The History of Musculoskeletal Tumors
Henry J. Mankin MD
Massachusetts General Hospital
The History of Treatment of Musculoskeletal
Tumors
Figure 2:
A portrait of Claudius Galen (130 AD- 200 AD)
who was a celebrated physician who published
multiple articles describing diseases. As is
evident from this portrait, he disagreed with
Hippocrates over many issues!
ANCIENT HISTORY
There is little doubt that cancerous limbs were well recognized by ancient societies and their physicians although
little was known about the nature of the lesions, particularly
in the early years of our civilization. The Egyptians reported
cancerous growths on various parts of the body in the Ebers
papyrus believed to have been written around 1500 BC (1,2).
The manuscript recommended cauterization of benign lesions
but warned of the cruel nature of fungating or ulcerating
tumors. It was pointed out that those tumors that involved
peripheral parts of the body sometimes required amputations
or resections and it is likely that some of these procedures
were done for cancerous limbs (3). In fact, studies of the bones
of Egyptian mummies have shown lesions consistent with
benign and malignant tumors of bone and cartilage, myeloma
and metastatic carcinoma (4,5).
The early concepts of the causes of cancer were dominated by the views of two individuals, Hippocrates and Galen.
According to John Hunter, Hippocrates recognized various
Figure 3:
A picture of a patient with a soft tissue
sarcoma of the shoulder region in early days.
No treatment was possible.
forms of cancer and attributed them to the pervasiveness of
black bile, one of four humoral elements he postulated to
be responsible for all disease (6) (figure 1). It was his view
that cancer was a systemic disease related to this humoral
abnormality rather than a localized process. He coined the
word karkinos for the hard lump seen in places such as the
breast, likening cancer to a crab because of its way of growth
(7). Clarissimus Galen wrote a treatise on abnormal swellings in 192 AD (8,9,10) (figure 2). He adhered and advanced
the humoral theory and listed an array of abnormal swellings
including karkinoi and karkinoma in many sites, further
enlarging the description of the hard nodules originally defined
as cancer by Hippocrates (10) (figure 3). He also is believed to
have introduced the word sarcoma for lesions clearly arising
in the soft tissues (figure 4). The writings of these two great
scientists provided the world before and shortly after the birth
of Christ with views as to the nature of cancerous growth and
equally importantly, the need for concern regarding outcome
and effective treatment for these lesions. It was not until the
16th and 17th centuries however that the black bile humoral
theory was rejected, mainly on the basis of the observations
of morbid anatomists such as Vesalius (11) who postulated
that cancer grew at one site and then spread via lymphatics or
blood stream to other areas of the body.
Figure 1:
A classic portrait of Hippocrates who
was born in 460 BC on the island of Cos
in the Aegean Sea. He died in 377 BC
in Larissa Greece.
Henry J. Mankin MD
Orthopaedic Oncology Service
Massachusetts General Hospital
Edith M. Ashley Professor of Orthopaedics Emeritus
Harvard Medical School
129
Figure 6.
Statue of St. Peregrine. Note the
bandaged limb. Prayer cured the
tumor before the amputation could
take place.
Figure 4:
Early concept of the gross structures of chondrosarcoma which appears as multiple
lesions; and an osteosarcoma which is a solid tumor attached to the femur.
Miracle of the Black Leg was reportedly successful and because
of that, the twins were subsequently canonized, receiving their
sainthood in approximately the year 550 AD. Of note is the fact
that the occasion and drama associated with the procedure was
so extraordinary that it captured the imagination of first the
painter Fra Angelico and then many other artists; and literally
hundreds of some of the most extraordinary paintings depicting the procedure can now be found in many of the world
museums (13).
A second miracle occurred in the case of Saint Peregrine
Laziosi who lived in the 14th century (14). After an initial
rebellious and anti-religious youth, the Virgin Mary came
to Peregrine in a vision asking him to mend his ways. He
responded by becoming a devout Catholic and subsequently a
priest. In his later years, he developed a cancer of the foot and
leg, which caused him great pain. The surgeons advised him
to have an amputation but on the night prior to the procedure
after praying to God, he fell asleep and awoke without a trace
of the tumorous process. For this miracle as well as for his life
of great giving, he was canonized in 1726 (Figure 6).
