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Cancer has been recognized from antiquity. The Papyrus Ebers (1500 BC) contains the first reference to soft tissue tumor, “a fatty tumor,” with the recommendation that it should be treated with the knife. However, it continued, “If there is a large tumor in any part of the limb… do nothing against.” Hippocrates (460–375 BC) recognized “superficial and deep-seated tumors in the arm and thigh in older people.” Celsus (25 BC to AD 50), a native of Greece practicing in Rome, separated benign tumors, eg, lipoma, from malignant growths, cancer. Galen (AD 131–200), another Greek physician who settled in Rome, described sarcoma as “fleshy excrescence” having the appearance of raw meat “sarkos.” Under the term of sarcoma, he combined swellings, benign tumors, as well as undefined tumors, such as “fungus.”1

With regard to treatment, Celsus, Galen, and most physicians and surgeons for centuries advised refraining from the surgical excision of tumors, including sarcomas, that were irregular in shape, livid in color, insensible, ulcerated, or could not be moved with fingers. Theodoric of Salerno (1205–1296), a priest physician, noted that lipomatous tumors that were dark in color and firm to touch were cancerous, and treatment was not appropriate for such lesions. A French surgeon, Guy de Chauliac (1300–1368), who was the physician to 3 Popes in Avignon, held a different view. He recommended wide excision for cancer at an early stage when the cancer was small and superficial.2

Progress in medicine was hindered until the end of the 1600s by Galen's humoral theory, insufficient knowledge of anatomy, and lack of microscopy. Microscopic study of connective tissue was inaugurated by the description and illustration of voluntary muscle, in 1721, by the Dutch Leeuwenhoek (1632–1723). Etmullerus (1644–1683) in his book,3 which was published posthumously in 1712, urged the readers to study tumor through the microscope and gave the first description of a tumor originating from the membranes of the knee joint. He indicated that, for the most part, such lesions were very dangerous because of their tendency to become cancer (Fig. 1).

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Figure 1. Title page of Etmullerus' book of 1712 in which there is reference to “dangerous tumors of the membranes of the knee.” (Reprinted from the author's private collection.)

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By the end of the 1700s, it was accepted that cancers, including sarcomas, should be treated by surgery. John Hunter (1728–1793), the famous English surgeon, proposed that cancers, including sarcomas, should be excised with some of the surrounding substance (tissue). This was the first recommendation that malignant tumors should be removed with clear surgical margins. It seems that, although surgeons advanced the treatment of cancers, progress in understanding the composition of tumors was lacking.

The microscope was not appreciated as a valuable medical instrument by such giants in pathology as Morgagni (1682–1771) of Italy, Baillie (1761–1823) of England, and Bichat (1771–1802) of France. Despite lagging support by pathologists, surgeons (particularly in England) made steady progress in understanding the nature of sarcomas. In 1803, Hey (1736–1819), who was a surgeon at Leeds, England, introduced the term “fungus haematodes” for highly vascular, fungating tumors of the limbs.4 Wardrop (1782–1869), an Edinburgh surgeon, defined fungus haematodes as “soft cancer.” He learned about soft cancers in Vienna after he escaped from France in 1803, when Napoleon ordered that English residents in France be arrested and placed in prison. In his book,5 which included many cases of fungus haematodes, he described and illustrated 3 cases of soft cancer of the extremities (Fig. 2). At about the same time, Abernethy (1764–1831), who was a pupil of John Hunter and a leading surgeon in London, suggested that tumors should be named according to their anatomic structure and offered the first classification of sarcomas6 (Table 1). Another eminent British surgeon, Charles Bell (1774–1842), called attention to characteristic features that distinguished soft cancers from carcinomas. In his book,7 he described many tumors, including soft cancers. Bell wrote that, “Soft cancer may attack any of the structures of the body… it certainly arises in the soft substance of the limbs” (Fig. 3). Bell described soft cancers (sarcomas) in the liver; the lungs; the orbits; and, in 1 case, in the popliteal nerve.

