Pediatric Annals

Surgery in Childhood Cancer Patients

Daniel M Hays, MD

Abstract

Pediatric oncology is a field with major current advances in many areas. The surgical therapy of neuroblastoma, rhabdomyosarcoma, and thelymphomas have been selected for review here because of the relatively large patient populations involved. This group includes one tumor type in which the effects of chemotherapy-radiotherapy have been minimal; one in which they have been substantial but still limited; and one in which they have completely reversed the disease prognosis. The remarkable response of nephroblastoma, the hepatomas, germ-cell and other tumors to new chemotherapy regimens might be of equal interest. In all of these, the significance of early diagnosis remains paramount; and management, to be effective, must be multidisciplinary with contributions from all modalities.

NEUROBLASTOMA

Neuroblastoma appears in such a variety of clinical forms and the response to therapy is so variable that generalizations in regard to management are difficult. It is apparent that chemotherapy has not achieved the dramatic reversal in mortality in neuroblastoma, seen in Wilm's tumor or rhabdomyosarcoma. Many children with neuroblastoma on an intensive chemotherapy regimen will respond with marked reduction in tumor size, but it is difficult to demonstrate that long-term survival is influenced by this initial response to therapy.

Stage I to H

Neuroblastomas that are localized and resectable are very effectively treated by surgical excision.1 These tumors are usually located in the thoracic (posterior mediastinal mass), cervical or pelvic regions, but may be abdominal. They constitute a minority of the abdominal neuroblastomas. Survival rates in this group are greater than 90%, and it has been repeatedly shown that neither chemotherapy nor radiotherapy significantly affect the outcome in this group.

Stage IVs

A second group of children with neuroblastoma are placed in a special category (IVs) because of their remarkably high survival rate.2 These patients have primary tumors, that in the absence of metastasis, would place them in Stage I or II, but have known métastases to liver, subcutaneous tissues, or bone marrow (not demonstrable by x-ray). Almost all are infants and the majority are less than one year of age. This group responds to minimal forms of therapy (chemotherapy or radiotherapy), or may regress spontaneously. They are treated conservatively in respect to all modalities, and metastatic lesions of all types respond to this approach. Resection of the primary tumor is of questionable value, but usually carried out if a tumor mass remains and the infant is otherwise tumor-free. Mortality during the first four months of life is usually associated with respiratory distress secondary to abdominal tumor volume, for which surgical "decompression" procedures have been developed; or to other complications of therapy.

"Dumbbell" Tumors

Patients with the "dumbbell" form of neuro blastoma, which has an abdominal or thoracic component and passes through an intervertebral foramen to expand into a connected intrathecal mass, also have a relatively favorable prognosis. This group may require emergency decompression of the spinal cord, and tumor excision both anteriorly and posteriorly; but despite the ominous nature of the symptoms the mortality is low, although morbidity, particularly when radiotherapy is added to laminectomy, may be considerable.

Stage III

Management problems of a quite different magnitude are presented by neuroblastomas localized to the abdomen but unresectable because of involvement of the major branches of the aorta or extension into adjacent structures. These tumors frequently respond to chemotherapy regimens but rarely to the extent that they become resectable. Even when this can be accomplished the patients usually subsequently develop metastasis, and the overall survival rate in this group is less than 10%. Those centered around the celiac axis are particularly resistant to resection. Radiotherapy has a limited, but definite, influence in increasing survival…

Pediatric oncology is a field with major current advances in many areas. The surgical therapy of neuroblastoma, rhabdomyosarcoma, and thelymphomas have been selected for review here because of the relatively large patient populations involved. This group includes one tumor type in which the effects of chemotherapy-radiotherapy have been minimal; one in which they have been substantial but still limited; and one in which they have completely reversed the disease prognosis. The remarkable response of nephroblastoma, the hepatomas, germ-cell and other tumors to new chemotherapy regimens might be of equal interest. In all of these, the significance of early diagnosis remains paramount; and management, to be effective, must be multidisciplinary with contributions from all modalities.