Two early references to cancer affecting the extremities
are included in the canonical literature. The first of these was
most extraordinary and consisted of a miracle performed by
Saints Cosmas and Damian in the sixth century AD (12,13).
The saints were twin physicians born in the third century AD
in the town of Egea in Cilicia in Asia Minor. They traveled
widely in Greece, Turkey and Rome, treating ailments of all
sorts and refusing payment for their services. They somehow
angered the emperor Diocletian and they and their three
brothers were beheaded and buried in a grave in Egea in the
year 287 AD. They returned however in the 5th century to a
Basilica in the Roman Forum, which now bears their name,
where Deacon Justinian, a faithful church retainer with a
cancerous limb was so exhausted by his pain that he fell asleep
during his prayers. There came to him in a dream, the twin
physicians who after amputating the limb of a Moor who had
died that morning replaced the diseased part with the obtained
allograft implant (figure 5). The procedure, known as the
Figure 7:
Wilhelm Konrad Roentgen was (1845-1923)
discovered X-rays in 1895 and received a Nobel
Prize in 1901. The technology greatly advanced
medical science and particularly cancer care.
Earliest Identifications of Bone Tumors
The earliest views of bone tumors in historical data were
that they were simply cancers of the limbs rather than neoplasms arising from connective tissue. It should be noted that
histologic evaluation of tumors depended on the microscope
which was not in common use for that purpose until the mid
19th century and of perhaps greater importance was the fact
that Wilhelm Conrad Roentgen did not introduce X-ray imaging until 1895 (15) (Figure 7). Recognition of tumors of bone
Figure 5: A painting depicting the Miracle of the Black Leg. Cosmas and Damian
are seen after the resection of Justinian’s cancerous limb, applying the allograft
component obtained from a Moor who had died that morning. Artist Anonymous,
15th Century.
130
and soft tissue and their histologic definition and origin were
at best rudimentary early in the 19th century. It was therefore
not until the latter part of that century that imaging allowed
sophisticated recognition of tumorous processes in the bones
and histology allowed speculation as to cellular origin of the
tumor.
The first description of a tumor arising within connective
tissue probably was that of Abernathy in 1803 who described a
neoplasm of the limb probably of soft tissue origin (4). He is
alleged to have re-introduced the term sarcoma from the Greek
term for tumors of soft tissue, suggesting that tumors of connective tissue may have substantially different cellular origins.
It was shortly thereafter that Baron Guillaume Dupuytren
further defined the entity of osteosarcoma (describing it as
an aggressive lesion arising from bony elements) and alluded
to its malignancy and ability to metastasize (16). However, it
was not until 1845 that histologic evidence of a lesion arising
in bone was presented and documented as containing cells
which seemed bony in origin. In that year Hermann Lebert
described a case of giant cell tumor of bone (17), the cells of
Hermann Lebert who published an illustrated atlas entitled
Physiologie Pathologique in 1845 which not only contained
pictures of the histologic structures of tumors but some of
these were in color (17). In the same year, the Scottish clinician and anatomist John Hughes Bennett described microscopic differences between benign and malignant cells (21).
In 1853, Donaldson reported on the microscopic characteristics of cancer (22) and in the following year, Lionel Beale
a Professor at King’s College wrote a treatise The Microscope
in its Application to Practical Medicine in which he proposed
some histologic markers which distinguished normal from
cancerous tissue (23). All of these techniques were very useful
but were only available on examination of the histologic section of a specimen submitted to a pathologist. It was not until
1891 that surgeons and pathologists collaborated in providing
a diagnosis of malignant disease on a rapidly performed frozen
section (24).
Perhaps the first real identification of the nature of bone
tumors was the report of Samuel Gross, a Professor of Surgery
in Philadelphia who in 1879 published a paper in the American
Journal of Medical Science based on a study of 165 cases (25).
His article stated that 70 could be histologically identified as
giant cell tumors, 45 were probably parosteal osteosarcomas
and 28 were central sarcomas. Of that last group, 16 were
considered to be forming a matrix (probably osteosarcoma or
chondrosarcoma) and 12 consisted of small round cells (probably in retrospect, Ewing’s sarcomas). He also noted that
these tumors frequently metastasized to the lung and much
less commonly to lymph nodes. Because of the nature of
these lesions and their aggressive character, he recommended
amputation as the treatment of choice.
