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Neuroblastoma as a cause of antenatal death
Neuroblastoma as a cause of. _..
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W. FREDERIC BIRNER, M.D. Chicago, Illinois
M A L I G N A N C I E S of the sympathetic nervous system are not rare. 1 However, these lesions infrequently have their start in the antenatal period and seldom progress far enough to cause intrauterine death. This case is of interest because extensive involvement of visceral organs by neuroblastoma tissue presumably led to antenatal death of a full-term fetus in whom Rh incompatibiliiy was suspected.
ately macerated with large areas of skin missing from the body surface. The face was slightly edematous and the abdomen markedly distended but there were no visible malformations. Head. The head was normal in proportion to the rest of the body. The bones of the calvarium seemed of normal thickness and appearance. The brain was severely macerated a.qd in a semiliquid state. The orbital and nasal cavities and the base of the brain were normal. The membranes of the brain showed no evidence of lesions. Neck. The organs and structures of the neck were normal. Thorax. The pleural and pericardia! cavities contained small amounts of dark brown liquid. The organs and structures of the thoracic cavity appeared normal except for the lungs which were not expanded. No gross evidence of neoplastic growth could be seen. Abdomen. The peritoneal cavity contained a small amount of dark brown liquid as a result of maceration. The intestinal tract was normal throughout its length. The liver was uniformly enlarged and weighed 390 grams. The surface was smooth and glistening. The consistency of the liver seemed to be firmer than usual. On the cut surface its color was light brown. No evidence of tumor infiltration or congestion was apparent. The spleen was of normal size and weighed 15 grams. Periaortic sympathetic ganglia and retroperitoneal lymph nodes were not enlarged. Genitourinary system. The left adrenal gland appeared to be replaced by a firm, round, wellencapsulated tumor which depressed the upper pole of the left kidney. Both the tumor and the left kidney were surrounded by perirenal fascia and fat. The tumor measured 5 em. in diameter and weighed 43 grams. The cut surface was reddish brown. The tumor was solid. No hemorrhage or cystic areas could be seen. Adrenal cortical tissue could not be identified. The right adrenal weighed 5 grams and appeared normal.
Case report Maternal histocy. Mrs. A., a 25-year-old white primipara, had a normal prenatal course except for mild water retention which was controlled by a low-salt diet. Her blood type is B III, Rh negative, and that of her husband is 0 IV, Rh positive. She gave no history of previous transfusions and had no antibodies when tested during each trimester of pregnancy. During the thirty-ninth week of gestation, fetal heart tones and fetal movements, which were recorded regularly during previous visits, disappeared. Intrauterine death due to unknown causes was diagnosed. At approximately 40 weeks' gestation the patient went into natural labor and was delivered of a term-sized macerated fetus by low-forceps extraction. The fetus had a somewhat edematous appearance and a distended abdomen. These findings, together with a large placenta, suggested to the clinicians that the fetus might be hydropic because of erythroblastosis. Gross postmortem examination. External surface. The body was that of a white male infant weighing 3,925 grams and having a crown-heel length of 51 em. and crownrump length of 35 em. The body was moderFrom the Department of Obstetrics and Gynecology, The University of Chicago and The Chicago Lying-in Hospital.