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Figure 2. The first illustration of an amputated arm with “soft cancer” by Wardrop in 1809. (Reprinted from the author's private collection.)

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Figure 3. The first clinical illustration of a sarcoma of the thigh by Bell in 1816. (Reprinted from the author's private collection.)

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Table 1. Classification of Sarcomas According to Abernethy in 1809*
  • *

    See Abernathy, 1809.6

Vascular sarcoma
Adipose sarcoma
Cystic sarcoma
Tuberculated sarcoma
Medullary sarcoma
Mammary sarcoma
Pancreatic sarcoma
Carcinomatous sarcoma

Two decades after Bell observed7 that sarcomas were cancers and that there were such things as soft cancers (sarcomas), Johannes Muller (1801–1858), a very influential German pathologist, introduced his concept8 in 1838 that “some of the sarcomas are merely new formations without any malignant tendency.” Adhering to his postulate, he coined the term “cystosarcoma phyllodes,” meaning a benign tumor of the breast. He also introduced the term “desmoid tumor,” although, 6 years earlier, an “organized sarcomatous tumor between the layers of the abdominal muscles” was reported in women who had children.9 It was most likely an abdominal desmoid tumor. Johannes Muller's opinion about sarcomas was seconded by a distinguished Austrian pathologist, Carl Rokitansky (1804–1878), who wrote in his book10 that “sarcomas are benign new growths that are always local affections curable by complete extirpation, and do not recur locally, and very seldom spread to other sites.”

Although the name sarcoma continued to mean many different things to many physicians, individual case reports of true sarcomas (malignant tumors) began to accumulate. Sarcomas were reported in various organs, and the term “liposarcoma” was introduced and illustrated.11 In France, pathologists applied more and more the microscope for studying cancers, including sarcomas. In 1845, Lebert (1813–1878) published an atlas illustrating, the first time, the microscopic appearance of true sarcomas of soft tissues12 (Fig. 4). A new name, “rhabdomyosarcoma,” was introduced13; and a case of “extraabdominal desmoid” tumor was reported.14

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Figure 4. The first illustration of spindle and round cells of soft tissue sarcomas by Lebert in 1845. (Reprinted from the author's private collection.)

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Simultaneously, 3 physicians—a pathologist, Rudolph Virchow (1821–1902), in Berlin15; a surgeon, Samuel Gross (1805–1884), in Philadelphia16; and an internist, Samuel Wilks (1824–1911), in London17—presented a series of clinical and pathologic features by which sarcomas could be distinguished from carcinomas. They indicated that all sarcomas are composed of immature connective tissue elements and are known by such synonymous names as fungus hematodes, medullary sarcoma, cerebriform cancer, and soft cancer. All of them proposed that sarcomas should be named with consideration of their histologic composition. From the 1860s, knowledge about sarcomas began to accumulate from published case reports. Case reports of synovial sarcoma,18 fibrosarcoma of the extremities,19 paratesticular rhabdomyosarcoma,20 leiomyosarcoma of the saphenous vein,21 extraskeletal osteosarcoma,22 and chondrosarcoma23 were reported. The term “angiosarcoma” was introduced24; and Kaposi (1837–1902), a Hungarian dermatologist, reported the first cases of a cutaneous disease25 that since then has been known eponymically as “Kaposi's sarcoma.” The spread of a soft tissue sarcoma through blood vessels was reported first in 1874.26

Hamilton in his book27 indicated that there is a difference in the malignancy of soft tissue sarcomas according their site and reported the first soft tissue sarcomas diagnosed from aspirate, years earlier, by Joseph Woodward (1833–1884), the Surgeon General of the United States. The terms “embryonal rhabdomyosarcoma”28 and “pleomorphic rhabdomyosarcoma”29 were introduced. Frank B. Mallory (1862–1941) of Boston was able to distinguish various sarcomas by using special stains.30 Depending on the accumulated reports on sarcomas and using available special histologic stains, Borst (1869–1946) of Germany was able to establish, once and for all, that sarcomas are malignant mesodermal (mesenchymal) tumors31 (Table 2). He described and illustrated for the first time the microscopy of “hemangioendothelioma,” “lymphangioendothelioma,” and “perithelioma” (later known as hemangiopericytoma).