At approximately the same time, a number of studies
defined the tumor population which are considered hematopoetic in origin. In 1848 Dalrymple in an article in the Dublin
Quarterly, described the entity of myeloma (26) and in the
same year Henry Bence-Jones described the characteristics of
the urinary protein in these patients that bears his name and
is believed to be diagnostic for that disease (27). Similarly
several authors described bone lesions with a greenish color
which became known as chloromas; and which were established as having a relationship and indeed being diagnostic of
leukemia (26).
Figure 8:
Rudolf, Ludwig Karl Virchow
(1821-1902) was the father of
modern pathology. He described
many entities and published the
Virchow Archives, still in use today.
which resembled bone cells, particularly the osteoclasts seen
in normal tissues. Subsequently, Rudolf Virchow (18,19) (figure 8) and Sir James Paget (20) showed convincing histological evidence that the giant cell tumor had some of the same
cellular elements that existed in bone and was almost surely
bony in origin. The investigators further showed that the
giant cell tumor could and did locally destroy the bone of origin (18,19). In his exceptional three volume work published
from 1863 to 1867, Rudolf Ludwig Karl Virchow, considered by
many to be the father of modern pathology and certainly one
of the famous pathologists of the 19th century, expressed the
opinion that although there were examples such as the giant
cell tumor and others such as fibrosarcoma, myxosarcoma,
osteosarcoma and chondrosarcoma, tumors primary in bone
were much rarer than other tumors that metastasized to bone
(18,19). These concepts are considered to be the foundation
of modern understanding of cancer (19).
Of critical importance to this system was the use of the
microscope in the definition of tumors. Despite earlier discovery of optics and the lens and the microscope. the technology was not applied to the body tissues and more specifically
tumors until the middle of the 19th century (3). The first
positive identification of tumorous tissues was attributed to
TUMOR RECOGNITION AND BIOLOGICAL BEHAVIOR
The next 35 year period was a time of development of an
understanding of connective tissue tumors, based not only
on the discoveries of the nature and characteristics of these
lesions; but also by establishing some concept of their biological
behavior. It was the period when the great pathologists of the
20th century contributed to our knowledge and established an
order to the prior chaos. The contributors of this era included
Paget, von-Recklinghausen, Erdheim, Bloodgood, Jaffe, Ewing,
Coley, Geschickter, Copeland, Phemister, Schmorl, Codman,
Fischer, Albright, Lichtenstein, Schajowicz, Enzinger, Dahlin
and many more. It should be noted that these individuals
not only defined and graded the tumor populations, but also131
Figure 9:
Earnest Amory Codman MD (1869-1940).
A surgeon at the Massachusetts General
Hospital established the first bone tumor
registry and published a book about
shoulder lesions.
Figure 11.
Henry L. Jaffe MD (1896-1979) was
perhaps the greatest contributor to the
knowledge of bone tumors. He was also
a great teacher and collector and was the
person who described many forms of bone
and soft tissue tumors.
described the histological and in some cases the radiologic
characteristics of a variety of neoplastic and non-neoplastic
disorders. Several of these contributors stand out. Earnest A.
Codman (1896-1940) was a general surgeon who worked at
the Massachusetts General Hospital, who was interested and
quite knowledgeable about bone disease and more specifically
tumors (figure 9). In 1920 in an effort to further define the
field of orthopaedic oncology, he along with James Ewing
and Joseph Bloodgood established a Bone Tumor Registry
(28,29,30). Codman became fascinated with the shoulder and
published a book on that subject in 1934 in which he not only
described the anatomical structure and particularly the rotator
cuff, but also described and defined the entity of chondroblastoma (known since as Codman’s tumor) (31).
enhanced the description of some already known entities and
described some new ones. He and in some cases his colleague
Louis Lichtenstein added substantially to our knowledge of
the pathology of giant cell tumor (33) and chondroblastoma
(34) but also initially described the entities of osteoid osteoma
(35), pigmented villonodular synovitis (36), osteblastoma (37),
aneurysmal bone cyst (38) and eosinophilic granuloma (39).
