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Embryonal rhabdomyosarcoma of the head and neck
Embryonal
Rhabdomyosarcoma Head
Report JAMES
K. MASSON,
and Neck
on
M.D. AND
EDWARD
H. SOULE,
From the Sections of Plastic Surgery and Surgical Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
MBRYONAL
Vol.110,OctoberI965
nt.rx, Rochester,
Minnesota
tumors” and classified with the mesodermal mixed tumors. During the past fourteen years the concepts of rhabdomyosarcoma have undergone considerable change. This change has perhaps best been presented by Horn and Enterline [2] who espoused the idea of four subtypes of rhabdomyosarcoma : pleomorphic, embryonal, alveolar, and botryoid, the last subtype being recognized as a morphologic variant of the embryonal subtype. More recently there has been a growing tendency to consider the alveolar subtype as also representing a variant of the embryonal subtype with a resurgence of the belief that the alveolar sarcoma of soft parts is a specific entity and best considered separately from rhabdomyosarcomas. Shipkey and colleagues [3] have recently demonstrated microscopic features of the alveolar soft parts sarcoma that would appear to substantiate this concept. Thus during the last few years embryonal rhabdomyosarcoma has become a widely recognized and accepted neoplasm. In 1962 Dito and Batsakis [4] collected reports of 161 cases in addition to presenting nine personal cases. Porterfield and Zimmerman [5] reviewed more than 1,000 orbital tumors and listed forty as embryonal rhabdomyosarcoma. Although most recognized lesions are in the head and neck and the genital tract, Lawrence, Jegge, and Foote [6] have described forty-eight identical tumors seen in the Memorial Sloan-Kettering Cancer Center that occurred in the somatic soft parts of the extremities and retroperitoneum. At the time of this writing Geitz and Soule [7] have
RHABDOMYOSARCOMA may be defined as a malignant tumor of rhabdomyoblasts whose microscopic pattern simulates that of embryonic striated muscle cells. This neoplasm tends to occur in the head and neck in children and young adults and in most cases is rapidly fatal. The gross features of the tumor are not distinctive except for those few lesions whose relationship to a body cavity or mucous membrane allows a polypoid or grape-like growth pattern, thus accounting for the term “botryoid tumor.” The microscopic appearance of this tumor may vary widely in individual cases, resulting in an inaccurate histologic diagnosis if the biopsy specimen is skimpy. In the past, except for those lesions demonstrating the most obvious features of a myogenic tumor, these tumors have been confused with malignant lymphoma, neuroretinoblastoma, hemangioendoblastoma, thelioma, amelanotic melanoma, myxosarcoma, and fibrosarcoma, or have simply been referred to as small cell malignant neoplasms. The tumor was rarely recognized as rhabdomyosarcoma before 1950, when Stobbe and Dargeon [I] proposed the concept that the histologic appearance of the tumor most closely resembled that of embryonic muscle cells. They stated that the tumor was related to those lesions of the urinary bladder, prostate, and vagina of children that in the past had customarily been referred to as “botryoid
E
of the
585
586
Masson
Averageageaf Average
63ch,ldren.7yr(Z*k-l5yri
age of 25aduIts
38yr 116yr:77yr.j
Age bydecades
FIG. 1. Patients with embryonal rhabdomyosarcoma of the head and neck. Distribution by age and sex. “Children” are patients not more than fifteen years old.
studied fifty-five verified embryonal rhabdomyosarcomas of the extremities and the limb girdles and have found that an appreciable number demonstrate alveolar features. MATERIAL
AND METHOD
is based on a study of eighty-eight cases of embryonal rhabdomyosarcoma treated at the Mayo Clinic from 1910 through 1964. These tumors were found during a systematic review of 1,093 sarcomas (exclusive of malignant lymphoma arising in lymphoid tissues) originating in the head and neck. Sections of tissue were available for review in all cases, and in many instances tissue was available for more extensive study. Prior to 1950 a few tumors in which cross striations were readily demonstrable were recognized as rhabdomyosarcomas, but in most instances the true nature of the tumors was not understood. Eleven of the eighty-eight cases have been previously reported by O’Day, Soule, and Gores [8]. This
paper
GROSS
AND
HISTOLOGIC
FEATURES
There is no characteristic gross pattern that may be ascribed to this neoplasm. Lesions that occur in the external auditory canal or nasopharynx or, for that matter, beneath any portion of the nasal or oropharyngeal mucosa may present as a polypoid tumor, thus simulating its more frequently recognized counterpart, the botryoid tumor of the urogenital tract. Since some of the material available for study consisted of only nondescript biopsy specimens, one is forced to rely on descriptions of the in situ lesions or on the myxoid appearance of the tissue and its association with a mucous membrane to designate a given In this series eight lesion as “botryoid.”
