in both patients reported here, as well as those from the literature, the first noted tumor was larger than a second symmetrically located lesion. The natural history of other multiple osteogenic sarcomas is reviewed illustrating a remarkable variability of clinical course including a relatively low grade but diary osteogenic sarcoma in adults and the more typical metastatic osteogenic sarcoma. An age and sex difference is suggested. It is concluded that the multicentric origin cannot be established.

Osteogenic sarcomata in 2 adolescent girls are reported with multiple,

I sarcomata, the almost simultaneous ap- pearance of multiple skeletal tumors and the absence of pulmonary metastases or their rel- atively late radiographic appearance suggested that the multiple lesions were independent primary tumors. However, in each patient and in those reported in the literature, the initial symptomatic lesion has always ap- peared to be larger, and the subsequent le- sions are probably metastatic. The 2 patients are reported and the general subject of mul- tiple osteogenicsarcomata is reviewed.

N

2

PATIENTS

WITH

MULTIPLE

OSTEOGENIC

CASEREPORTS

Case 1. N. B. A 14-year-old Negro girl entered Memorial Hospital on May 6, 1959, with a 2-week history of pain and swelling in her right knee. Her past history revealed sea- sonal asthma since the age of 9 which was treated with an occasional injection of epi- nephrine but did not require hospitalization. Physical examination revealed a regular tachy- cardia of 110-120 with scattered bilateral in- spiratory and expiratory wheezes. The right knee was held in a flexed position with hard tender swelling just proximal to the knee. Admission laboratory data included a HCT

to the knee. Admission laboratory data included a HCT Assistant Clinical Professor of Surgery (Ortho- paedics).

Assistant

Clinical

Professor

of

Surgery

(Ortho-

paedics). Cornell University Memorial Center-Hos- pita1 for Special Surgery. The author gratefully acknowledges the histologic review by Dr. Robert Hutter, Professor of Pathology, Yale University. The material presented was from Bone Tumor Service at Memorial Cancer Center and the Hospital for Special Surgery, Cornell University. Received for publication June 10, 1969.

923

44, WBC 13,000, normal urinalysis, FBS 75, BUN 17. Roentgenograms of the distal right femur revealed a predominantly sclerotic le- sion with new bone formation in the distal metaphyseal region. There was cortical ere sion and transepiphyseal extension consistent with osteogenic sarcoma (Fig. 1A). Chest films failed to show evidence of pulmonary metastasis. An aspiration biopsy confirmed the clinical diagnosis of pleomorphic osteo- genic sarcoma and a hip disarticulation was performed (Fig. 1B). She was discharged on May 28, 1967, after an uneventful immediate postoperative recovery. The histologic sec- tions revealed a malignant tumor infiltrating and eroding the spongy bone. The tumor con- sisted of fairly regular hyperchromatic cells forming an abundant finely trabeculated osteoid matrix, a characteristic pattern for sclerosing osteogenicsarcoma (Fig. IC). Three weeks subsequent to the surgery and 5 weeks after the onset of symptoms in the knee, the patient complained of pain in her left shoulder, A diffusely faint radiosclerotic area in the proximal left humeral metaphysis with a small central area of radiolucency which had been noticed on the admission chest roentgenogram was now an obvious osteogenic sarcoma (Fig. 1D). A skeletal sur- vey revealed nearly symmetrical foci in the proximal metaphysis of the right humerus with a dense band of sclerosis and an irregular thinned medial cortex (Fig. 1E). No addi- tional roentgenograms were taken at that time. The patient received 6 doses of 4500 pg Mitomycin C each based on 150 pg/kg. The 26,300 total was completed in 34 days. A painful swelling in the left knee prevented her from walking, and sclerotic lesions were

924

CANCERNouember 1969

Vol. 24

9 2 4 CANCER Nouember 1969 Vol. 24 FIG.1A. N.B., a 14-year-old Negro girl with right

FIG.1A. N.B., a 14-year-old Negro girl with right dis- tal femoral osteogenic sarcoma. In addition, the sclerosis noted at the proximal tibia epiphyseal line may have represented an additional focus of osteogenic sarcoma.

noted roentgenographically in the proximal tibia and distal femoral metaphysis (Fig. 1F). Because of bone marrow depression chemo- therapy was temporarily discontinued. She was readmitted to the hospital on August 5,