Joseph Bloodgood (1867-1935) was a student of Halsted
and gained renown as a tumor surgeon at Johns Hopkins
Hospital where he subsequently became Director of Surgical
Pathology. In 1912 he became fascinated with the entity of
giant cell tumor, partly because most patients survived, despite
the malignant appearance of the lesion (40).
William B. Coley (1862-1936) was one of the early treating
physicians at the Memorial Hospital in New York and defined
the natural history of osteosarcoma and the effect of radiation
on high grade cancers of bone (41). He was impressed with
the amazing remission of a patient with wide spread malignant
disease which appeared to coincide with the development of
erysipelas. He introduced Coley’s toxins, a sterilized bacterial solution, which appeared to act on the patient’s immune
system to help ameliorate neoplastic disease (42). This is
considered by some to be the first example of adjuvant therapy
for cancer.
Charles Geschickter and Murray Copeland published a
book in 1936 which established the state of the science and
specifically the pathology at the time for bone tumors (43)
and subsequently identified the entity known as parosteal
osteosarcoma and indicated its less malignant nature than
the centrally placed lesions (44). Several years later George
Pack and Irving Ariel did the same for soft tissue tumors but
with special emphasis on surgical management (45). Several
authors defined the development of a peculiarly virulent bone
sarcoma in patients with Paget’s disease (46,47). In 1888,
Friedrich von Recklinghausen defined neurofibromatosis of
soft tissue (48). .
Figure 10:
James Ewing (1866-1943) was a great
pathologist who worked with Codman
to start the tumor registry and described
Ewing’s tumor. He was Chief of Pathology
at Sloan-Kettering Hospital in New York
City.
James Ewing (1866-1943) was a pathologist who was born
in Pittsburgh and developed an osteomyelitis of the femur
from which he was never cured (32) (Figure 10). He became
fascinated with the microscope and with bone disease based
in part on his illness and became a pathologist in New York
City around the turn of the century. He was the first Chief
of Pathology at Cornell University and was not only Chief of
Pathology at Cancer Memorial Hospital but served as Director
of that Hospital for a number of years. He described the tumor
that bears his name in 1921 calling it diffuse endothelioma of
bone, indicating the highly malignant nature of the lesion (32).
Henry L. Jaffe (1896-1979) (Figure 11) and his colleague
Louis Lichtenstein (1906-1977) were perhaps the most prolific
contributors to our knowledge of bone tumors. Jaffe was born
in New York City and became Chief of Pathology at the Hospital
for Joint Diseases, a position he held from 1928 to 1965. He
was an excellent educator, an astute clinical scientist and an
ardent collector. Based in large measure on his well catalogued and massive collection of tumor material he beautifully
MANAGEMENT OF BONE AND SOFT TISSUE TUMORS
The management of malignant bone and soft tissue
tumors was until the middle of the 20th century and somewhat beyond a very discouraging area. Benign tumors were
managed well with little major problem aside from a high
local recurrence rate for such tumors as giant cell tumor
or osteoblastoma. The malignant tumors such as Ewing’s
tumor or osteosarcoma or high grade soft tissue tumors had
132
very high local recurrence, metastasis and death rates. High
grade chondrosarcoma had a lower rate of metastasis but those
lesions about the pelvis did poorly. The great changes that
occurred in the last thirty years arose principally because of
the use of chemotherapeutic agents, radiation oncologic treatments and improved imaging technology.
Shortly after Roentgen discovered the X-ray as an imaging technique in 1895, radiation was considered a potential
treating agent for cancer. The Curie’s provided a radioactive
source of considerable strength in 1898 (49). Shortly thereafter, in 1900 Kienbock reported some experiments with rats
who were radiated who underwent an unmistakable series of
effects; and it was then agreed that radiation might well be of
value in the management of patients (50). Armed with this
information, the treating radiologists became concerned about
sources of radiation, the amount of radiant energy delivered to
the patient and the dosage required to treat disease (51). It
should be noted however that in 1933, Emil Grubbe of Chicago
reported that he had treated a patient with breast cancer in
1896 and also noted the occurrence of dermatitis (in his own
hands) (52). He also was allegedly the first to use lead shields
to reduce the amount of radiation to unaffected anatomical
parts.(52). Radium or Crooke’s tubes and subsequently radon
seeds were initially the sources of the radiation but devices
to shield and focus the beam became an essential part of the
system (51,53,54). The first treatment of a sarcoma with
radiation was reported by Coley in 1905 and soon thereafter
with better equipment the radiation technology became an
essential part of oncologic management of patients with bone
and soft tissue tumors (41).