1388
Volume 82 Number 6
Kidneys, ureters, and the bladder appeared normal, although the left kidney weighed slightly less than the right. Skeletal system. All the bones appeared normal and there was no evidence of bone metastasis. Placenta. The placenta weighed 1,240 grams and measured 22 by 21 em. The cotyledons were well demarcated, thick, and of soft consistency. Small hematomas were noticed on the cut surface. The maternal surface had a reddish yellow coloration. Microscopy examination. Liver. Only a small amount of liver tissue was still visible and most of the parenchyma was replaced by islands of tumor cells (Fig. 1 ) . The islands were fairly uniform in size and appeared to be separated by sinusoidal tissue which in a few places had parenchymal cells persisting. The extent of maceration obscured the exact relationship of the tumor cells to the finer structures of the liver. Left adrenal. The central portion contained innumerable islands of large uniform cells with prominent hyperchromatic nuclei. These were identical to those found in the liver and are characteristic of the pattern generally designated to neuroblastomas. No rosette formation could be seen. The masses of tumor tissue appeared to be largely within sinusoids and extended peripherally toward the definitive cortex but did not seem to invade this area (Fig. 2). Right adrenal. This gland retained its normal histologic appearance. However, a few small islands of typical tumor cells were contained in the sinusoids ol'.the medulla. Lung. The tissue was moderately macerated but histologic details could stili be made out fairly well. The alveoli were not expanded. Small groups of tumor cells were scattered throughout the parenchyma. The majority appeared to be in the lymphatics surrounding medium-sized veins but interstitial tissue unrelated to large blood vessels also contained scattered groups of tumor cells. Neoplastic cells could be seen in areas of the visceral pleura immediately adjacent to the pulmonary tissue. Spleen. The general appearance was normal except for mild degenerative changes secondary to intrauterine death. Tumor cells could be identified in the peripheral part of the wall of the large vein and in several irregular spaces which were probably lymphatic channels. Kidneys. Changes secondary to intrauterine
Neuroblastoma as cause of antenatal death 1389
Fig. 1. Low-power view of the liver showing uniform replacement of liver parenchyma by tumor islands. The tumor is undifferentiated with no evidence of rosette formation.
Fig. 2. Low-power view of the left adrenal showing masses of tumor tissue within the sinusoids. The definitive cortex is free from invasion.
1390 Birner Am.
death made diiferentiation of tumor cells somewhat difficult and for the most part it was impossible to be certain whether groups of cells were actually neoplastic or whether they were undifferentiated nephrogenic tissue. Oniy in one area could a large mass of tumor cells positively be identified, in the interstitial tissue a short dis-
tance beneath the capsule. Other areas were highly suggestive of tumor formation. In addition, parts of the connective tissue surrounding the kidney was infiltrated by tumor cells. Placenta. The villi were unusually large. The blood vessels seemed somewhat reduced in number and there was an unusual amount of connective tissue containing many histiocytes of the variety generally designated as Hofbauer cells. In some places scattered Langhans cells were still visible beneath the syncytial covering of the villi. In many places the surface was separated suggesting that there had been considerable edema. No sections of the brain, skin, skeletal system, thyroid, thymus, or other visceral organs were taken because of the advanced stage of maceration of the fetus. Comment
The neuroblastoma is one of the most common and most highly malignant tumors of infancy and childhood. Approximately half of the reported cases are in infants less than 2 years old and 75 per cent in children less than 4 years old. 2 The occurrence of neuroblastoma in the fetus and newborn is relatively uncommon. In an extensive review of the literature, Wells,S in 1940, was able to find only 17 authenticated cases. Bachmann/ in 1955, reported 650 cases of neuroblastoma which included 3 cases in stillborn, 31 in the newborn, and 51 in the first 3 months of life. Gross/ in 1959, reported on 217 cases at the Boston Children's Hospital, his youngest patient being 4 hours old and his oldest 16 years. Within recent years the occurrence of tumors in adolescent and even adult patients has been clearly recognized. The neuroblastoma may develop in any site where sympathetic ganglion cells or their precursors are located. Their growth takes origin from undifferentiated neural tissue of sympathetic ganglia or the adrenal
December, 1961 & Gynec.