NEUROBLASTOMA

Neuroblastoma appears in such a variety of clinical forms and the response to therapy is so variable that generalizations in regard to management are difficult. It is apparent that chemotherapy has not achieved the dramatic reversal in mortality in neuroblastoma, seen in Wilm's tumor or rhabdomyosarcoma. Many children with neuroblastoma on an intensive chemotherapy regimen will respond with marked reduction in tumor size, but it is difficult to demonstrate that long-term survival is influenced by this initial response to therapy.

Stage I to H

Neuroblastomas that are localized and resectable are very effectively treated by surgical excision.1 These tumors are usually located in the thoracic (posterior mediastinal mass), cervical or pelvic regions, but may be abdominal. They constitute a minority of the abdominal neuroblastomas. Survival rates in this group are greater than 90%, and it has been repeatedly shown that neither chemotherapy nor radiotherapy significantly affect the outcome in this group.

Stage IVs

A second group of children with neuroblastoma are placed in a special category (IVs) because of their remarkably high survival rate.2 These patients have primary tumors, that in the absence of metastasis, would place them in Stage I or II, but have known métastases to liver, subcutaneous tissues, or bone marrow (not demonstrable by x-ray). Almost all are infants and the majority are less than one year of age. This group responds to minimal forms of therapy (chemotherapy or radiotherapy), or may regress spontaneously. They are treated conservatively in respect to all modalities, and metastatic lesions of all types respond to this approach. Resection of the primary tumor is of questionable value, but usually carried out if a tumor mass remains and the infant is otherwise tumor-free. Mortality during the first four months of life is usually associated with respiratory distress secondary to abdominal tumor volume, for which surgical "decompression" procedures have been developed; or to other complications of therapy.

"Dumbbell" Tumors

Patients with the "dumbbell" form of neuro blastoma, which has an abdominal or thoracic component and passes through an intervertebral foramen to expand into a connected intrathecal mass, also have a relatively favorable prognosis. This group may require emergency decompression of the spinal cord, and tumor excision both anteriorly and posteriorly; but despite the ominous nature of the symptoms the mortality is low, although morbidity, particularly when radiotherapy is added to laminectomy, may be considerable.

Stage III

Management problems of a quite different magnitude are presented by neuroblastomas localized to the abdomen but unresectable because of involvement of the major branches of the aorta or extension into adjacent structures. These tumors frequently respond to chemotherapy regimens but rarely to the extent that they become resectable. Even when this can be accomplished the patients usually subsequently develop metastasis, and the overall survival rate in this group is less than 10%. Those centered around the celiac axis are particularly resistant to resection. Radiotherapy has a limited, but definite, influence in increasing survival duration and possibly survival rates in this group (Stage III).

Stage IV

More than half of the children with neuroblastoma (55% to 60%) have disseminated or Stage IV disease. They must be clearly distinguished from patients in the IVs category in which the prognosis is excellent. Patients in this category (Stage IV) usually have recognized (x-ray evident) osseous metastasis. Even very young patients (O to 11 months) rarely survive under these circumstances, and a mortality of more than 90% is usual for patients of all ages. Patients over six years of age may have a somewhat better prognosis than those between two and six years.

Figure 1. Neuroblastoma is a protean disease with many clinical "syndromes." Forms with a favorable prognosis include the (a) mediastinal mass in an asymptomatic infant or child, and (b) cervical or pelvic tumor masses. Massive abdominal tumor, distinct from the liver, is a frequent initial presenting sign in infancy. Paraplegia, secondary to "dumbbell" tumors originating in either the thoracic or abdominal retroperitoneal space, may be an initial sign. Neuroblastoma is frequently recognized by the effects of dissemination, including osseous métastases associated with separation of the cranial sutures, fractures or ecchymosis; multiple subcutaneous nodules; or massive hepatomegaly. Symptoms may include diarrhea, hypertension, or the effects of encephalopathy.