Table 2. Classification of Sarcomas According to Borst in 1902*
  • *

    See Borst, 1902.31

Differentiated sarcomas
 Fibroma sarcomatosum
 Myxoma sarcomatosum
 Lipoma sarcomatosum
 Myoma sarcomatosum
 Neuroma sarcomatosum
 Angioma sarcomatosum
 Osteoma sarcomatosum
 Chondroma sarcomatosum
 Glioma sarcomatosum
 Lymphoma sarcomatosum
 Myeloma multiplex
 Chloroma
 Melanosarcoma
Undifferentiated sarcomas
 Spindle cell sarcoma
 Round cell sarcoma
 Giant cell sarcoma

A few years before the outbreak of the First World War, “epithelioid” (biphasic) and “fusiform” (monophasic) types of synovial sarcoma,32 liposarcoma ex lipoma,33 and radiation-induced fibrosarcoma in a patient and in experimental animals were published.34 Simultaneously, at the Rockefeller Institute in New York City, Rous (1879–1970) and his associates produced sarcoma from cell-free filtrate,35 established the same “Rous sarcoma” in long-term tissue culture,36 and succeeded in growing the first human sarcoma in vitro.37 In recognition, Rous received the Nobel Prize for his work, 56 years later, in 1966. Across the street from the Rockefeller Institute, James Ewing (1866–1943), Professor of Pathology at the Cornell University Medical College and Director of Pathology at the Memorial Hospital for Cancer, classified sarcomas by using a dual system: histogenesis and microscopic appearance. In the first edition of his seminal book, which went through 4 editions,38 he reviewed all that was known about sarcomas. He agreed with Borst's classification and added to it “neurogenic sarcoma”. Ewing introduced aspiration cytology for routine preoperative diagnosis of soft tissue and bone tumors and warned physicians that, compared with epithelial tumors, sarcomas present a wider and more complex field in oncology. Although amputative surgery remained the preferred modality of treatment for sarcomas,39 occasionally, wide excision followed by radiation was employed.40 Ewing himself41 and others42 advocated radiotherapy for liposarcomas and for certain other sarcomas with myxoid component. However, a review of the literature on synovial sarcomas43 and fibrosarcomas44 indicated that they are resistant to radiation. Broders (1885–1964) and his colleagues at the Mayo Clinic followed45 Ewing's suggestion from a few years earlier46 that grading of the malignancy of soft tissue sarcomas is an important undertaking by pathologists, and no sarcoma should be treated without knowing its histologic grade. Broders also interjected that xanthomas (histiocytomas) are undiffer- entiated fibrogenic tumors.

Although case reports of unusual soft tissue tumors, eg, rhabdomyosarcoma in a nerve tumor, sarcoma with an alveolar pattern, and round cell sarcoma of the stomach, were noted, a number of important original reports also were published. A definitive account of osteosarcoma of soft tissues was published.47 The first authentic report appeared of soft tissue sarcoma observed with the electron microscope.48 New terms, such as “postmastectomy lymphangiosarcoma”,49 “chordoid tumor”,50 and “alveolar soft part sarcoma”,51 were introduced. After the fourth edition of Ewing's Neoplastic Diseases was published in 1942, the year before his death, Columbia University in New York City evolved into a hub for soft tissue tumors. Arthur P. Stout (1885–1967) and his associates published several scholarly contributions ranging from tissue culture studies and case reports52–55 to the introduction of new entities, such as “hemangiopericytoma”,56 “mesenchymoma”,57 “malignant fibrous histiocytoma”,58 and “malignant schwannoma”.59 Stout's efforts culminated in the publication of a slim monograph on peripheral nerve tumors59 and another, somewhat more substantial text on soft tissue tumors (Fig. 5.60 In the latter work, Stout skillfully presented the complex problem of classification and subclassification of soft tissue sarcomas (Table 3). With regard to therapy, his opinion was that too few cases had been studied to permit any definitive conclusion about the best form of treatment or the efficacy of radiotherapy as a supplement or replacement to surgery. In addition, he acknowledged that the least understood and probably the most inadequately treated of all tumors were mesenchymal tumors of the soft tissues.60 Although the first reference to malignant histiocytoma was published in Argentina,61 Stout's definition of fibrous histiocytomas as embryonal forms of fibroblastic neoplasms is a time-honored statement. Similarly, his conclusions that soft tissue sarcomas vary in prognosis and in natural history, depending on the cell type, the anatomic site, and the patient's age,62 are permanently established principles.