J. Obst.
medulla. In fact, 3 types of tumors may derive from this tissue-the pheochromocytoma, the ganglioneuroma, and the neuroblastoma. The latter is the highly malignant form of sympathetic ganglion tumor, and is made up of only poorly differentiated anaplastic imitations of neuroblasts which are, of course, the precursors of adult ganglion cells. The neuroblastoma, therefore, is truly an embryonic tumor since it arises from immature tissue which never attains completely adult differentiation. Microscopically neuroblastomas are diffuse masses of rounded cells resembling large lymphocytes with frequent mitosis which might explain why neuroblastomas originally were considered round cell sarcomas. 6 Even today we find a wide variety of descriptive terminology in the literature for the same tumor (neurocytoma, sympathoma embryonale, sympathicoblastoma, sympathogonioma). The wide range of differentiation of neuroblastomas undoubtedly accounts for these specific terms. In the least differentiated tumors round celled growth is dominant and rosette formation is often indistinct or absent. The first recognizable stage of neuron differentiation is the appearance of rosettelike clusters of cells. Further differentiation converts some of the pyroform neuroblasts into recognizable young nerve cells and their outgrowing axons into bundles of parallel fibers which will stain specifically as nerve fibers. About 40 per cent of neuroblastomas originate in the adrenal medulla. Other sites are the sympathetic chains of the abdomen, neck, and thorax-in that order of frequency. Probably none originate in the central nervous system. 2 Metastatic spread may be via either the lymphatic system or the blood stream and secondary lesions may appear rapidly in a variety of locations. The bones, especially the calvarium and orbit, and the liver are the most frequent sites of metastasis. In cases of neuroblastoma in the newborn the enlargement of the liver is most striking. Hagstrom 7 reports on a case in which a 700 gram liver caused dystocia in a newborn infant. Richards 8 records a liver
Volume 82 Number 6
weighing 1>850 grams in a 2-week-old infant. Occasionally, rupture of a blood vessel in the liver, eroded by neoplastic tissue, has caused hemoperitoneum and dystocia. Early metastasis of neuroblastoma to the bones is not as common in the newborn as in the age group between 2 and 4 years. Metastasis to the lungs and other visceral organs is rare at any age. This case is of interest not only because of a neuroblastoma causing antenatal death but also because of the occult involvement of multiple organs by tumor tissue. Except for the well-circumscribed, encapsulated left adrenal neoplasm, no gross evidence of tumor metastasis was detectable. The commonly described discrete, rounded> white, or hemorrhagic metastatic nodules were completely lacking. The tumor cells apparently were uniformly scattered and a well-integrated part of the organ involved. This raises the old question again as to whether we are dealing with a multicentric proliferation of undifferentiated sympathetic cell groups in these organs or with metastatic lesions. The wide distribution of sympathetic cells in the body certainly could give support to this theory. The lack of tumor cells in the placenta in our case would seem to speak against a blood=bornc metastasis from the adrenal tumor. At least a number of cases in the literature, especially those in
Neuroblastoma as cause of antenatal death 1391
which no primary tumor site was apparent, also support the theory of multicentric origin of neuroblastomas. Potter and Parrish 9 reported a case of a stillborn fetus in which all tissue of nervous origin, except the brain, had undergone neoplastic hyperplasia. Recently Gross 5 reported 4 instances of multiple neuroblastomas apparent at necropsy. Of these, one child was found to have 6 separate tumors arising from different parts of the retroperitoneal sympathetic chains, all presumably having arisen independently. Multiplicity of these lesions must clearly depend on influences affecting many parts of the developing tissues simultaneously and we may well be dealing with a systemic disorder of the sympathetic nervous tissue as a whole. 10 Summary
A mature stillborn fetus is described in which a small, well-encapsulated neuroblastoma of the left adrenal gland was the only gross finding. Microscopic examination revealed diffuse neoplastic involvement of the liver, adrenals, spleen, kidneys, and lungs. Multicentric proliferation of undifferentiated sympathetic cell groups in these organs is suggested. I am indebted to Dr. Edith Potter for aid and advice.
REFERENCES
1. Bartok, I., and Baradnay, G. Y.: Zentralbl. allg. Path. u. path. Anat. 194: 194, 1958. 2. Willis, R. A.: Pathology of Tumours, St. Louis, 1953, The C. V. Mosby Company, p. 852. 3. Wells, H. G.: Arch. Path. 30: 543, 1940. 4. Bachmann, K. D.: Ztschr. Kinderh. 77: 391, 1955. 5. Gross, R. E., Farbers, S., and Martin, L. W.: Pediatrics 23: 1179, 1959.
6. Woods, R. G.: M. ]. Australia 26: 125, 1958. 7. Hagstrom, H. T.: AM. J. OnsT. & GYNEC. 19: 673, 1930. 8. Richards, H.: Cited by Willis. 2 9. Potter, E. L., and Parrish, J. L.: Am. J. Path. 18: 141, 1942. 10. Potter, E. L.: Pathology of the Fetus and the Newborn, Chicago, 1952, The Year Book Publishers, Inc.