Figure 1. Neuroblastoma is a protean disease with many clinical "syndromes." Forms with a favorable prognosis include the (a) mediastinal mass in an asymptomatic infant or child, and (b) cervical or pelvic tumor masses. Massive abdominal tumor, distinct from the liver, is a frequent initial presenting sign in infancy. Paraplegia, secondary to "dumbbell" tumors originating in either the thoracic or abdominal retroperitoneal space, may be an initial sign. Neuroblastoma is frequently recognized by the effects of dissemination, including osseous métastases associated with separation of the cranial sutures, fractures or ecchymosis; multiple subcutaneous nodules; or massive hepatomegaly. Symptoms may include diarrhea, hypertension, or the effects of encephalopathy.

The diagnosis in the majority of these patients can be made by studies of catecholamine excretion in urine (or serum) and the aspiration of tumor cells from marrow sites. This eliminates the need for initial surgery. Response rates to intensive chemotherapy regimens are frequently as high as 60% with marked reduction in the size of the primary tumor and regression or elimination of measurable metastatic lesions. At this stage in many centers an attempt is made to excise the primary tumor.4 In patients in which initial chemotherapy (usually vincristine, cyclophosphamide, DTIC* or adriamycin) has resulted in apparent elimination of all tumors (ie, both primary and metastatic lesions), viable tumor tissue is still usually found at the primary site at secondary surgical procedures. Neuroblastoma tissue removed in a series of laparotomies in the same patient usually demonstrates tumor "maturation." It has not been shown that excision of the primary tumor after a clinical response to chemotherapy is detrimental, and it may contribute to survival duration. Relapse rates are high, however, and reports of long range survival of greater than 10% to 15% in series of patients in Stage IV are exceptional.

Although age is a paramount factor in determining survival in neuroblastoma and this has been assumed to be due to factors associated with immunological surveillance or a related system, no attempts to manipulate these factors or otherwise employ immunotherapy have been clinically effective in treating neuroblastoma. These tumors are rathosensitive but the overall effects of radiotherapy, except possibly in some patients with Stage III disease, is questionable. A minority of children with neuroblastoma exhibit endocrine-related symptoms including chronic diarrhea, hypertension, and encephalopathy (unrelated to métastases), which pose unique therapeutic problems.

In addition to the standard predictors of response and survival in neuroblastoma, (ie, age, site, stage, and histopathology),5 the relative excretion levels of different catecholamines and the in vitro survival and enzymatic activity of tumor cells (from marrow or tumor) have been demonstrated to be significant predictors of survival duration.

Neuroblastoma remains a tumor in which the effective chemotherapeutic agent(s), or other therapy modality, is yet to be identified.

RHABDOMYOSARCOMA

This tumor, as seen in the pediatrie hospital population, appears to be increasing in incidence. This may be due to the inclusion of tumors formerly labeled "small cell sarcomas"; or the trend for pediatrie institutions to admit older patients to adolescent units, including the second peak (approximately 15 years) as well as the first peak (approximately four years) of frequency in the occurrence of this tumor.

Rhabdomyosarcomas are not confined to structures containing striated muscle, and in the current intergroup study of rhabdomyosarcoma, they have been recognized as primary in almost all body organs with the exception of brain, bone and skin. The diagnoses of rhabdomyosarcoma must be made by conventional surgical biopsy as there are no "markers," or unique diagnostic studies available.

Despite the wide dispersion of sites, the usual locations are predictable by age group. The standard age for patients with genitourinary tract rhabdomyosarcomas (bladder, prostate and vagina) and rhabdomyosarcomas arising in the nasopharynx, middle ear, or paranasal sinuses, is the first four years of life. Children with paratesticular, extremity and trunk lesions are usually over five years, with a peak at 15 years.

The histologie subtypes of rhabdomyosarcoma (ie, alveolar, embryonal - botryoid and non-botryoid, undifferentiated, etc.) have proved to be of significance in predicting outcome.6 The important consideration here is that among patients with grossly resected tumors (Stages I to II) most deaths occur in patients with alveolar rhabdomyosarcomas, although these represent only 20% to 25% of the total group. In more advanced stages, (Stages III to IV) the overall low survival rate appears to obliterate this effect. Embryonal rhabdomyosarcomas, (botryoid or non-botryoid) have a relatively better outlook irrespective of site or age.