1967, with

a

Hgb of

6.7, HCT 20, and

a

platelet count of 109,000. She received packed red blood cells and ten 2.5 mg doses of Acti- nomycin KS4 between August 5, 1959 and August 28, 1959 with little visible effect. The development of seizures and inability to void necessitated sedation and an indwelling cathe- ter. There were mixed sclerotic and lytic le- sions in both distal radii and ulnae (Fig, 1G). Numerous foci were also noted in the pelvis, fourth and sixth right anterior and second, fourth, and fifth left anterior ribs, bilateral clavicles, inferior scapular poles, right mas- toid region of the skull, and in the C4, C5,

T7, T11, L1 vertebral bodies and sacrum. The patient developed paraplegia with a cord bladder presumably secondary to a patho- logic compression fracture of the first lumbar vertebra. Many of the skeletal lesions were associated with large, symptomatically painful extra- skeletal masses. Gradually enlarging cervical and axillary lymphadenopathy was noted. She was discharged on September 10, 1959, after having received several transfusions for anemia. She died at home 6 months after symptomatic onset on November 1, 1959. De- tails of her death are not known, and an autopsy was not performed, but the known

lesions are

(Fig. 1H). The alkaline phosphatase was 59 Bodansky

shown

in

the

units at the time of initial hospital admission. Although still elevated after disarticulation (indicating probable residual osteogenic sar- comatous activity), the level fell to 26 units before rising to 430 units at the time of her discharge from the hospital one month before

time of her discharge from the hospital one month before FIG. 1B. Gross section of femur

FIG.1B. Gross section of femur after hip disarticula- tion. The lesion has extended into the epiphysis, but there was no tumor in the upper 3/a of the shaft.

No. 5

MULTIPLEOSTEOCENICSARCOMATA*

Amstutz

925

No. 5 MULTIPLE OSTEOCENIC SARCOMATA * Amstutz 925 FIG. 1C. Histologic appearance. Note infiltration of malignant

FIG. 1C. Histologic appearance. Note infiltration of malignant tumor into spongy bone.

death. Chest roentgenograms just prior to discharge on September 10, 1959 revealed clear lung fields, although the rib and hu- meral tumors had increased in size and were not prominent on the lateral view (Fig. 1 I, J).

Case 2. A. Y. The clinical history and the course of this 12-year-old Caucasian girl was similar to that in the first case. Three weeks after onset of symptoms in the left knee the patient was admitted to Hartford Hospital on September 17, 1946. Physical examination re- vealed a swollen tender. knee, and roentgeno- grams showed a sclerotic distal femoral meta- physeal lesion (Fig. 2A). Open biopsy re- vealed an anaplastic osteogenic sarcoma his- tologically similar to the first patient, and a high thigh amputation was performed Sep- tember 29, 1946. Postoperatively, an acute ap- pendicitis developed; an appendectomy was performed on October 8, 1946. Pollowing un- eventful recovery, she was discharged on Oc- tober 23, 1946. Sclerotic lesions subsequently became symptomatic in the right knee and both shoulders (Figs. ZB,C). The patient was seen in consultation at Memorial Hospital where mixed sclerotic and lytic foci were also

demonstrated in the pelvis, mandible, and vertebrae, ultimately resulting in paraplegia. Pulmonary metastases were first noted roent- genographically 6 weeks prior to death (May

onset of

19, 1947) and 8 months after the symptoms. No autopsy was performed.

8 months after the symptoms. No autopsy was performed. FIG.1D. Chest roentgenogram revealing no evidence of

FIG.1D. Chest roentgenogram revealing no evidence of pulmonary metastases but a left humeral metaphys- eal sclerosis.

FIG. 1E. Three weeks later there are bilateral symmetrical primarilymedial meta- physical sarcomata. sclerotic FIG.

FIG. 1E. Three weeks

later there are bilateral

symmetrical

primarilymedial meta- physical sarcomata.

sclerotic

FIG.1F. Left distal fem- oral and proximal tib- ial sclerotic lesions.

FIG. 1G. Bilateral dis- tal radii mixed scle- rotic and lytic and ulnar foci.

No. 5

MULTIPLEOSTEOCENICSARCOMATA- Arnstzilz

927

There was no known contact with radio- active substances prior to treatment in either patient, and, histologically, both were highly cellular and pleomorphic with a large quan- tity of tumorous osteoid throughout but with- out evidence of underlying bone pathology.