--
-
~ntt:ln~t~f nA~th YV\..41 \ol I
....,.. I'""'' 1'-"' '-\.AI
W. FREDERIC BIRNER, M.D. Chicago, Illinois
M A L I G N A N C I E S of the sympathetic nervous system are not rare. 1 However, these lesions infrequently have their start in the antenatal period and seldom progress far enough to cause intrauterine death. This case is of interest because extensive involvement of visceral organs by neuroblastoma tissue presumably led to antenatal death of a full-term fetus in whom Rh incompatibiliiy was suspected.
ately macerated with large areas of skin missing from the body surface. The face was slightly edematous and the abdomen markedly distended but there were no visible malformations. Head. The head was normal in proportion to the rest of the body. The bones of the calvarium seemed of normal thickness and appearance. The brain was severely macerated a.qd in a semiliquid state. The orbital and nasal cavities and the base of the brain were normal. The membranes of the brain showed no evidence of lesions. Neck. The organs and structures of the neck were normal. Thorax. The pleural and pericardia! cavities contained small amounts of dark brown liquid. The organs and structures of the thoracic cavity appeared normal except for the lungs which were not expanded. No gross evidence of neoplastic growth could be seen. Abdomen. The peritoneal cavity contained a small amount of dark brown liquid as a result of maceration. The intestinal tract was normal throughout its length. The liver was uniformly enlarged and weighed 390 grams. The surface was smooth and glistening. The consistency of the liver seemed to be firmer than usual. On the cut surface its color was light brown. No evidence of tumor infiltration or congestion was apparent. The spleen was of normal size and weighed 15 grams. Periaortic sympathetic ganglia and retroperitoneal lymph nodes were not enlarged. Genitourinary system. The left adrenal gland appeared to be replaced by a firm, round, wellencapsulated tumor which depressed the upper pole of the left kidney. Both the tumor and the left kidney were surrounded by perirenal fascia and fat. The tumor measured 5 em. in diameter and weighed 43 grams. The cut surface was reddish brown. The tumor was solid. No hemorrhage or cystic areas could be seen. Adrenal cortical tissue could not be identified. The right adrenal weighed 5 grams and appeared normal.
Case report Maternal histocy. Mrs. A., a 25-year-old white primipara, had a normal prenatal course except for mild water retention which was controlled by a low-salt diet. Her blood type is B III, Rh negative, and that of her husband is 0 IV, Rh positive. She gave no history of previous transfusions and had no antibodies when tested during each trimester of pregnancy. During the thirty-ninth week of gestation, fetal heart tones and fetal movements, which were recorded regularly during previous visits, disappeared. Intrauterine death due to unknown causes was diagnosed. At approximately 40 weeks' gestation the patient went into natural labor and was delivered of a term-sized macerated fetus by low-forceps extraction. The fetus had a somewhat edematous appearance and a distended abdomen. These findings, together with a large placenta, suggested to the clinicians that the fetus might be hydropic because of erythroblastosis. Gross postmortem examination. External surface. The body was that of a white male infant weighing 3,925 grams and having a crown-heel length of 51 em. and crownrump length of 35 em. The body was moderFrom the Department of Obstetrics and Gynecology, The University of Chicago and The Chicago Lying-in Hospital.