Figure 2. In the age range from birth through 21 years, rhabdomyosarcoma may be the most common single solid tumor. In infancy, the two usual areas of origin are the head and neck, and the lower genitourinary tract. In childhood and adolescence, sites of origin are more diverse. Rhabdomyosarcoma of the paratesticular and inguinal canal structures are almost confined to the second decade of life. Primary tumors of the extremities and trunk have greater similarity to those found in young adults, and approximately 50% are of the alveolar subtype. It is apparent that rhabdomyosarcoma may arise from many tissues and structures which contain no mature striated muscle. Many tumors previously described as "undifferentiated, smallcell sarcomas" are now included in the category of rhabdomyosarcoma, at least for therapeutic purposes. The prognosis in rhabdomyosarcoma varies according to both the site and the predominant histologie subtype. These differences have been modified, but not eliminated, by the effectiveness of long-range multiple-agent chemotherapy.

Figure 2. In the age range from birth through 21 years, rhabdomyosarcoma may be the most common single solid tumor. In infancy, the two usual areas of origin are the head and neck, and the lower genitourinary tract. In childhood and adolescence, sites of origin are more diverse. Rhabdomyosarcoma of the paratesticular and inguinal canal structures are almost confined to the second decade of life. Primary tumors of the extremities and trunk have greater similarity to those found in young adults, and approximately 50% are of the alveolar subtype. It is apparent that rhabdomyosarcoma may arise from many tissues and structures which contain no mature striated muscle. Many tumors previously described as "undifferentiated, smallcell sarcomas" are now included in the category of rhabdomyosarcoma, at least for therapeutic purposes. The prognosis in rhabdomyosarcoma varies according to both the site and the predominant histologie subtype. These differences have been modified, but not eliminated, by the effectiveness of long-range multiple-agent chemotherapy.

Resectable Tumors

The current management of rhabdomyosarcoma is truly multidisciplinary with each form of therapy essential.7 Patients in which the primary tumor can be completely excised (grossly), with or without microscopic residual, have a much better prognosis than patients in which gross tumor remains following surgery. When adjacent lymph nodes are positive, but are excised, the outlook remains favorable. Following surgery these patients are routinely treated by chemotherapy consisting of vincristine, actinomycin-D and cyclop h osphamide (VAC); simply vincristine and actinomycin-D; or similar regimens; ordinarily for two years. If microscopic residual disease remains after surgery, or there were involved nodes, local radiotherapy is employed. Patients in which the tumor can be grossly excised now have longrange survival rates of approximately 75%.

Unresectable Tumors

Patients in whom residual (local) tumor remains following an excision attempt (or following biopsy) are treated by local irradiation and continued chemotherapy, employing more intensive regimens, such as "Pulse" VAC. If response is apparent, attempts at re-excision of the primary tumor are made at this point. Approximately 40% of these patients are long-term (over three-year) survivors.

Children with metastatic rhabdomyosarcoma are treated similarly. Occasional patients have survived an aggressive approach including excision of local and metastatic lesions, radiotherapy to primary and distant sites, and intensive multiagent chemotherapy. Approximately 10% of the patients with rhabdomyosarcoma who relapse after initial chemotherapy can be salvaged. These are usually those who relapse late (ie, off chemotherapy); and locally or regionally rather than in distant sites.

Differences by Site

Rhabdomyosarcoma was traditionally regarded as a group of different tumors as it occurred at diverse sites; and significant differences still exist in respect to the proportion of different histologie subtypes, forms of therapy, and prognosis.

Orbital rhabdomyosarcomas are now treated by biopsy, radiotherapy and chemotherapy, with orbital exenteration performed only for relapse. The survival rate in these patients is over 90% and many retain useful vision. The nasopharynx, paranasal sinuses and middle ear were formerly regarded as sites in which rhabdomyosarcoma was uniformly lethal. Following biopsy, and at times partial excision, these children are now managed with radiotherapy-chemotherapy regimens with success rates of approximately 50%. In this area the most disturbing group are those children with tumors adjacent to the méninges, as central nervous system extension is usually fatal. Prophylactic radiotherapy across the base of the skull has been employed in some series and prophylactic intrathecal chemotherapy in others, with prevention of intracranial extension and improvement in survival.