and Soule tumors were classified as a botryoid variant of embryonal rhabdomyosarcoma. Histologically, embryonal rhabdomyosarcoma may be described as a small cell neoplasm, the most characteristic feature being round or spindle cells that possess distinctive eosinophilic granular cytoplasm. The amount of distinctive cytoplasm varies considerably from area to area in a given tumor and from tumor to tumor. The loose arrangement of very small spindle and stellate cells in a matrix that simulates tissue mucin results in a pattern that closely resembles myxoma or, in the presence of capillaries and scattered inflammatory cells, granulation tissue. While the sine qua non for the diagnosis of rhabdomyosarcoma is the presence of cross striations in the cytoplasm of the tumor cells, whether in the pleomorphic or other subtypes, the absence of such a feature does not preclude the diagnosis. Cross striations were found in only thirteen of the eighty-eight tumors. They were prominent in only one tumor and in others were often found in only the very occasional cell. The small biopsy specimen available in a number of instances and the inferior preservation of some tissue probably precluded the finding of striations in a number of tumors. The histologic features of this tumor encompass a rather broad spectrum ranging from myxoid areas that simulate myxoma through areas of closely packed spindle cells to areas of small round cells that are readily confused with those of malignant lymphoma. An alveolar pattern may be observed in portions of a tumor, a feature that was present in five of our tumors. This feature is best ascribed to the clustering of tumor cells within a fine reticulin network. True alveolar formation was not observed. An excessive amount of fibrous stroma may also result in pseudoclefting of the tumor cells. Very occasionally, collections of somewhat bizarre large cells were observed. These cells were reminiscent of the cell type that makes up the bulk of Such cell pleomorphic rhabdomyosarcoma. clusters were found in eight of our cases and serve to demonstrate the slight tendency for overlap of the pleomorphic subtype. CLINICAL
FINDINGS
Age and Sex. Eighty-seven patients were white and one was Negro. The ages on admisAmerican
Journal
of Surgery
Embryonal
Rhabdomyosarcoma
of Head and Neck
sion ranged from two weeks to seventy-seven The distribution of the patients by age and sex is shown in Figure 1. The presence of more female than male patients is not in accord with the reports by most authors that male patients outnumber female patients slightly. Site qf Primary Lesion. In nearly 60 per cent of patients the tumor occurred in the orbits, nasopharynx, and nose. (Fig. 2.) The eight tumors with botryoid features occurred in the external auditory canal, nose, nasopharynx, and orbit. There was no favored site for the five tumors with alveolar features. In dial Symptoms. The initial symptom was the presence of a painless tumor, usually of sudden onset, in thirty-six patients, nasal stuffiness and difficulty in breathing in sixteen, pain and proptosis in six each, swelling of the upper eyelid with ptosis in seven, nosebleeds in two, facial paralysis and a draining ear in two, and, in single instances, numbness of the lower lip, hoarseness, epiphora, pimple on the nose, diplopia, and swollen lymph nodes in the neck. In two cases no record was made of the initial complaints. The duration of symptoms before admission ranged from one week to five and a half years and was three months or less in forty-four. In only six cases did symptoms exist more than a year before admission. Clinical C’ourse. Like the patients in Moore and Grossi’> [9] review series reported in 1959, most patients in our series were seen early by their physicians and a diagnosis by biopsy was usually made. The patient was then either treated in his home community or referred to the Mayo Clinic for definitive treatment. Of the eighty-eight patients sixty-two had received previous treatment or had had biopsy before coming to this clinic, twenty-three had received no prior treatment, and for three the records were adequate on this point. Seventy-two per cent of the patients in this series were children, and approximately three fourths of these were in the first decade of life. The youngest patient, a newborn who exhibited protrusion of the left eye at the age of five days, died eight months later from widespread metastasis. The oldest patient, a seventy-seven year old man who had intermittent nasal obstruction for seven months, was found on examination to have an extensive lesion of the right nasal fossa and antrum. The tumor
years.
. FIG. 2. Distribution
of primary tumors by site.
responded poorly to radiation and the patient died one and a half years after initial treatment. This tumor exhibited occasional microscopic foci of pleomorphic cells and suggested an overlap with the pure pleomorphic type of rhabdomyosarcoma as mentioned by Horn and Enterline [Z]. Four other tumors in this series presented similar scattered foci of pleomorphic cells, one occurring in an adult and three in children. In the histologic review of all sarcomas of the head and neck, from which our series was taken, we found thirteen cases (all in aclults) of the pure pleomorphic subtype. Cross striations in the cytoplasm of tumor cells were observed most often in tumors occurring in the first decade of life. Twelve such tumors were observed in children and one in an adult (a sixty-eight year old man). There was no correlation between the presence of cytoplasmic cross striations and length of survival although a ten year old boy has survived more than ten years after excision and irradiation of such a tumor situated in the tongue. With one exception, these tumors exhibited only an occasional cell with cross striations and are not to be classified with the well differentiated rhabdomyosarcomas of the orbit that were described by Porterfield and Zimmerman [5]. The one patient in our series, a twelve year old boy, who exhibited many spindle cells with cross striations died five months after exenteration of the left orbit. Figures 3, 4, and 5 illustrate some of the variations in the clinical picture seen in this series of patients. Metastasis. Thirty-three of the eighty-eight patients had proved or clinically demonstrable
3. Recurrent subcutaneous tumor in left cheek of a four year old girl. Tumor grew slowly for four monthsafter onset and was excised. It recurred in two months. Insertion of radon seeds into tumor was followed by complete regression. Pulmonary metastasis was noted nine months after insertion of radon seeds, and patient died two years ten months after first treatment, without further evidence of primary tumor. FIG.
FIG. 4. Rapidly enlarging orbital tumor of four weeks’ duration with displacement of eye outward and downward in a twenty-one year old woman. Biopsy was followed by exenteration of left orbit and radium treatments. Patient died less than two months after operation.
5. A sixty-two year old woman had symptoms of a “head cold” for ten months before initial examination elsewhere. Biopsy more than three months before admission to clinic had revealed a malignant tumor of the left naris. Treatment included wide destruction with surgical diathermy and interstitial radiation with radium points. Radium was used again in the nostril after three months and five months. After nine months, lymph nodes in both axillae were metastatically involved. A mass was seen in the left side of the chest on x-ray examination, and the liver was clinically enlarged. Patient died of the disease ten months after admission. FIG.