1388
Volume 82 Number 6
Kidneys, ureters, and the bladder appeared normal, although the left kidney weighed slightly less than the right. Skeletal system. All the bones appeared normal and there was no evidence of bone metastasis. Placenta. The placenta weighed 1,240 grams and measured 22 by 21 em. The cotyledons were well demarcated, thick, and of soft consistency. Small hematomas were noticed on the cut surface. The maternal surface had a reddish yellow coloration. Microscopy examination. Liver. Only a small amount of liver tissue was still visible and most of the parenchyma was replaced by islands of tumor cells (Fig. 1 ) . The islands were fairly uniform in size and appeared to be separated by sinusoidal tissue which in a few places had parenchymal cells persisting. The extent of maceration obscured the exact relationship of the tumor cells to the finer structures of the liver. Left adrenal. The central portion contained innumerable islands of large uniform cells with prominent hyperchromatic nuclei. These were identical to those found in the liver and are characteristic of the pattern generally designated to neuroblastomas. No rosette formation could be seen. The masses of tumor tissue appeared to be largely within sinusoids and extended peripherally toward the definitive cortex but did not seem to invade this area (Fig. 2). Right adrenal. This gland retained its normal histologic appearance. However, a few small islands of typical tumor cells were contained in the sinusoids ol'.the medulla. Lung. The tissue was moderately macerated but histologic details could stili be made out fairly well. The alveoli were not expanded. Small groups of tumor cells were scattered throughout the parenchyma. The majority appeared to be in the lymphatics surrounding medium-sized veins but interstitial tissue unrelated to large blood vessels also contained scattered groups of tumor cells. Neoplastic cells could be seen in areas of the visceral pleura immediately adjacent to the pulmonary tissue. Spleen. The general appearance was normal except for mild degenerative changes secondary to intrauterine death. Tumor cells could be identified in the peripheral part of the wall of the large vein and in several irregular spaces which were probably lymphatic channels. Kidneys. Changes secondary to intrauterine
Neuroblastoma as cause of antenatal death 1389
Fig. 1. Low-power view of the liver showing uniform replacement of liver parenchyma by tumor islands. The tumor is undifferentiated with no evidence of rosette formation.
Fig. 2. Low-power view of the left adrenal showing masses of tumor tissue within the sinusoids. The definitive cortex is free from invasion.
1390 Birner Am.
death made diiferentiation of tumor cells somewhat difficult and for the most part it was impossible to be certain whether groups of cells were actually neoplastic or whether they were undifferentiated nephrogenic tissue. Oniy in one area could a large mass of tumor cells positively be identified, in the interstitial tissue a short dis-
tance beneath the capsule. Other areas were highly suggestive of tumor formation. In addition, parts of the connective tissue surrounding the kidney was infiltrated by tumor cells. Placenta. The villi were unusually large. The blood vessels seemed somewhat reduced in number and there was an unusual amount of connective tissue containing many histiocytes of the variety generally designated as Hofbauer cells. In some places scattered Langhans cells were still visible beneath the syncytial covering of the villi. In many places the surface was separated suggesting that there had been considerable edema. No sections of the brain, skin, skeletal system, thyroid, thymus, or other visceral organs were taken because of the advanced stage of maceration of the fetus. Comment
The neuroblastoma is one of the most common and most highly malignant tumors of infancy and childhood. Approximately half of the reported cases are in infants less than 2 years old and 75 per cent in children less than 4 years old. 2 The occurrence of neuroblastoma in the fetus and newborn is relatively uncommon. In an extensive review of the literature, Wells,S in 1940, was able to find only 17 authenticated cases. Bachmann/ in 1955, reported 650 cases of neuroblastoma which included 3 cases in stillborn, 31 in the newborn, and 51 in the first 3 months of life. Gross/ in 1959, reported on 217 cases at the Boston Children's Hospital, his youngest patient being 4 hours old and his oldest 16 years. Within recent years the occurrence of tumors in adolescent and even adult patients has been clearly recognized. The neuroblastoma may develop in any site where sympathetic ganglion cells or their precursors are located. Their growth takes origin from undifferentiated neural tissue of sympathetic ganglia or the adrenal
December, 1961 & Gynec.