40% (59,60). Cis-platinum was introduced in 1979 by Baum
and shortly thereafter, Marti introduced ifosfamide, thus
establishing the four principal players in the chemotherapeutic regimen for this and other malignant connective tissue
neoplasms (3). In the 1970’s Rosen introduced the concept of
neoadjuvant therapy, which allowed the treating physicians to
assess the impact of the drugs chosen on the tumor prior to
resective surgery, and thus allow possible changes in protocol
(61). This brought the curve up further and also made limbsparing resective surgery considerably safer. These drugs and
the neoadjuvant approach have shifted the curve for all the
high grade tumors such that the average long term survival
rate for osteosarcoma and other tumors is as much as 70% or
80%. We owe a debt to the intrepid pioneers in this important
field who have provided us these adjuvants which offer the
patients a much greater chance at local control and prolonged
disease free survival.
ORTHOPAEDIC MANAGEMENT OF PATIENTS WITH
SARCOMAS
Until the 1940’s, tumor management was difficult at best
and at least for high grade tumors the patients usually had
amputations performed (mostly for osteosarcoma or chondrosarcoma) or received radiation (principally for Ewing’s
sarcoma, lymphoma, myeloma or metastatic carcinoma).
Reconstructive surgery had little place in their care and limbsparing surgery was a very rare event. Local resection could
be performed but often failed because the surgeon had limited
ability to know the extent of the lesion or to provide a wide
enough margin to prevent recurrence. The success of local
resection depended on the site of the tumor, the proximity of
adjacent neural or vascular structures and whether sufficient
skin or soft tissue could be maintained to avoid problems with
wound closure. Such surgery was made more difficult by the
fact that without modern imaging techniques, planning was
difficult and without frozen sections at the time of definitive
surgery, the assessment of the proximity of the tumor to the
surgical margin was often inaccurate.
It should be clearly evident that amputation was the
method of choice for malignant bone or soft tissue tumors
unless the lesions were small or remarkably accessible (figure
13). Mott in 1828 reported on having performed a resection
of the clavicle for osteosarcoma (62) and Langenbeck reported
on a complete scapular resection for a cartilage tumor in
Figure 12:
In 1973, Norman Jaffe introduced
high dose methotrexate with citrovorum
rescue which was very effective in the
treatment of osteosarcoma and changed
10% survival rate to greater than 50%
In terms of chemotherapy, the earliest approaches
were those of Coley (Coley’s toxins) (42) and Sullivan with
L-pheylalanine mustard (55) but neither were considered successful. It was not until 1954 that Sidney Farber reported successful treatment of several children with Wilm’s tumors with
actinomycin D (56), which began the period of discovery for
chemotherapeutic agents. In 1973, Norman Jaffe and coworkers introduced high-dose methotrexate with leukovorin rescue
for the treatment osteosarcoma (57,58) (figure 12). At almost
the same time, Cortes and Holland and others reported the
effect of adriamycin or doxorubicin on osteosarcoma and
found that they could bring the survival rate to greater than
Figure 13:
Cancer surgery
in the early days
consisted principally
of amputation. This
ancient artwork shows
the way the physician
and patient dealt with
the problem prior to
anesthesia and surgical
technique.
133
1850 (63). Morris partially resected a forearm for a giant cell
tumor successfully and reported the procedure in 1876 (64)
and Hinds introduced scraping for palliative treatment of
myeloma in 1895 (65). Amputations could be modified such
as with the turnabout procedure as designed by Van Nes and
applied to the management of sarcomas by Kotz and Salzer
(67). Another similar approach for tumors of the upper end
of the femur was the turnup-plasty advocated by Sauerbruch
in 1922 (68). Despite problems with surgical complications,
Pringle reported on a two interpelvic abdominal resections in
1916 (69).