DISCUSSION

In 1883, a case of osteogenic sarcoma with multiple skeletal foci was described.6 The possibility of multicentric or multifocal os- teogenic sarcomata was first suggested by Sil- verman in 193619 and has been subsequently supported by Jaffe and Lichtenstein.0011 This hypothesis would seem plausible where, in the absence of Paget’s disease or other under- lying bone disorder or of exposure to radio- active substances, multiple skeletal tumors arise simultaneously with late-appearing or completely absent pulmonary metastases. While patients with obvious metastatic os- teogenic sarcoma to bone are not as rare as generally believed, there are several apparent differences between these and those obviously metastatic. In the 9 selected cases from the Memorial Hospital files with 2 or more foci (Type IIIa in the table), the secondary bony lesions were scattered and asymmetrical in distribution, predominantly lytic radiograph- ically, and appeared 5 or more months after the primary lesion was noted. There were pulmonary lesions in all but one case, and these were generally roentgenographically evident before or about the same time as the earliest observed bony metastasis. The aver- age age at onset was 29 years. There have been scattered reports of other

FIG.1H.Skeletal

Diagram. Distri- bution of known lesions in the first patient. Note: The prox- imalfemoraland

tibia1metaphysis

of the hip disar- ticulation speci- men were not examined histo- logically and no lesions were noted roentgen- ographically about the elbow where the epi- physes were closed.

metastatic osteogenic sarcomata, and, undoubt-

edly, there

routine skeletal surveys were performed.11 3, 6.

7, 9, 11, 14

Four females similar to the patients reported here21 8, 13, 21 (referred to as Type 1) have been

cases if

would

be

many

more

FIG.11. Five months after symp- tomatic onset. Note the enlarg- ing fourth and sixth anterior and second, fourth, and fifth left rib, and humeral lesions. The scapular and clavicular lesions are not apparent.

and second, fourth, and fifth left rib, and humeral lesions. The scapular and clavicular lesions are

928

CANCERNovember 1969

Vol. 24

9 2 8 CANCER November 1969 Vol. 24 FIG. 1 J. Lateral chest roentgenogram confirms the

FIG.1J. Lateral chest roentgenogram confirms the ex- trapleural location of the rib lesions.

previously reported manifesting multiple sym- metrical long-bone metaphyseal osteogenic sarcomatous tumors. In 3 of these cases, the patients had short tubular bone and multiple epiphyseal foci. All of the tumors were pre- dominantly osteoblastic, especially initially. The average age of onset of the combined group of 6 cases was 9 years, with a range of 5 to 14. The survival time averaged 6 months.

range of 5 to 14. The survival time averaged 6 months. FIG. 2A. A.P., a 12-year-old

FIG.2A. A.P., a 12-year-oldCaucasion girl with left

distal femoral osteogenic sarcoma.

Pulmonary metastases were absent roentgen- ographically prior to death in 3 and developed relatively late in the course in 2. In the only autopsied case, there were metastases in the ovaries and lymphatics as well as in the lungs.' One 6-year-oldgirl has been reported in which multiple, asymmetrically located tumors and widespread pulmonary metastases were not detected on initial examination.12 Seven male patients with multiple osteo- genic, sarcoma almost simultaneously appear- ing, have been reported, with average age at onset of 14 years?. 10,11, 14+18, 2O- 21 with a range of 5 years, 10 months to 17 years. In 5, the long bone lesions were not sym- metrical, in contrast to those reported in the females, and multiple pulmonary as well as skeletal lesions were noted on admission. The other patients developed pulmonary metas- tasis, but the chronology was not known. The survival time vaned from 10 weeks to one year, with one patient reported alive 7 months after onset. The patients are grouped by sex in Table 1 because of slight variations noted in distri- bution of lesions and clinical course. As has been pointed out, both symmetrical and non- symmetrical multiple tumors were noted in both sexes. In all cases, the initial sympte matic lesion was larger than the other tumors, including the contralateral similar lesion, whereas subsequently noted symmetrically sit- uated lesions were often more similar in size -an observation which suggests metastasis rather than multiple primary tumors. The average survival time of 7 months for these cases is less than the 22-month average reported by Price14 (survivors excluded) in a series of osteogenic sarcoma. While the sur- vival time appears shorter in the patients with multiple lesions, the date of onset is always difficult to establish, making meaningful com- parison difficult. In contrast to these highly malignant tu- mors occurring in childhood and adolescence, 3 adult women, 26, 50, and 51 years of age, had histologically and clinically low-grade multiple highly differentiated histologically sclerotic osteogenic sarcomatous tumors with- out evidence of Paget's diseasel5. 22. 23 (referred to in the table as Type 11). Their survival averaged 4 years, and none manifested pul- monary or visceral metastases at autopsy. Interestingly, the lesions were confined to the axial and proximal appendicular skeleton.

The lamest " lesions were observed in the Delvis.