to cervical lymph nodes during the course of the disease. At the time of initial treatment, twelve of the thirty-three patients had histologically proved metastasis to lymph nodes, six had clinically enlarged regional lymph nodes probably due to metastasis, and fifteen subsequently presented clinical evidence of metastasis to cervical lymph nodes. Bloodborne metastasis to the lungs appeared to be the usual mode of spread although widely disseminated metastatic lesions were occasionally observed. Metastasis to the spine, pelvis, or long bones was observed in nine patients. There was rather frequent, extensive local spread of the tumor, which caused metastasis
TABLE
I
EMBRYONALRHABDOMYOSARCOMAOFHEADANDNECK IN
EIGHTY-EIGHT
CASES:
TREATMENT
Treatment Surgery alone (excluding biopsy) Surgery and radiation Surgery, radiation, and chemotherapy Radiation alone Radiation and chemotherapy No known treatment
-CasesNo. % 7 39 3 30 6 3
8 44 4 34 7 4
destruction of the adjacent bone stuctures and often led to direct intracranial extension. One patient died from massive intracranial extension with no evidence of metastasis found at autopsy despite an eighteen month clinical course. Treatment. Table I shows irradiation therapy (including use of radium blocks, radium points, radon gold-filtered seeds, 250 kv. roentgenotherapy, and cobalt 60 teletherapy) used alone or combined with surgery, chemotherapy, or both in the treatment of 88 per cent of the patients in our series. Surgery (not including biopsy) consisted primarily of wide local excision. For orbital tumors this meant exenteration of the orbit, Some tumors of the nasal fossa and one involving the nasal septum were removed through a lateral rhinotomy approach. Wide excision of a cheek tumor, total parotidectomy, laryngectomy, and removal of the mandible combined with radical dissection of the neck were necessary in individual cases. In most cases radiation therapy also was used before or after operation. In addition, surgery along with radiation and occasionally chemotherapy was used in the treatment of some recurrences. One patient listed in Table II as living with American
Journal of Surgery
Embryonal
Rhabdomyosarcoma TABLE
EMBRYOSAL
RHABDOMYOSARCOMA
Primarv. *Site
OF HEAD
Age (yr.) and Sex
AND NECK
IN
of Head and Neck
II EIGHTY-EIGHT
Treatment
CASES:
DATA
ON
NINE
LIVISG
PATIENTS
Recurrence or Metastasis
Alive, Years after Admission
3 recurrences 0 0 0 1 recurrence 0 0 0
15 8 5 20 18 4% 2% 1%
Living with No Evidence of Disease
Lower jaw Parotid Larynx Lower jaw Tongue Soft palate Orbit Tongue
21, 9, 7, 37, 10, 24, 25, 13,
Surgery and Radiation Radiation Surgery and Surgery and Surgery and Surgery and Surgery
F F F M
M
M M M
Living
Tongue
11, M
with Known
radiation radiation radiation radiation radiation
Recurrent
Radiation and chemotherapy
no evidence of disease underwent excision of the primary lesion in the dorsum of the tongue by excisional biopsy by his personal physician. Ten days later, wide excision of the biopsy site revealed no residual tumor and no further treatment has been given. It has now been one and three quarter years with no recurrence. Chemotherapy was used on nine patients in our series: six times in conjunction with irradiation and three times with both surgery and irradiation. It was not used alone but secondarily and for residual, recurrent, or metastatic disease. The effects of the chemotherapeutic agents we have used have been discouraging. Although in one case the recurrent orbital tumor completely resolved for a year after therapy with actinomycin D and radium needles, it recurred again and failed to respond to vincaleukoblastine (Velban”) given in twenty-five weekly injections. Then because of progression of the disease even despite cyclophosphamide (Cytoxan@) given by mouth daily for two weeks, all therapy was discontinued. This child died twenty-four months after onset. Another child had a similar history. Surgery and therapy with cobalt 60, actinomycin D, vincaleukoblastine, and cyclophosphamide were of little if any benefit in controlling progression of the growth. She died, after twenty-three months, with extensive disease. A third patient who has had chemotherapy Vol. IlO, OctoOer1965
or Metastatic
Disease
Metastasis in neck
was given initially vincaleukoblastine intravenously at weekly intervals for four months. His condition improved only minimally if at all, and he was given a full course of cobalt 60 therapy. In two months there was definite and dramatic reduction in the size of the primary tumor in the tongue and the metastatically involved lymph nodes in the neck. He recently has been started on treatment with actinomycin D and clinically continues to improve. However, after ten months he still has the primary tumor and palpable nodes in the neck. He is listed in Table II as living with known disease, and the prognosis is predictably poor. Three patients are not known to have been treated (one refused treatment and two returned home and were lost to follow-up study). The over-all results of therapy of this disease are poor. In this series sixty-nine patients died of their disease, nine are living, and ten were lost to follow-up study. (Table III.) Of the nine patients living, eight (9 per cent of the series) are well and apparently free of disease one and three-quarter to twenty years after admission; the other patient is living with recurrent tumor and is considered beyond further therapeutic help. (Table II.) COMMENTS
Embryonal rhabdomyosarcoma, although prone t.o wide and varied distribution in the
590
Masson TABLE
EMBRYONAL IN
III
RHABDOMYOSARCOMA
OP HEAD
EIGHTY-EIGHT
SURVIVAL
CASES:
AND
NECK
-Cases--. Result
No.