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Figure 5. Title page of Stout's Armed Forces Institute of Pathology fascicle. (Reprinted from the author's private collection.)

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Table 3. Classification of Soft Tissue Sarcomas by Stout in 1953*
  • *

    See Stout, 1953.60

Fibrosarcoma
Dermatofibrosarcoma protuberans
Myxoma
Liposarcoma
Leiomyosarcoma
Rhadbomyosarcoma
Malignant granular cell myoblastoma
Malignant hemagioendothelioma
Malignant hemangiopericytoma
Kaposi sarcoma
Lymphangiosarcoma
Lymphosarcoma
Plasma cell tumor
Osteogenic sarcoma
Chondrosarcoma
Synovial sarcoma
Malignant mesenchymoma

Discussion about the best surgical modality of treatment continued,63–65 and general agreement was reached about the limited effectiveness of radiation therapy.66 Although the debate about therapy continued, pathologists pursued further classification of soft tissue sarcomas with the electron microscope67 and discovered new entities, eg, “alveolar rhabdomyosarcoma”,68 “metastasizing dermatofibrosarcoma”,69 and “epithelioid sarcoma”.70 The first cytogenetic study of sarcomas was carried out by a pathologist without finding any specific markers for sarcomas.71 In Mexico, a monograph on soft tissue tumors was published in a limited edition,72 and the World Health Organization printed a booklet on histogenetic classification of soft tissue tumors.73

The 1970s turned out to be the most momentous years in the history of soft tissue sarcomas. A small book was published on fibrous tumors in England.74 The author concluded, very properly, that innocent morphology is not necessarily an indication of innocent behavior. Nevertheless, cumulative experience with histologic composition of sarcomas indicated that histologic grade translates to the expression of tumor behavior and aggression. Therefore, attention to cell morphology may play pivotal role in predicting not only histologic grade but also prognosis. However, pathologists were cautioned that tissue conditions in vivo and in vitro may alter the microscopic morphology of cells, eg, spindle cells may change to round cells by losing intercellular adhesion.75, 76 By studying synovial sarcomas, it become apparent that spindle cell synovial sarcoma (monophasic synovial sarcoma) is a particularly aggressive neoplasm compared with the round or epithelioid cell-containing (biphasic) synovial sarcoma.77, 78 Variations in the cytologic appearance of sarcomas, as observed in aspiration smears and preparations from body cavity fluids, were illustrated in a book on the cytopathology of sarcomas.79 For the first time, improved imaging (angiography, tomography, xeroradiography, computerized transaxial tomography, and sonography),80 less than mutilating surgical procedures,81 the option of interstitial radiation or fractional external beam radiation,81, 82 and new chemotherapeutic agents (cyclophosphamide, vincristine, methotrexate, and doxorubicin)83 offered new potentials in early detection and optimal therapy of soft tissue sarcomas.