In more recent times, with the neoadjuvant and adjuvant radiation and chemotherapy and improved surgical
technology, orthopaedists have developed a series of systems
for surgical eradication of the lesions and replacement with
autograft, allograft, plastic materials and metallic implants.
These systems are in many cases quite successful in maintaining a functional limb and have greatly decreased the disability
of the affected patients. and allowed the patient to maintain a
functional limb.
It should be apparent however that none of these specialized surgical procedures could have been done earlier.
Orthopaedic management of patients with bone and soft tissue
tumors has advanced considerably since the early part of the
20th century and have established new and exciting parameters in treatment of these difficult and unpredictable lesions.
There are several reasons for these advances:
6. The ability to effectively treat lung metastases with
chemotherapy and resective surgery, thus enhancing
the patient’s chance at survival.
7. Modern technology for construction of custom or
modular prostheses has made it possible to replace
joints and adjacent bony parts.
8. Allograft banks have allowed a supply of good bony segments with attachment sites for ligaments and tendons
and improved selection and harvest technology have
made grafts biologically safer and more successful.
SUMMARY AND DISCUSSION
Perhaps there is no area within the specialty of
Orthopaedics where there has been such a spectacular achievement in dealing with potentially life threatening disease. In
early days, virtually everyone with high grade sarcomas succumbed and if they had a surgical solution to their problem,
it was an amputation. Over the decades that followed these
dreadful early days, the pathologists contributed knowledge
about the tumors and identified their features and the radiologists their cardinal findings on radiological imaging. The
medical oncologists provided drugs in adjuvant and neoadjuvant protocols and the radiation oncologists offered better
and better means of safely radiating the lesional area, both of
which vastly enhanced the patient=s survival rate. The orthopaedist provided a means of staging the patient and developing a protocol for assessing the patient’s degree of disease and
stage and at least in part predicting the outcome. In addition
based on the modern technology of surgery and the information gained as a result of the staging studies, the treating
team has developed protocols for the resection of the bone and
soft tissue tumors which are safe and cause the least damage
to adjacent muscular, vascular and neurological structures.
Finally the orthopaedists and their engineering and tissue
banking colleagues have developed methods of safely and functionally replacing a part of the skeleton after resection of the
tumors. No greater success or achievement has been recorded
in tumor treatment.
1. For both benign and malignant lesions, the knowledge of the nature of the lesion has made behavior
more predictable and allowed the surgeons and
caretakers greater leeway in planning the patient’s
therapy.
2. Vastly improved imaging technology using radiographs, bone scans, computerized tomography and
magnetic resonance imaging have allowed the surgeons to define with greater certainty the anatomical
position of the tumor and what would be necessary
to remove it
3. A staging technique for bone and soft tissue tumors
has advanced our ability to predict outcome and
define the goals of treatment; and another system has
been introduced to evaluate end results.
4. Clearer assessment of biopsy technology has made it
possible to know in advance what the tumor’s behavior is likely to be.
5. The use of neoadjuvant chemotherapy and radiation
has made marginal or wide surgery safer than in the
past and allows better and far less disabling limbsparing surgery.
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References
Bryan CP: The Papyrus Ebers, 1930
Ebbell B: The papyrus Ebers: The greatest Egyptian medical document. 1937.
Olson JS: The History of Cancer: An Annotated Bibliography. New York. Greenwood Press, 1989.
Abernathy J: Surgical Observations On Tumors. London, Longman and Rees, 1804.
Struhal E: Tumors in the remains of ancient Egyptians. Amer J Physical Anthropol. 45:613-19, 1976.
Dobson J: John Hunter’s view on cancer. Ann Roy Coll Surg Eng 25: 167-181, 1959.
Hippocrates. Translated by WHS Jones 4 volumes. London, Heinemann. 1953-57.
Galen C: De Tumoribus Praeter Naturam 192 AD
Kardinal GC, Yarbro JW: A conceptual history of cancer. Seminars in Oncology 6: 396-408, 1979.
Lytton DG, Resuhr LM: Galen on abnormal swellings. J Hist Med Allied Sci 33, 531-49, 1978.
Vesalius, A: De Humani Corporis Fabrici. Base;. 1543.
Gerlitt J: Cosmas and Damian, the patron saints of physicians. Ciba Found Symp 1:118-121, 1939.
Rinaldi E: The first homoplastic limb transplant according to the legend of Saint Cosmas and Saint Damian. Ital J Orthop Traumatol. 13:394‑406, 1987.
Jackson R: St. Peregine, OSMCPatron saint of cancer patients. Canad Med Assoc J. 111,824-827, 1971.
Roentgen WC. Ueber eine neue Art von Strahlen. Sitzungsberichte der physikalisch-medicinischen Gesellschaft zu Wurzburg. Sitzung 30: 132-141, 1895.
Dupuytren, G. Tumors of bone. Bull Ecole Med de Paris 2: 13-24, 1805.
Lebert H: Physiologie Pathologique. 2 volumes. Paris, 1845.
Virchow R: Die Krankhaften Gewulste. Berlin. Hirschwald, 1863-1867.
Wilson JW. Virchow’s contribution to the cell theory. J History Med. 2: 163-78, 1947.
Paget J. Lectures in Surgical Pathology. 2 Vol. London, 1853.
Bennett JH: Introductory address to a course of lectures on histology and the use of the microscope. Lancet 1: 51-7-522, 1845.
Donaldson F: The practical application of the microscope to the diagnosis of cancer. Am J Med Sci. 25: 43-70, 1853.
Beale L: The microscope in its application to practical medicine. London John Churchill, 1858.
Wright JR Jr: The development of the frozen section technique, the evolution of surgical biopsy, and the origins of surgical pathology. Bull Hist Med.
59: 295-326, 1985.
Gross SW. Sarcoma of the long bones: Based on the study of one hundred and sixty-five cases. Am J Med Sci. 78:2-57, 338-77, 1879.
Clemp JR: Some aspects of the first recorded case multiple myeloma. Lancet 7530:1354-56, 1967.
Bence Jones H: On a new substance occurring in the urine of a patient with mollites ossium Philos Tr R Soc London 138: 55-62, 1848.
Codman EA: The registry of cases of bone sarcoma. Surg Gyne Obstet. 34: 335-343, 1922.
Codman EA: Bone Sarcoma. New York. Paul B. Hoeber, Inc 1925.
Ewing J: A review and classification of bone sarcomas. Arch Surg. 4:: 485-533, 1919.
Codman EA: The Shoulder. Boston, Thomas Todd Co. 1934.
Ewing J: Diffuse endothelioma of bone. Proc NY Path Soc. 21:17-24, 1921.
Jaffe HL, Lichtenstein L, Portis, RB: Giant cell tumor of bone. Its pathologic appearance, grading, supposed variants and treatment. Arch Pathol. 30:993-1031, 1940.
Jaffe HL, Lichtenstein L: Benign chondroblastoma of bone. A reinterpretation of the so called calcifying or chondromatous giant cell tumor. Am J. Pathol
28: 96f9-983, 1942.
Jaffe HL: Osteoid osteoma: a benign osteoblastic tumor composed of osteoid and atypical bone. Arch Surg. 31: 709-728, 1934.
Jaffe HL, Lichtenstein L, Sutro CJ: Pigmented villonodular synovitis, bursitis and tenosynovitis. Arch Pathol. 31: 731-765, 1941.
Jaffe HL. Benign osteoblastoma. Bull Hosp Joint Dis 17:141-151, 1956.
Jaffe HL: Aneurysmal bone cyst. Bull Hosp Joint Dis. 11: 3-13, 1950.
Jaffe HL, Lichtenstein L: Eosinophilic granuloma of bone. Arch Pathol 37: 99-118, 1944.
Bloodgood JC: The conservative treatment of giant cell sarcoma with the study of bone transplantion. Ann Surg 56:210-239, 1912.
Coley WB. Final results in the X-ray treatment of cancer including sarcoma. Ann Surg 42: 161-184, 1905.
Coley WB: The treatment of malignant tumors by repeated innoculations of erysipelas: with a report of ten original cases. Am J Med Sci 105: 487-511, 1893.