A dramatic development in the management of rhabdomyosarcomas is associated with attempts to avoid pelvic exenterations in infants and small children with tumors primary in the bladder, prostate, vagina or uterus.8 Survival rates in children with these tumors treated by exenteration, local radiotherapy and longrange chemotherapy are good. These trials are designed to retain these high survival rates but attempt to avoid pelvic exenteration (and radiotherapy, when possible), by employing intensive chemotherapy initially.

Following biopsy, these regimens begin with intensive chemotherapy, followed by radiotherapy when required, and by limited tumor excision when this is possible. Patients who required secondary pelvic exenteration (30%) are regarded as "failures," although they usually survive. Exenteration must be regarded as an effective "salvage" procedure when it is required. Success in regard to infants with vaginal lesions has been remarkable with almost all of the bladders salvaged in this group, although many have undergone simple hysterectomy and vaginectomy. Vaginal reconstruction in such cases is feasible.

Following chemotherapy (with or without radiotherapy) some bladder lesions have been successfully treated by partial cystectomy. It would appear that approximately 50% of the bladders in children with bladder or prostate tumors can be saved.9 It is still uncertain whether the delay in carrying out radical surgery, in those patients in which it is eventually necessary, will result in an increase in overall mortality. To date, it appears that the bladders that have been saved by primary chemotherapy or chemotherapyradiotherapy regimens function adequately. In some past series bladder function has been so poor following combination therapy that cystectomy was performed even though the bladder was tumor-free.

The rhabdomyosarcomas that occur adjacent to the testes and along the spermatic eord have a particularly good prognosis (more than 80% survival), although they frequently (more than 35%) involve retroperitoneal lymph nodes.10 Retroperitoneal node dissections are indicated in these children and lead to abdominal radiotherapy only when they are positive.

Among all major sites, rhabdomyosarcomas of the extremities and trunk have proved the most difficult to manage successfully." Here surgery continues to play a major role, as patients in which the tumor is completely excised have a far better outlook than those in which this is not technically possible or is not carried out. Success with primary chemotherapy or primary chemotherapyradiotherapy regimens has been limited. Approximately 50% of these tumors have the alveolar histologie subtype. Dissection of regional lymph nodes is helpful in planning therapy. These patients are now being treated by more intensive chemotherapy regimens than are patients in the same stage with tumors of sites more responsive to chemotherapy. Rhabdomyosarcomas arising in the perineum, the retroperitoneal space, and the intra- or extrahepatic biliary tract involve adjacent structures early in the course of the disease and survival is uncommon.

Great advances have been made since the era in which radical surgery was the only effective therapy for rhabdomyosarcoma. It is apparent that when all modalities are employed the majority of these patients can be treated successfully. Survival in children with unresectable, recurrent and even metastatic disease has occasionally been achieved employing a multimodality approach.

LYMPHOMAS

Hodgkin's Disease in Childhood

The steadily improving results seen in the treatment of Hodgkin's disease in adults, employing radiotherapy and combinations of radiotherapy-chemotherapy, have direct counterparts in pediatrie series. Likewise, the forms of Hodgkin's disease, pathologic variants, and natural history are quite similar in adults and children (in the United States). A major difference is in the significance of the secondary effects of therapy. Radiotherapy regimens routinely employed in adults produce startling growth retardation and deformity when employed in prepubertal children. Thus, although the staging laparotomy involves special dangers in childhood, because it includes splenectomy, it also may be regarded as more significant in respect to restricting radiotherapy, when this is indicated by findings at laparotomy.

Figure 3. Actuarial rates of disease-free survival in the four clinical groups of children in the first lntergroup Rhabdomyosarcoma Study Group 1972 to 1978). This demonstrates the significant differences in relapse rate between patients with tumors that can be completely excised (Stage I), grossly excised (Stage II), or are not surgically resectable (Stage III), as well as those with disseminated disease (Stage IV).

Figure 3. Actuarial rates of disease-free survival in the four clinical groups of children in the first lntergroup Rhabdomyosarcoma Study Group 1972 to 1978). This demonstrates the significant differences in relapse rate between patients with tumors that can be completely excised (Stage I), grossly excised (Stage II), or are not surgically resectable (Stage III), as well as those with disseminated disease (Stage IV).

Relapse-free survival is now achieved for a minimum of three to four years in more than 90% of the children with Stages I to II disease.12 Rates for symptomatic patients (Stage B) and children with Stages III to IV disease are lower, but have shown corresponding increases. Evaluation of long-term survival in Hodgkin's disease remains difficult. Presentations associated with a particularly favorable prognosis include: unilateral high neck, isolated inguinal, and possibly the mediastinal mass with the nodular sclerosis histologie subtype.

Localized Hodgkin's disease is ordinarily treated with radiotherapy and more advanced disease with combinations of radiotherapy and chemotherapy usually employing mechlorethamine, vincristine (oncovin), prednisone, and procarbazine (MOPP). Other drug combinations (ABVD - adriamycin, bleomycin, vinblastine and DTIC) which may result in a lower incidence of longrange complications than MOPP are under study.

Laparotomy for staging is recommended in most centers for children over five years; and in some, for all children.'3 Its purpose is to direct therapy, and specifically to avoid unnecessary abdominal and pelvic irradiation. In female children, the ovaries can be moved away from the inverted "Y" field and protected from irradiation to some extent at the time of laparotomy.

The incidence of postsplenectomy sepsis has been reduced by the standard use of pneumococcal vaccine and prophylactic antibiotics; but can occur despite these safeguards. Rates of sepsis are directly related to the intensity of therapy required; and this complication is now most frequently seen during therapy for advanced disease or relapse.

MOPP chemotherapy has been associated with a high incidence of long-range gonadal dysfunction in both sexes,14 which may include permanent aspermia in males. Hypothyroidism is common following cervical radiotherapy; and the incidence of secondary malignancies following all forms of therapy for Hodgkin's disease is estimated from 8% to 12%, with leukemia a major component.

Non-Hodgkin's Lymphoma

Dramatic improvement in the duration of survival among children with Non-Hodgkin's Lymphoma has followed the development of specific intensive chemotherapy regimens, employing four to as many as ten agents for one to two years, usually supplemented with concurrent intrathecal prophylactic therapy.15 Threeyear disease-free survival rates of 80% for localized, and of 40% to 50% for disseminated disease, have been reported. In one cooperative group study, these patients have been divided into "lymphoblastic" and "nonlymphoblastic" forms and maximum response has been achieved in these variants by different types of multiple agent chemotherapy. Radiotherapy is usually employed in the treatment of bulk disease.

Staging laparotomy has been employed in some adult series and has revealed extensive abdominal involvement, including mesenteric and retroperitoneal nodes. In pediatrie patients, it is rarely indicated as it is assumed that the majority of patients will have abdominal involvement.

Localized disease may be removed surgically. This is of particular significance in approximately 15% of these patients who have primary intestinal involvement which can be grossly resected. These patients are frequently clinically indistinguishable from children with benign abdominal disease (ie, appendicitis or intussusception). When the primary lesion can be excised and this is followed by chemotherapy (and possibly radiotherapy) survival rates are high. In some institutions, laparotomy is performed following the initial response to the chemotherapy for tumor "dubulking." This may permit the elimination of abdominal radiotherapy, which will preserve the function of the vertebral marrow and permit more intensive chemotherapy. Surgery may be required for the relief of trachéal compression in mediastinal disease, but this usually can be more safely accomplished with immediate chemotherapy-radiotherapy. Early, intense chemotherapy appears to be the most important factor influencing survival.

REFERENCES

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10.3928/0090-4481-19821101-14

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