The tumor lymph node metastases (TNM) system for staging of cancer that was developed by Pierre Denoix of France in the 1960s under the authority of the International Union Against Cancer (UICC) was reviewed by the American Joint Committee on Cancer (AJCC). It was concluded that the international staging system was less than adequate for soft tissue sarcomas. Consequently, the AJCC appointed a multidisciplinary Task Force under the leadership of William O. Russell (1910–1997) of the M. D. Anderson Cancer Center of Houston. After years of collaborative efforts of members of the Task Force, in 1977, a simple clinical and pathologic TNM staging system was published84 (Fig. 6). Shortly after publication of the AJCC's staging system, it become apparent that the classification was less than perfect and required modification. A modified staging system, which listed soft tissue sarcomas not only by histologic grade and size but according to whether the sarcoma was superficial (located above the superficial fascia) or deep (located beneath the superficial fascia), was published in 1979 in a textbook on Pathology of Soft Tissue Tumors that contained >400 black-and-white and color illustrations.85 The staging system designed and introduced by the author has become known as the Memorial Sloan-Kettering Staging System. In the 1990s, as a postscript, the AJCC, the UICC, the American College of Surgeons, and various oncology societies accepted the modified staging system as the official TNM staging for soft tissue sarcomas.

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Figure 6. The original TNM system for staging of soft tissue sarcomas was published in the journal Cancer in 1977. (Reprinted from the author's private collection.)

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Historically, surgery, radiation, and chemotherapy, as they were applied to soft tissue sarcomas up to the 1970s, failed to achieve an impact on survival. However, the innovative prospective clinical trials pioneered at the National Cancer Institute in the United States during the 1970s showed improved survival of patients who were treated by wide local excision, radiation therapy, and adjuvant chemotherapy.86

Disappointing as it may be, despite that in the understanding of soft tissue sarcomas, more progress has been made during the last 25 years than had been made in the previous 2000 years (Table 4), and the cause of soft tissue sarcomas remains to be discovered. None of the anecdotal cases linked to physical trauma or Agent Orange herbicide could be verified on review.

Table 4. Chronology of Events
Year(s)Events in medical historyYear(s)Events in world history
131–200Galen names sarcoma177Marcus Aurelius wrote Meditations
1667Hook introduced the term cell1666Great Fire of London
1842Rokitansky calls sarcoma a benign growth1842The Stars and Stripes raised over Monterey, California
1874Kaposi sarcoma described1876Mark Twain completed Tom Sawyer
1892Cells aspirated from sarcoma1895Motion picture camera invented
1914Human sarcoma grown in culture1915Einstein formulated the Theory of Relativity
1939Histologic grading by Broders1938Nylon invented
1958Surgical management of sarcomas summarized1956Khrushchev denounces Stalin's dictatorship
1977TNM cancer staging system published1976Apple computer goes on sale

Historians, as a rule, should not dwell on matters that occurred during the immediate past decades; however, for the reader's benefit, I include here a list of books and monographs that were published the last 20 years, after the first TNM staging system,84 the first prospective randomized trial,86 and the first pathology book on soft tissue tumors85 were printed: Tumors of the Soft Tissues by Lattes (1982); Soft Tissue Sarcomas by Baker (1983); Tumors of the Soft Tissues by Das Gupta (1983); Soft Tissue Tumors by Enzinger and Weiss (1st edition, 1983; 4th edition, 2001); Differential Diagnosis of Soft Tissue and Bone Tumors by Hajdu (1983); Atlas of Extremity Sarcoma Surgery by Sugarbaker and Nicholson (1984); Surgical Management of Soft Tissue Sarcomas by Arlen and Marcove (1987); Soft Tissue Sarcomas by Eilber, Morton, Sondak, and Economou (1987); Surgical Management of Soft Tissue Sarcomas by Shiu and Brennan (1988); Soft Tissue Sarcomas by Nash (1988); Cytopathology of Soft Tissue and Bone Tumors by Hajdu and Hajdu (1989); Tumors and Tumor-like Lesions of Soft Tissue by Nifo, Chung, and Cavazzana (1991); Soft Tissue Sarcomas of the Limbs by Lawrence (1993); Histological Typing of Soft Tissue Tumors by Weiss (1994); Color Atlas of Soft Tissue Tumors by Meis-Kindblom (1996); and Tumors of the Soft Tissues by Kempson, Fletcher, Evans, Hendrickson, and Sibley (2001).

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