Geshickter, CF, Copeland MM: Tumors of bone (Including the Jaws and Joints). New York. The American Journal of Cancer. 1936.
Geschickter CF, Copeland MM: Parosteal osteoma of bone: a new entity. Ann Surg. 103: 790-807, 1951.
Pack GT, Ariel IM: Tumors of the Soft Somatic Tissues. A Clinical Treatise. New York, Hoeber- Harper, 1958.
Poretta CA, Dahlin DC, Janes JM: Sarcoma in Paget’s disease of bone. J Bone Joint Surg. 39A: 1314-1329, 1957.
Schajowicz F: Tumors and Tumor-like Lesions of Bones and Joints. New York, Springer-Verlag, 1981.
Von Recklinghausen FD: Uber die multiplen fikbroma der haut und ihre beziehungen zu die neuromen. Berlin A Hirschwald 1882.
Curie P, Curie M: Sur une substance nouvelle radioactive, contenue dans la pechblende. Compt Rendus Acad d Sci Paris 127: 175, 1898.
Kienbock R: Die einwirkung des roentgenlichtes auf die haut. Med Wschr. 47:1581-82, 1900.
Lederman M: The early history of radiotherapy: 1895-1939. Int J Rad Oncol Biol Phys. 7:639-648, 1981.
Grubbe EH: Priority in the therepeutic use of X-rays. Radiol. 21:156-162, 1933.
Lederman M, Greatorex CA: A cobalt 60 telecurie unit. Brit J. adio 26: 525-532, 1953
Lysholm E: Apparatus for the production of a narrow beam of rays in treatment by radium at a distance. Act Radiol 2: 516-519, 1923.
Sullivan MP, Sutow WW, Taylor G: L-phnenylalanine mustard as a treatment for metastatic osteogenic sarcoma in children. J peiatr 63: 227-237, 1963.
Foley GE: Sidney Farber (1903-1973). CA Cancer Jour for Clinicians. 24: 294-296, 1974
Jaffe N, Frei III E, Traggis D, Bishop Y: Adjuvant methotrexate and citrovorum factor treatment of osteogenic sarcoma. N Eng J Med 291: 994-97, 1974
Jaffe N, Farber S, Traggis D, Geiser C, Kim BS, Das L, Frauenberger G, Dierassi I, Cassady JR: Favorable response of osteogenic sarcoma to high dose methotrexate
with citrovorum rescue and radiation therapy. Cancer 31: 1367-1373, 1973.
Cortes EP, Holland JF, Wang JJ, Sinks LF: Doxorubicin in disseminated osteosarcoma. J Am Med Assoc. 221:1132-1138, 1972.
Cortes EP, Holland JF, Wang JJ, Sinks LF, Blom J, Senn H, Bank A, Glidewell O: Amputation and adriamycin in primary osteosarcoma. N Eng J Med 291: 998-1000,
1974.
Rosen G, Caparros B, Huvos AG et al.: Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response
of the primary tumor to preoperative chemotherapy. Cancer. 49: 1221‑1230, 1982.
Mott V: An account of a case of osteosarcoma of the left clavicle in exsection of that bone was succcessfully performed. Am J Med Sci 3:100-108, 1828.
Langenbeck B: Grosses enchondrom (gallertknorpel-geschwulst) des Schulterblattes: Extirpation des ganzen Schulterblattes mit Ausnahme des process coracoides.
Dtsch Klin-Berl 2:302-319, 1850.
Morris H: Conservative surgery. Lancet 1: 440, 1876.
Hinds F: Case of myeloid sarcoma of the femur treated by scraping. Br Med J 1:555, 1898.
Kotz R, Salzer M: Rotation-plasty for childhood osteosarcoma of the distal part of the femur. J Bone Joint Surg 64A: 959-969, 1982.
Van Nes CP: Rotation-plasty for congenital defects of the femur. J Bone Joint Surg. 32B:12-16. 1950.
Sauerbruch F: Die Extirpation des Femur mit Umkipp-Plastik des Unterschenkels. Dtsch Zeit Chir 169: 1-12, 1922.
Pringle JH: The intrapelvic-abdominal amputation with notes on two cases. Brit J Surg. 4:283-287, 1916.
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