%
Dead within 1 year after admission to clinic Died during second year Died during third to fifth year Living and well 1% to 20 years after admission Living with recurrence 10 months after admission Lost to follow-up study
43 18 8
49 20 9
8
9
1 10
1 11
head and neck, appears to show a predilection for the orbits and paranasal structures. Lesions originating in the orbits most often appear in the upper inner quadrant and not infrequently involve the upper lid early in their clinical course. Embryonal rhabdomyosarcoma is particularly lethal in children and young adults: 88 per cent of traced patients in our series died within five years and 55 per cent died during the first twelve months. The tendency for metastasis to lymph nodes would appear to be greater with embryonal rhabdomyosarcoma than with most other types of somatic soft tissue sarcoma. Linscheid, Some, and Henderson [IO] found metastasis to regional lymph nodes in 9 per cent of eighty-seven patients with pleomorphic rhabdomyosarcoma of the extremities and limb girdles. The inordinate number of patients (nine) exhibiting bone metastasis in our series is somewhat unusual when compared with the number seen in series of the pleomorphic type. Caffey and Andersen [II] commented on this finding in the growing skeleton and mentioned the differential diagnosis of neuroblastoma. Those tumors exhibiting alveolar or botryoid features did not present any specific pattern for metastasis. Treatment of embryonal rhabdomyosarcoma is most discouraging. Present day management with surgery, supervoltage irradiation, and chemotherapy has offered little improvement in survival rates over conventional 250 kv. x-ray irradiation and local excision as practiced thirty or forty years ago. Diagnosis of this tumor and a knowledge of its biologic behavior have not been‘-fully appreciated until recent years. Of prime importance in proper
and Soule treatment is early accurate diagnosis, and of utmost importance to the pathologist is adequate biopsy material. The most logical approach, when possible, now seems to be wide surgical excision and removal of regional lymphatics, if feasible, in conjunction with chemotherapy followed by irradiation for any recurrences. However, because the primary lesions are in the head and neck, wide surgical excision and en bloc removal of the regional lymphatics are often not possible. Because of the discouraging results of any form of treatment, often a radical mutilating procedure on a child is avoided and instead irradiation therapy with or without chemotherapy is proposed initially. It is known that embryonal rhabdomyosarcomas are radiosensitive, often markedly so. Any treatment of such malignant tumors must necessarily be radical, and this applies to irradiation as well as surgery. If a cure is to be expected, some marks will have to be left. Moore and Grossi [9] presented a case that shows the effect of high dosage x-ray therapy in a child: the tumor was eradicated but treatment caused faulty development of the mandible and facial skeleton and lack of development of the teeth of the lower jaw. This is a risk that must be accepted in treating a lesion as lethal as embryonal rhabdomyosarcoma. We believe that the initial treatment now should include the use of a chemotherapeutic agent such as actinomycin D, cyclophosphamide, and vincaleukoblastine. Such chemotherapy may be given before, during, or after surgical removal of the tumor or during irradiation. These tumors are radiosensitive, and the forms of irradiation used include conventional 250 kv. roentgenotherapy, cobalt 60 therapy, and occasionally radium therapy in the form of radium needles or points which can be placed interstitially, radon seeds placed interstitially, or radium applicators which may be used within a cavity such as the nasopharynx, orbit, and antrum. Recurrences even after intensive treatment are common and must be dealt with by a combination of surgery, irradiation, and chemotherapy. Albores-Saavedra, Martin, and Smith [12] have mentioned the consistently favorable response of these tumors to actinomycin D, which contrasts with the unimpressive results that we have observed from the use of chemotherapeutic agents.
Embryonal
Rhabdomyosarcoma
SIJMMARY
Of eighty-eight patients with embryonal rhabdomyosarcoma of the head and neck, forty-eight were female and forty were male patients. ages ranged from two weeks to seventy-seven years. Sixty-three were children (average age: 6.8 years) and twenty-five were adults (average age: 37.6 years). In nearly 60 per cent of patients the tumor occurred in the orbit, nasopharynx, or nose. The presenting complaint was usually that of a rapidly enlarging, asymptomatic mass. Half the patients had had evidence of the tumor for three months or less and only six had had it for more than a year on admission. Seventy-eight per cent of patients are known to have died as a result of the tumor, 49 per cent within the first year, 20 per cent in the secoud year, and 9 per cent within three to five years after admission. Eight patients (nine per cent) are known to be alive and free of disease twenty-one months to twenty years after admission, one patient (1 per cent) is alive with tumor metastasis, and ten (11 per cent) have been lost to follow-up study. Of the eight surviving p atients assumed to be free of disease, one was treated by surgery alone, five by combined surgery and radiation, and two by radiation only. Histologically, the tumor often presents a varied pattern that in part may be readily confused with many quite dissimilar neoplasms, among which are reticulum cell sarcoma, neuroblastoma, myxoma, and amelanotic melanoma. An error in tissue diagnosis may be minimized by securing adequate and repre-
Vnl. 110, October 1965
of Head and Neck
591
sentative tissue for biopsy and by awareness of a chance encounter with such a lesion. REFERENCES 1. STOHBE, G. D. and DARGEON, H. W. Embryonal rhabdomyosarcoma of the head and neck in children and adolescents. Cancer, 3 : 826, 1950. 2. HORN, R. C., JR. and ENTERLINE, H. T. Rhabdomyosarcoma: a clinicopathological study and classification of 39 cases. Cancer, 11: 181, 1958. 3. SHIPKEY, F. H., LIEBERMAN, P. H., FOOTE, F. W., JR., and STEWART, F. W. Ultrastructure of alveolar soft part sarcoma. Cancer, 17: 821, 1964. 4. DITO, W. R. and BATSAKIS, J. G. Rhabdomyosarcoma of the head and neck: an appraisal of the biologic behavior in 170 cases. Arch. Surg., 84: 582, 1962. 5. PORTERFIELD,J. F. and ZIMMERMAN,L. E. Rhabdomyosarcomas of the orbit: a clinicopathologic study of 55 cases. Arch. Path. Amt., 335: 329, 1962. 6. LAWRENCE, W., JR., JEGGE, G., and FOOTE, F. W., JR. Embryonal rhabdomyosarcoma : a clinicopathological study. Cancer, 17: 361, 1964. 7. GEITZ, M. and SOULE, E. H. Embryonal rhabdomyosarcoma of extremities and limb girdles. (Unpublished data.) 8. O’D.~Y, R. A., SOULE, E. H. and GORES, R. J. Soft tissue sarcomas of the oral cavity. Proc. Staf Meet., Mayo Clin., 39: 169, 1964. 9. ~TOORE,0. and GROSSI, C. Embryonal rhabdomyosarcoma of the head and neck. Cancer, 12: 69, 1959. 10. LINSCHEID, R. L., SOULE, E. H., and HENDERSON, E. D. Pleomorphic rhabdomyosarcomata of the extremities and limb girdles: a clinicopathological study. J. Bone 8 Joint Surg., 47A: 715, 1965. 11. CAF~~EY, J., and ANDERSEN, D. H. Metastatic embryonal rhabdomyosarcoma in the growing skeleton : clinical, radiographic, and microscopic features. Am. J. Dis. Child., 95: 581, 1958. 12. ALBORES-SAAVEDRA,J., MARTIN, R. G., and SMITH, J. L. Rhabdomyosarcoma: a study of 35 cases. AWL S’urg., 157: 186, 1963.