~

I

No. 5 MULTIPLEOSTEOGENICSARCOMATA- Amstulz 929

vertebrae, proximal femora, and humeri. Lesions were also observed in the ribs, skull, and sternum, but not distal to the elbows and knees. Generally, these tumors were associated with relatively small extraskeletal masses. Two other cases should be mentioned to complete the survey of all types of multiple osteogenic sarcomata (Type IIIb). One 34- year-year old woman had a seemingly 44- month “tumor-free” period between a tibia1 lesion treated by an above knee amputation and the onset of symptoms due to a distal humeral lesion. Two similar cases have ap- peared in the literature. A 78-year-old man had a 3-year “tumor-free’’ period between bi- lateral phalangeal osteogenic sarcomas,5 and

a 34-year-old woman had a five-year interval between femoral and calvarial lesions.25

five-year interval between femoral and calvarial lesions.25 FIG. 2B. Final roentgenograms taken 6 months later show

FIG.2B. Final roentgenograms taken 6 months later show the advanced right distal femoral and lower leg foci.

CONCLUSION

The true origin of the multiple osteogenic sarcomatas cannot be established. The ab- sence radiographically (or even histologi- cally) of pulmonary lesions does not appear to be sufficient criteria for establishing the multicentric hypothesis, even accepting the usual hematogenous route as the primary means of metastasis in osteogenic sarcoma, be- cause knowledge about metastatic site selec- tivity and factors governing growth of em- bolic anaplastic cells is scarce. More impor- tantly, there has always been an apparent interval, however short, between the first 2 symptomatic lesions in all reported patients, including those of this report, and the initial

lesion has always been grossly larger than the second noted lesion. Therefore, it is perhaps logical to assume that the lesion started in one area alone. The general pattern, espe- cially in the majority of Type I female pa- tients, has been one not only of symmetrically located but similarly sized lesions in the long bone metaphyseal regions of greatest growth and then lesions in other skeletal sites. This pattern could be consistent with extremely rapid growing and metastasizing osteogenic sarcoma. Nevertheless, the cases of the childhood- adolescent type with multiple osteogenic sar- comata does raise the question of whether there is some underlying mesenchymal or hu-

FIG.2C. Bilateral humeral foci.

comata does raise the question of whether there is some underlying mesenchymal or hu- FIG. 2C.

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CANCERNovember 1969

Vol. 24

TABLE1. Multiple Osteogenic

 

First

 

No.

Av.

Sex

Age

symptomatic

No. known

Interval between

Type

cases

age-yrs.

distr.

range

site

foci

1st* 2nd

I

6

8

1/2

F

5-14

Long bone

Miliary

Present on

Child-

metaphyses

admission

Adolescent

-4 cases.

Multiple

1 month-1

almost

unknown-I

simultaneous

2.4.8 .lo,

11.12 .la.

14,18,20,Pl

7

14

M

5-17

Long bone

Miliary

Present on

 

metaphyses

admission

I1

3

42

F

26-56

Long bones

Miliary

Present at first

Adult low

examination

grade multi-

ple malig-

nancies.6va2.2'

 

~

IIIa

9

29

7M

12-42

Long bones

2 to

5 months to 16

Metastatic

1F

predomi-

several

8.5 average

(selected

nantly meta-

from cases)

physis

IIIb

2

34

F

Mid tibia

Several

44 months

 

and

 

miliary

78

M

R. long

finger

2

36 months

meral disturbance predisposing to neoplasia such as may exist in Paget's disease or other bone disorder. The multicentric hypothesis is perhaps most tenable but still highly specu-

lative when cases of the low-grade adult type are considered. The 3 types reviewed illus- trate the variability in the clinical course with differing age and sex distribution.

REFERENCES

1. Ackerman, A. J.: Multiple osteogenic sarcoma. Re- port of two cases. Amer. J. Roentgen. 60:623, 1948.

10. Karlen, A.:

Osteogenic sarcomatosis or multifocal

osteogenic sarcoma. Acta Path. Microbiol. Scand. 55: 1,

2. Basso, M. J., and Schajowicz, F.:

Sarcoma osteo-

1962.

genico a localization multiple. Rev. Ortop. Traum. 15:

11.

Lichtenstein, L.: Bone Tumors. St. Louis, C. V.

85.1945.

3. Cohen, B.:

Secondary tumors

of

the mandible.

Ann. Roy. Coll. Surg. Eng., 23:118, 1958.

4. Davidson, J. W., Chacha. P. B

and James, W.:

Multiple osteosarcomata. J. Bone Joint

1965.