J. Obst.
medulla. In fact, 3 types of tumors may derive from this tissue-the pheochromocytoma, the ganglioneuroma, and the neuroblastoma. The latter is the highly malignant form of sympathetic ganglion tumor, and is made up of only poorly differentiated anaplastic imitations of neuroblasts which are, of course, the precursors of adult ganglion cells. The neuroblastoma, therefore, is truly an embryonic tumor since it arises from immature tissue which never attains completely adult differentiation. Microscopically neuroblastomas are diffuse masses of rounded cells resembling large lymphocytes with frequent mitosis which might explain why neuroblastomas originally were considered round cell sarcomas. 6 Even today we find a wide variety of descriptive terminology in the literature for the same tumor (neurocytoma, sympathoma embryonale, sympathicoblastoma, sympathogonioma). The wide range of differentiation of neuroblastomas undoubtedly accounts for these specific terms. In the least differentiated tumors round celled growth is dominant and rosette formation is often indistinct or absent. The first recognizable stage of neuron differentiation is the appearance of rosettelike clusters of cells. Further differentiation converts some of the pyroform neuroblasts into recognizable young nerve cells and their outgrowing axons into bundles of parallel fibers which will stain specifically as nerve fibers. About 40 per cent of neuroblastomas originate in the adrenal medulla. Other sites are the sympathetic chains of the abdomen, neck, and thorax-in that order of frequency. Probably none originate in the central nervous system. 2 Metastatic spread may be via either the lymphatic system or the blood stream and secondary lesions may appear rapidly in a variety of locations. The bones, especially the calvarium and orbit, and the liver are the most frequent sites of metastasis. In cases of neuroblastoma in the newborn the enlargement of the liver is most striking. Hagstrom 7 reports on a case in which a 700 gram liver caused dystocia in a newborn infant. Richards 8 records a liver
Volume 82 Number 6
weighing 1>850 grams in a 2-week-old infant. Occasionally, rupture of a blood vessel in the liver, eroded by neoplastic tissue, has caused hemoperitoneum and dystocia. Early metastasis of neuroblastoma to the bones is not as common in the newborn as in the age group between 2 and 4 years. Metastasis to the lungs and other visceral organs is rare at any age. This case is of interest not only because of a neuroblastoma causing antenatal death but also because of the occult involvement of multiple organs by tumor tissue. Except for the well-circumscribed, encapsulated left adrenal neoplasm, no gross evidence of tumor metastasis was detectable. The commonly described discrete, rounded> white, or hemorrhagic metastatic nodules were completely lacking. The tumor cells apparently were uniformly scattered and a well-integrated part of the organ involved. This raises the old question again as to whether we are dealing with a multicentric proliferation of undifferentiated sympathetic cell groups in these organs or with metastatic lesions. The wide distribution of sympathetic cells in the body certainly could give support to this theory. The lack of tumor cells in the placenta in our case would seem to speak against a blood=bornc metastasis from the adrenal tumor. At least a number of cases in the literature, especially those in
Neuroblastoma as cause of antenatal death 1391
which no primary tumor site was apparent, also support the theory of multicentric origin of neuroblastomas. Potter and Parrish 9 reported a case of a stillborn fetus in which all tissue of nervous origin, except the brain, had undergone neoplastic hyperplasia. Recently Gross 5 reported 4 instances of multiple neuroblastomas apparent at necropsy. Of these, one child was found to have 6 separate tumors arising from different parts of the retroperitoneal sympathetic chains, all presumably having arisen independently. Multiplicity of these lesions must clearly depend on influences affecting many parts of the developing tissues simultaneously and we may well be dealing with a systemic disorder of the sympathetic nervous tissue as a whole. 10 Summary
A mature stillborn fetus is described in which a small, well-encapsulated neuroblastoma of the left adrenal gland was the only gross finding. Microscopic examination revealed diffuse neoplastic involvement of the liver, adrenals, spleen, kidneys, and lungs. Multicentric proliferation of undifferentiated sympathetic cell groups in these organs is suggested. I am indebted to Dr. Edith Potter for aid and advice.
REFERENCES
1. Bartok, I., and Baradnay, G. Y.: Zentralbl. allg. Path. u. path. Anat. 194: 194, 1958. 2. Willis, R. A.: Pathology of Tumours, St. Louis, 1953, The C. V. Mosby Company, p. 852. 3. Wells, H. G.: Arch. Path. 30: 543, 1940. 4. Bachmann, K. D.: Ztschr. Kinderh. 77: 391, 1955. 5. Gross, R. E., Farbers, S., and Martin, L. W.: Pediatrics 23: 1179, 1959.
6. Woods, R. G.: M. ]. Australia 26: 125, 1958. 7. Hagstrom, H. T.: AM. J. OnsT. & GYNEC. 19: 673, 1930. 8. Richards, H.: Cited by Willis. 2 9. Potter, E. L., and Parrish, J. L.: Am. J. Path. 18: 141, 1942. 10. Potter, E. L.: Pathology of the Fetus and the Newborn, Chicago, 1952, The Year Book Publishers, Inc.