Rhabdomyosarcoma Head
Report JAMES
K. MASSON,
and Neck
on
M.D. AND
EDWARD
H. SOULE,
From the Sections of Plastic Surgery and Surgical Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
MBRYONAL
Vol.110,OctoberI965
nt.rx, Rochester,
Minnesota
tumors” and classified with the mesodermal mixed tumors. During the past fourteen years the concepts of rhabdomyosarcoma have undergone considerable change. This change has perhaps best been presented by Horn and Enterline [2] who espoused the idea of four subtypes of rhabdomyosarcoma : pleomorphic, embryonal, alveolar, and botryoid, the last subtype being recognized as a morphologic variant of the embryonal subtype. More recently there has been a growing tendency to consider the alveolar subtype as also representing a variant of the embryonal subtype with a resurgence of the belief that the alveolar sarcoma of soft parts is a specific entity and best considered separately from rhabdomyosarcomas. Shipkey and colleagues [3] have recently demonstrated microscopic features of the alveolar soft parts sarcoma that would appear to substantiate this concept. Thus during the last few years embryonal rhabdomyosarcoma has become a widely recognized and accepted neoplasm. In 1962 Dito and Batsakis [4] collected reports of 161 cases in addition to presenting nine personal cases. Porterfield and Zimmerman [5] reviewed more than 1,000 orbital tumors and listed forty as embryonal rhabdomyosarcoma. Although most recognized lesions are in the head and neck and the genital tract, Lawrence, Jegge, and Foote [6] have described forty-eight identical tumors seen in the Memorial Sloan-Kettering Cancer Center that occurred in the somatic soft parts of the extremities and retroperitoneum. At the time of this writing Geitz and Soule [7] have
RHABDOMYOSARCOMA may be defined as a malignant tumor of rhabdomyoblasts whose microscopic pattern simulates that of embryonic striated muscle cells. This neoplasm tends to occur in the head and neck in children and young adults and in most cases is rapidly fatal. The gross features of the tumor are not distinctive except for those few lesions whose relationship to a body cavity or mucous membrane allows a polypoid or grape-like growth pattern, thus accounting for the term “botryoid tumor.” The microscopic appearance of this tumor may vary widely in individual cases, resulting in an inaccurate histologic diagnosis if the biopsy specimen is skimpy. In the past, except for those lesions demonstrating the most obvious features of a myogenic tumor, these tumors have been confused with malignant lymphoma, neuroretinoblastoma, hemangioendoblastoma, thelioma, amelanotic melanoma, myxosarcoma, and fibrosarcoma, or have simply been referred to as small cell malignant neoplasms. The tumor was rarely recognized as rhabdomyosarcoma before 1950, when Stobbe and Dargeon [I] proposed the concept that the histologic appearance of the tumor most closely resembled that of embryonic muscle cells. They stated that the tumor was related to those lesions of the urinary bladder, prostate, and vagina of children that in the past had customarily been referred to as “botryoid
E
of the
585
586
Masson
Averageageaf Average
63ch,ldren.7yr(Z*k-l5yri
age of 25aduIts
38yr 116yr:77yr.j
Age bydecades
FIG. 1. Patients with embryonal rhabdomyosarcoma of the head and neck. Distribution by age and sex. “Children” are patients not more than fifteen years old.
studied fifty-five verified embryonal rhabdomyosarcomas of the extremities and the limb girdles and have found that an appreciable number demonstrate alveolar features. MATERIAL
AND METHOD
is based on a study of eighty-eight cases of embryonal rhabdomyosarcoma treated at the Mayo Clinic from 1910 through 1964. These tumors were found during a systematic review of 1,093 sarcomas (exclusive of malignant lymphoma arising in lymphoid tissues) originating in the head and neck. Sections of tissue were available for review in all cases, and in many instances tissue was available for more extensive study. Prior to 1950 a few tumors in which cross striations were readily demonstrable were recognized as rhabdomyosarcomas, but in most instances the true nature of the tumors was not understood. Eleven of the eighty-eight cases have been previously reported by O’Day, Soule, and Gores [8]. This
paper
GROSS
AND
HISTOLOGIC
FEATURES
There is no characteristic gross pattern that may be ascribed to this neoplasm. Lesions that occur in the external auditory canal or nasopharynx or, for that matter, beneath any portion of the nasal or oropharyngeal mucosa may present as a polypoid tumor, thus simulating its more frequently recognized counterpart, the botryoid tumor of the urogenital tract. Since some of the material available for study consisted of only nondescript biopsy specimens, one is forced to rely on descriptions of the in situ lesions or on the myxoid appearance of the tissue and its association with a mucous membrane to designate a given In this series eight lesion as “botryoid.”
and Soule tumors were classified as a botryoid variant of embryonal rhabdomyosarcoma. Histologically, embryonal rhabdomyosarcoma may be described as a small cell neoplasm, the most characteristic feature being round or spindle cells that possess distinctive eosinophilic granular cytoplasm. The amount of distinctive cytoplasm varies considerably from area to area in a given tumor and from tumor to tumor. The loose arrangement of very small spindle and stellate cells in a matrix that simulates tissue mucin results in a pattern that closely resembles myxoma or, in the presence of capillaries and scattered inflammatory cells, granulation tissue. While the sine qua non for the diagnosis of rhabdomyosarcoma is the presence of cross striations in the cytoplasm of the tumor cells, whether in the pleomorphic or other subtypes, the absence of such a feature does not preclude the diagnosis. Cross striations were found in only thirteen of the eighty-eight tumors. They were prominent in only one tumor and in others were often found in only the very occasional cell. The small biopsy specimen available in a number of instances and the inferior preservation of some tissue probably precluded the finding of striations in a number of tumors. The histologic features of this tumor encompass a rather broad spectrum ranging from myxoid areas that simulate myxoma through areas of closely packed spindle cells to areas of small round cells that are readily confused with those of malignant lymphoma. An alveolar pattern may be observed in portions of a tumor, a feature that was present in five of our tumors. This feature is best ascribed to the clustering of tumor cells within a fine reticulin network. True alveolar formation was not observed. An excessive amount of fibrous stroma may also result in pseudoclefting of the tumor cells. Very occasionally, collections of somewhat bizarre large cells were observed. These cells were reminiscent of the cell type that makes up the bulk of Such cell pleomorphic rhabdomyosarcoma. clusters were found in eight of our cases and serve to demonstrate the slight tendency for overlap of the pleomorphic subtype. CLINICAL
FINDINGS
Age and Sex. Eighty-seven patients were white and one was Negro. The ages on admisAmerican
Journal
of Surgery
Embryonal
Rhabdomyosarcoma
of Head and Neck
sion ranged from two weeks to seventy-seven The distribution of the patients by age and sex is shown in Figure 1. The presence of more female than male patients is not in accord with the reports by most authors that male patients outnumber female patients slightly. Site qf Primary Lesion. In nearly 60 per cent of patients the tumor occurred in the orbits, nasopharynx, and nose. (Fig. 2.) The eight tumors with botryoid features occurred in the external auditory canal, nose, nasopharynx, and orbit. There was no favored site for the five tumors with alveolar features. In dial Symptoms. The initial symptom was the presence of a painless tumor, usually of sudden onset, in thirty-six patients, nasal stuffiness and difficulty in breathing in sixteen, pain and proptosis in six each, swelling of the upper eyelid with ptosis in seven, nosebleeds in two, facial paralysis and a draining ear in two, and, in single instances, numbness of the lower lip, hoarseness, epiphora, pimple on the nose, diplopia, and swollen lymph nodes in the neck. In two cases no record was made of the initial complaints. The duration of symptoms before admission ranged from one week to five and a half years and was three months or less in forty-four. In only six cases did symptoms exist more than a year before admission. Clinical C’ourse. Like the patients in Moore and Grossi’> [9] review series reported in 1959, most patients in our series were seen early by their physicians and a diagnosis by biopsy was usually made. The patient was then either treated in his home community or referred to the Mayo Clinic for definitive treatment. Of the eighty-eight patients sixty-two had received previous treatment or had had biopsy before coming to this clinic, twenty-three had received no prior treatment, and for three the records were adequate on this point. Seventy-two per cent of the patients in this series were children, and approximately three fourths of these were in the first decade of life. The youngest patient, a newborn who exhibited protrusion of the left eye at the age of five days, died eight months later from widespread metastasis. The oldest patient, a seventy-seven year old man who had intermittent nasal obstruction for seven months, was found on examination to have an extensive lesion of the right nasal fossa and antrum. The tumor
years.
. FIG. 2. Distribution
of primary tumors by site.
responded poorly to radiation and the patient died one and a half years after initial treatment. This tumor exhibited occasional microscopic foci of pleomorphic cells and suggested an overlap with the pure pleomorphic type of rhabdomyosarcoma as mentioned by Horn and Enterline [Z]. Four other tumors in this series presented similar scattered foci of pleomorphic cells, one occurring in an adult and three in children. In the histologic review of all sarcomas of the head and neck, from which our series was taken, we found thirteen cases (all in aclults) of the pure pleomorphic subtype. Cross striations in the cytoplasm of tumor cells were observed most often in tumors occurring in the first decade of life. Twelve such tumors were observed in children and one in an adult (a sixty-eight year old man). There was no correlation between the presence of cytoplasmic cross striations and length of survival although a ten year old boy has survived more than ten years after excision and irradiation of such a tumor situated in the tongue. With one exception, these tumors exhibited only an occasional cell with cross striations and are not to be classified with the well differentiated rhabdomyosarcomas of the orbit that were described by Porterfield and Zimmerman [5]. The one patient in our series, a twelve year old boy, who exhibited many spindle cells with cross striations died five months after exenteration of the left orbit. Figures 3, 4, and 5 illustrate some of the variations in the clinical picture seen in this series of patients. Metastasis. Thirty-three of the eighty-eight patients had proved or clinically demonstrable
3. Recurrent subcutaneous tumor in left cheek of a four year old girl. Tumor grew slowly for four monthsafter onset and was excised. It recurred in two months. Insertion of radon seeds into tumor was followed by complete regression. Pulmonary metastasis was noted nine months after insertion of radon seeds, and patient died two years ten months after first treatment, without further evidence of primary tumor. FIG.
FIG. 4. Rapidly enlarging orbital tumor of four weeks’ duration with displacement of eye outward and downward in a twenty-one year old woman. Biopsy was followed by exenteration of left orbit and radium treatments. Patient died less than two months after operation.
5. A sixty-two year old woman had symptoms of a “head cold” for ten months before initial examination elsewhere. Biopsy more than three months before admission to clinic had revealed a malignant tumor of the left naris. Treatment included wide destruction with surgical diathermy and interstitial radiation with radium points. Radium was used again in the nostril after three months and five months. After nine months, lymph nodes in both axillae were metastatically involved. A mass was seen in the left side of the chest on x-ray examination, and the liver was clinically enlarged. Patient died of the disease ten months after admission. FIG.
to cervical lymph nodes during the course of the disease. At the time of initial treatment, twelve of the thirty-three patients had histologically proved metastasis to lymph nodes, six had clinically enlarged regional lymph nodes probably due to metastasis, and fifteen subsequently presented clinical evidence of metastasis to cervical lymph nodes. Bloodborne metastasis to the lungs appeared to be the usual mode of spread although widely disseminated metastatic lesions were occasionally observed. Metastasis to the spine, pelvis, or long bones was observed in nine patients. There was rather frequent, extensive local spread of the tumor, which caused metastasis
TABLE
I
EMBRYONALRHABDOMYOSARCOMAOFHEADANDNECK IN
EIGHTY-EIGHT
CASES:
TREATMENT
Treatment Surgery alone (excluding biopsy) Surgery and radiation Surgery, radiation, and chemotherapy Radiation alone Radiation and chemotherapy No known treatment
-CasesNo. % 7 39 3 30 6 3
8 44 4 34 7 4
destruction of the adjacent bone stuctures and often led to direct intracranial extension. One patient died from massive intracranial extension with no evidence of metastasis found at autopsy despite an eighteen month clinical course. Treatment. Table I shows irradiation therapy (including use of radium blocks, radium points, radon gold-filtered seeds, 250 kv. roentgenotherapy, and cobalt 60 teletherapy) used alone or combined with surgery, chemotherapy, or both in the treatment of 88 per cent of the patients in our series. Surgery (not including biopsy) consisted primarily of wide local excision. For orbital tumors this meant exenteration of the orbit, Some tumors of the nasal fossa and one involving the nasal septum were removed through a lateral rhinotomy approach. Wide excision of a cheek tumor, total parotidectomy, laryngectomy, and removal of the mandible combined with radical dissection of the neck were necessary in individual cases. In most cases radiation therapy also was used before or after operation. In addition, surgery along with radiation and occasionally chemotherapy was used in the treatment of some recurrences. One patient listed in Table II as living with American
Journal of Surgery
Embryonal
Rhabdomyosarcoma TABLE
EMBRYOSAL
RHABDOMYOSARCOMA
Primarv. *Site
OF HEAD
Age (yr.) and Sex
AND NECK
IN
of Head and Neck
II EIGHTY-EIGHT
Treatment
CASES:
DATA
ON
NINE
LIVISG
PATIENTS
Recurrence or Metastasis
Alive, Years after Admission
3 recurrences 0 0 0 1 recurrence 0 0 0
15 8 5 20 18 4% 2% 1%
Living with No Evidence of Disease
Lower jaw Parotid Larynx Lower jaw Tongue Soft palate Orbit Tongue
21, 9, 7, 37, 10, 24, 25, 13,
Surgery and Radiation Radiation Surgery and Surgery and Surgery and Surgery and Surgery
F F F M
M
M M M
Living
Tongue
11, M
with Known
radiation radiation radiation radiation radiation
Recurrent
Radiation and chemotherapy
no evidence of disease underwent excision of the primary lesion in the dorsum of the tongue by excisional biopsy by his personal physician. Ten days later, wide excision of the biopsy site revealed no residual tumor and no further treatment has been given. It has now been one and three quarter years with no recurrence. Chemotherapy was used on nine patients in our series: six times in conjunction with irradiation and three times with both surgery and irradiation. It was not used alone but secondarily and for residual, recurrent, or metastatic disease. The effects of the chemotherapeutic agents we have used have been discouraging. Although in one case the recurrent orbital tumor completely resolved for a year after therapy with actinomycin D and radium needles, it recurred again and failed to respond to vincaleukoblastine (Velban”) given in twenty-five weekly injections. Then because of progression of the disease even despite cyclophosphamide (Cytoxan@) given by mouth daily for two weeks, all therapy was discontinued. This child died twenty-four months after onset. Another child had a similar history. Surgery and therapy with cobalt 60, actinomycin D, vincaleukoblastine, and cyclophosphamide were of little if any benefit in controlling progression of the growth. She died, after twenty-three months, with extensive disease. A third patient who has had chemotherapy Vol. IlO, OctoOer1965
or Metastatic
Disease
Metastasis in neck
was given initially vincaleukoblastine intravenously at weekly intervals for four months. His condition improved only minimally if at all, and he was given a full course of cobalt 60 therapy. In two months there was definite and dramatic reduction in the size of the primary tumor in the tongue and the metastatically involved lymph nodes in the neck. He recently has been started on treatment with actinomycin D and clinically continues to improve. However, after ten months he still has the primary tumor and palpable nodes in the neck. He is listed in Table II as living with known disease, and the prognosis is predictably poor. Three patients are not known to have been treated (one refused treatment and two returned home and were lost to follow-up study). The over-all results of therapy of this disease are poor. In this series sixty-nine patients died of their disease, nine are living, and ten were lost to follow-up study. (Table III.) Of the nine patients living, eight (9 per cent of the series) are well and apparently free of disease one and three-quarter to twenty years after admission; the other patient is living with recurrent tumor and is considered beyond further therapeutic help. (Table II.) COMMENTS
Embryonal rhabdomyosarcoma, although prone t.o wide and varied distribution in the
590
Masson TABLE
EMBRYONAL IN
III
RHABDOMYOSARCOMA
OP HEAD
EIGHTY-EIGHT
SURVIVAL
CASES:
AND
NECK
-Cases--. Result
No.
%
Dead within 1 year after admission to clinic Died during second year Died during third to fifth year Living and well 1% to 20 years after admission Living with recurrence 10 months after admission Lost to follow-up study
43 18 8
49 20 9
8
9
1 10
1 11
head and neck, appears to show a predilection for the orbits and paranasal structures. Lesions originating in the orbits most often appear in the upper inner quadrant and not infrequently involve the upper lid early in their clinical course. Embryonal rhabdomyosarcoma is particularly lethal in children and young adults: 88 per cent of traced patients in our series died within five years and 55 per cent died during the first twelve months. The tendency for metastasis to lymph nodes would appear to be greater with embryonal rhabdomyosarcoma than with most other types of somatic soft tissue sarcoma. Linscheid, Some, and Henderson [IO] found metastasis to regional lymph nodes in 9 per cent of eighty-seven patients with pleomorphic rhabdomyosarcoma of the extremities and limb girdles. The inordinate number of patients (nine) exhibiting bone metastasis in our series is somewhat unusual when compared with the number seen in series of the pleomorphic type. Caffey and Andersen [II] commented on this finding in the growing skeleton and mentioned the differential diagnosis of neuroblastoma. Those tumors exhibiting alveolar or botryoid features did not present any specific pattern for metastasis. Treatment of embryonal rhabdomyosarcoma is most discouraging. Present day management with surgery, supervoltage irradiation, and chemotherapy has offered little improvement in survival rates over conventional 250 kv. x-ray irradiation and local excision as practiced thirty or forty years ago. Diagnosis of this tumor and a knowledge of its biologic behavior have not been‘-fully appreciated until recent years. Of prime importance in proper
and Soule treatment is early accurate diagnosis, and of utmost importance to the pathologist is adequate biopsy material. The most logical approach, when possible, now seems to be wide surgical excision and removal of regional lymphatics, if feasible, in conjunction with chemotherapy followed by irradiation for any recurrences. However, because the primary lesions are in the head and neck, wide surgical excision and en bloc removal of the regional lymphatics are often not possible. Because of the discouraging results of any form of treatment, often a radical mutilating procedure on a child is avoided and instead irradiation therapy with or without chemotherapy is proposed initially. It is known that embryonal rhabdomyosarcomas are radiosensitive, often markedly so. Any treatment of such malignant tumors must necessarily be radical, and this applies to irradiation as well as surgery. If a cure is to be expected, some marks will have to be left. Moore and Grossi [9] presented a case that shows the effect of high dosage x-ray therapy in a child: the tumor was eradicated but treatment caused faulty development of the mandible and facial skeleton and lack of development of the teeth of the lower jaw. This is a risk that must be accepted in treating a lesion as lethal as embryonal rhabdomyosarcoma. We believe that the initial treatment now should include the use of a chemotherapeutic agent such as actinomycin D, cyclophosphamide, and vincaleukoblastine. Such chemotherapy may be given before, during, or after surgical removal of the tumor or during irradiation. These tumors are radiosensitive, and the forms of irradiation used include conventional 250 kv. roentgenotherapy, cobalt 60 therapy, and occasionally radium therapy in the form of radium needles or points which can be placed interstitially, radon seeds placed interstitially, or radium applicators which may be used within a cavity such as the nasopharynx, orbit, and antrum. Recurrences even after intensive treatment are common and must be dealt with by a combination of surgery, irradiation, and chemotherapy. Albores-Saavedra, Martin, and Smith [12] have mentioned the consistently favorable response of these tumors to actinomycin D, which contrasts with the unimpressive results that we have observed from the use of chemotherapeutic agents.
Embryonal
Rhabdomyosarcoma
SIJMMARY
Of eighty-eight patients with embryonal rhabdomyosarcoma of the head and neck, forty-eight were female and forty were male patients. ages ranged from two weeks to seventy-seven years. Sixty-three were children (average age: 6.8 years) and twenty-five were adults (average age: 37.6 years). In nearly 60 per cent of patients the tumor occurred in the orbit, nasopharynx, or nose. The presenting complaint was usually that of a rapidly enlarging, asymptomatic mass. Half the patients had had evidence of the tumor for three months or less and only six had had it for more than a year on admission. Seventy-eight per cent of patients are known to have died as a result of the tumor, 49 per cent within the first year, 20 per cent in the secoud year, and 9 per cent within three to five years after admission. Eight patients (nine per cent) are known to be alive and free of disease twenty-one months to twenty years after admission, one patient (1 per cent) is alive with tumor metastasis, and ten (11 per cent) have been lost to follow-up study. Of the eight surviving p atients assumed to be free of disease, one was treated by surgery alone, five by combined surgery and radiation, and two by radiation only. Histologically, the tumor often presents a varied pattern that in part may be readily confused with many quite dissimilar neoplasms, among which are reticulum cell sarcoma, neuroblastoma, myxoma, and amelanotic melanoma. An error in tissue diagnosis may be minimized by securing adequate and repre-
Vnl. 110, October 1965
of Head and Neck
591
sentative tissue for biopsy and by awareness of a chance encounter with such a lesion. REFERENCES 1. STOHBE, G. D. and DARGEON, H. W. Embryonal rhabdomyosarcoma of the head and neck in children and adolescents. Cancer, 3 : 826, 1950. 2. HORN, R. C., JR. and ENTERLINE, H. T. Rhabdomyosarcoma: a clinicopathological study and classification of 39 cases. Cancer, 11: 181, 1958. 3. SHIPKEY, F. H., LIEBERMAN, P. H., FOOTE, F. W., JR., and STEWART, F. W. Ultrastructure of alveolar soft part sarcoma. Cancer, 17: 821, 1964. 4. DITO, W. R. and BATSAKIS, J. G. Rhabdomyosarcoma of the head and neck: an appraisal of the biologic behavior in 170 cases. Arch. Surg., 84: 582, 1962. 5. PORTERFIELD,J. F. and ZIMMERMAN,L. E. Rhabdomyosarcomas of the orbit: a clinicopathologic study of 55 cases. Arch. Path. Amt., 335: 329, 1962. 6. LAWRENCE, W., JR., JEGGE, G., and FOOTE, F. W., JR. Embryonal rhabdomyosarcoma : a clinicopathological study. Cancer, 17: 361, 1964. 7. GEITZ, M. and SOULE, E. H. Embryonal rhabdomyosarcoma of extremities and limb girdles. (Unpublished data.) 8. O’D.~Y, R. A., SOULE, E. H. and GORES, R. J. Soft tissue sarcomas of the oral cavity. Proc. Staf Meet., Mayo Clin., 39: 169, 1964. 9. ~TOORE,0. and GROSSI, C. Embryonal rhabdomyosarcoma of the head and neck. Cancer, 12: 69, 1959. 10. LINSCHEID, R. L., SOULE, E. H., and HENDERSON, E. D. Pleomorphic rhabdomyosarcomata of the extremities and limb girdles: a clinicopathological study. J. Bone 8 Joint Surg., 47A: 715, 1965. 11. CAF~~EY, J., and ANDERSEN, D. H. Metastatic embryonal rhabdomyosarcoma in the growing skeleton : clinical, radiographic, and microscopic features. Am. J. Dis. Child., 95: 581, 1958. 12. ALBORES-SAAVEDRA,J., MARTIN, R. G., and SMITH, J. L. Rhabdomyosarcoma: a study of 35 cases. AWL S’urg., 157: 186, 1963.