Surg. 47:537,

5. Drompp, B. W.:

Bilateral osteosarcoma in pha-

langes of hand. J. Bone Joint Surg. 43:199, 1961.

6. Durham, A. E.: Transactions Pathological Society,

London, 1883.

7. Finlayson,

skeletal

R.: Osteogenic sarcoma with multiple

tumors. 1. Path. Ract. 66:223, 1953.

8. Halpert,

B., Busso, P. E., and Hackney, V. C.:

Osteogenic sarcoma with multiple skeletal and visceral

involvement. Cancer 2:789, 1949.

9. Taffe. H.: Tumors and Tumorous Conditions of

the genes and Joints. Philadelphia. Len and Febiger,

1958: p. 266.

Mosby, 1959; p. 206.

12. Morse, D., Reed, J. O., and Bernstein, J.:

Scle-

rosing osteogenic sarcoma. Amer. /. Roentgen, 88:491,

1962.

13.

Moseley, J. E., and Bass, M. H.: Sclerosing osteo-

genic sarcomatosis.Radiology 66:41, 1956.

and

Brady, L. W.: Multiosseous osteosarcoma: report of one case and review of the literature. Radiol. Clin. Biolog-

ica, 35,43. 15. Price, C. H. G., and Truscott, D. E.: Multifocal osteogenic sarcoma. J. Bone Joint Surg. 39:524, 1957.

. Osteogenic sarcoma. An analysis of survi-

Val and its relationship to histologic grading and struc- ture. J. Bone Joint Surg. 43:300, 1961.

14. Owen, L. B., Eskey, W. C., Kashatus. W.C

1G. *-

17. Rowen, R. E.: Multiple primary malignant tu-

mors. Ann. Surg. 172311,1955.

No. 5

MULTIPLEOSTEOGENICSARCOMATA Amstutz

98 I

Sarcomata in Bone

No.

Length of

with

survival

skeletal

Roentgenographic

Histologic

Pulmonary

from initial

survey

Distribution

character

 

characteristics

metastases

Autopsy

symptoms

4

Tend to have

Sclerotic

Anaplastic

3 absent

1

4-8 month

been symmetrical

by x-ray.

6 months av.

in long bones,

3 definitely

spine, 3 cases short tubular bones and epiphyses

present.

Long bones not

Sclerotic

 

Anaplastic

Yes

4

8 months

2 1/2-6

yrs.

2

symmetrical-5

primarily

 

(1 living at

symmetrical-2

report)

3

Long and flat

Sclerotic

 

Low grade

None

Yes

1 unknown

bones. None

small extra-

osteogenic

4 yrs. av.

disfal to

known

elbows or knees.

skeletal

sarcoma.

masses.

 
 

-

 

~~~

~~

1 case

1. Predominantly

Initial lesion

 

Anaplastic

7 yes

2

1-38 months

spine and flat bones

2.

mixed.

Secondary

 

l?

19 months

av.

Scattered

lesions lytic

 

~~

~

Yes

Humerus-then

Sclerotic-

 

Anaplastic

Yes

Yes

7 years

scapulae, verteb.

lyt

ic

Yes

Left index

Sclerotic

 

Anaplastic

No

-

6 years

 

question of Paeet’s in tibia

(1961)

18. Ryan, J.: A case of multiple osteosarcoma. J. Coll.

osteogenic sarcoma case report.

Brit. J. Surg. 49:92.

Radiol. Aust. 7:93,1963.

1961.

19.

Silverman,

G.:

Multiple

osteogenic

sarcoma.

23.

Smokvina, M., Ribkin, K., Bunarevu, A., Franulo-

Arch. Path. 21:88, 1936.

20.

Singh, A. D., and Scudder, I. B.: Multiple osteo-

genic

sarcoma. J. Bone Joint Surg. 47542, 1965.

21.

Singleton, E. B., Rosenberg, H. S., Dodd, G. O.,

and Dolan, P.

Arner. J. Roentgen. 88:483, 1962. 22. Smithers, D. W., and Gowing, N. F. C.: Multifocal

.4.:

Sclerosing osteogenic sarcomatosis.

vic, P., and Zimola, A.: Uber Einen Multiplen, Osteo-

genen, Osteoplastichen Tumor von Langsamen Wach- stum. Fortschr. Roentgenstr. 94:44, 1961.

The Spread of Tumors in the Hu-

man Body, London, J. and A. Churchill, 1937; p. 325.

ScIerosing osteogenic sarcomatosis.

J. Clin. Path. 14:109, 1961.

24. Willis, R. A.:

25. Wolman, L.: