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Late recurrence in neuroblastoma
Late Recurrence in Neuroblastoma By Yoshinobu
Hata, Fumiaki
Sasaki, Haruhiko
Naito, Hiromasa Takahashi, Sapporo, Japan
Tsutomu
Namieno,
and Junichi
Uchino
0 Recurrence in neuroblastoma more than 5 years after diagnosis is extremely rare. One case of neuroblastoma recurring 10 years after complete remission from disseminated neuroblastoma at the 5th month of life is reported. Twelve additional cases in the literature are reviewed. Despite the apparent rarity of this event, it should be considered that the patients with disseminated neuroblastoma induced to complete remission without definitive treatment have a potential for late recurrence and should be followed over long periods of time, especially during puberty. Copyright o 1991 by W.B. Saunders Company INDEX
WORDS:
Neuroblastoma,
late
recurrence.
EUROBLASTOMA is a biologically mysterious tumor in childhood. Spontaneous regression with histological and/or biologic maturation occasionally occurs with patients in stage IV-S. On the other hand, most of the tumors show widespread metastasis and have a poor prognosis. Two-year disease-free survival is considered highly predictive of therapeutic success with neuroblastoma. Recurrence more than 5 years after diagnosis is extremely rare. A lo-year-old girl experienced recurrence of neuroblastoma 10 years after complete remission. Based on a review of the literature, the late recurrence in neuroblastoma is discussed.
N
CASE
REPORT
A 5-month-old girl was referred for examination with an abdominal tumor and jaundice in June 1974 (Fig 1A). Laparotomy showed a retroperitoneal tumor sized 10 x 13 cm behind the head of the pancreas and four metastatic tumors in the right liver. Cholecystojejunostomy was performed. Biopsy specimen showed a neuroblastoma with rosette formation (Fig 2A). Radiation therapy was delivered to the whole abdomen in a dose of 800 rads and Vincristine and Cyclophosphamide therapy was continued weekly for 1 year. A second-look operation showed no tumor foci in the abdomen in July 1975. There was no evidence of disease until July 1984, when she had an adenopathy in the left submandibular region. The bone marrow aspiration showed neuroblastoma cells and levels of various cathecholamine in urine were markedly elevated. Computed tomography scan showed a retroperitoneal mass sized 11.8 x 8.8 x 9.0 cm behind the pancreas and multiple low-density lesions in the liver. Bone scintigram using 99mTc-MDP showed hot spots in the left frontal cranium and right iliac bone. Irradiation and combination chemotherapy with vincristine and cyclophosphamide were performed. However, hepatomegaly continued to grow (Fig 1B). Operative cannulation in the hepatic artery was performed on February 21, 1985. A tumor arising from the retroperitoneum behind the pancreas was shown, along with enlarged paraaortic lymph nodes. Histological examination showed a neuroblastoma JournalofPediatricSurgery,
Vol26,
No 12 (December),
1991: pp 1417-1419
Fig 1. diagnosis
Primary tumor and/or and (B) late recurrence
enlarged liver at the time of (A) initial are marked in the abdomen.
(Fig 2B). Chemotherapy was changed to administration of vincristine and adriamycin via the hepatic artery. No significant response was generated. Metastasis in the lung and various other sites developed. She died of intrathoracic and intraabdominal hemorrhage due to disseminated intravascular coagulopathy.
DISCUSSION
The main prognostic factors in neuroblastoma are the age of patients, the primary site, and the extent of the disease at the time of diagnosis.’ Only a 1.4%’ to From the First Department of Surgeq, Hokkaido University School of Medicine, Sapporo, Japan. Address reprint requests to Yoshinobu Hata, MD, The First Depatiment of Surgery, Hokkaido University School of Medicine, N15 W, 060 Sapporo, Japan. Copyright o 1991 by W B. Saunders Company 0022.3468/91/2612-0022$03.00/O 1417
1418
HATA
Fig 2. neurblasts,
Photomicrographs of (A) initial tumor mass and (B) liver occasionally occurring in rosette arrangement and lying
metastasis in a loose
4%3 death rate has been reported in patients with complete response for 24 months. Being disease free for 2 years after diagnosis was generally considered equivalent to cure. It is very rare for a patient surviving disease-free for longer than 5 years after diagnosis of neuroblastoma Table
C%ie NO. 1
Investigators Ringertz
2
Horn
3*
Hinton
4t
Hinton
5
Konrad
6
Konrad
7$
Jaffe’
et al4
et al5 et al6
et al’ et al’ et al’
8$
Richard
9
Tess et al”
IO 11 12 13
et al8
Dannecker et allI Dannecker et alli Dannecker et allI Present case
Age at Diagnosis
Sex
Stage
5yr
M
?
Primary Site
?
Epidural
2yr
M
?
Thorax and neck
10mo
F
III
Retroperitoneal with epidural extension
3yr Birth
M F
IV IV
Left adrenal Retroperi-
lyr
F
?
toneal lntrapelvic
7 yr
F
IV
Mediastinal
3mo
M
IVS
3yr
M
II
+w
tumor cells, x200).
resembling
to relapse. Twenty-four cases of late recurrences in neuroblastoma were collected by a review of the English language literature. Among them, 12 patients were well documented4-” (Table 1). Stage IV neuroblastoma was represented in 60% of the collected cases. Because the rate of the number of
1. Late Recurrence
Distant Metastasis
in late recurrenca showing pleomorphic bibrillar stroma (H&E, original magnification
ET AL
in Neuroblastoma
Surgery
Radiation
?
Biopsy
Chemotherapy
?
Age at Late Recurrence
Site of Late Recurrence
Distant Metastasis at Late Recurrence
15yr
Same as
+(?I +tw
Biopsy
f
-
?
primary ?
Biopsy
+
-
12yr
Same as
Age at Death 150r
16vr 14yr
-
16yr
primary
+ (8) +(BM)
?
Biopsy Biopsy
+ +
Biopsy
-
+U%BM)
-
13yr
+
IOyr
+
6 vr
? Mediastinal
+NB.E.P) +(B,BM)
13yr
Same as primary
+(B,BM)
11 yr
? ?
+(a) +m
22 yr
?
+PJ) +W=V4
20 yr
IOyr 22 yr 10yr 19yr
6 vr
Biopsy
+
Retroperi-
Excision
?
?
12yr
-
+(W
?
toneal Right adrenal
Excision
+
+
1Oyr
-
+EMhW)
?
+
-
16yr
Left adrenal
+
15yr
+
1Oyr
Retroperitoneal Retroperi-
Left adrenal
+IH.D)
lyr
F
II
11 mo
M
IV
?
+(E)
Biopsy
8mo
M
IV
Mediastinal
+W)
Biopsy
5mo
F
IV
Retroperitoneal
+(H)
Biopsy
Abbreviations: B, bone; EM, bone marrow; H, liver; D, skin; E, orbit; *Ten years later a spinal fusion, incidental finding of ganglioneuroma. tFive years later, Ganglioneuroma of vertebra. *Two times of late recurrence.
+
toneal N, lymph
node;
P, lung.
?
16yr
+(N)
15yr
+(B,BM,H)
11 yr
LATE
RECURRENCE
1419
IN NEUROBLASTOMA
long-term survivors in stage IV neuroblastoma to all survivors is only 8.0’ to 15.4,” its incidence is very high. The possibility of late recurrence in survivors of stage IV neuroblastoma is very important and merits due consideration. The primary sites were too diverse to categorize in these patients. Two cases with bone metastasis were noted; Grosfeld and Baehner” cited that long-term disease-free survival with bone metastasis was uncommon and late recurrence may be possible in these cases. Among the stage IV patients with bone metastases, three were treated by irradiation only. Moreover, two were treated with chemotherapy only. However, the effective doses were not always applied. They seemed to be regarded as spontaneous regression. Our patient was also considered to have spontaneous regression.13 Spontaneous regression of the disease may have the potential to cause late recurrence. In the collected cases, all but two patients with stage II underwent biopsy only. Grosfeld and Baehner” reported that there were no long-term survivors
without complete resection; therefore, complete remission in 11 patients is a very rare outcome. In the two cases reported by Hinton and Buschke,6 ganglioneuroblastomas developed 5 years after remission and became disseminated neuroblastoma several years after this recurrence. In the two cases reported by Jaffe’ and Richard et al,* recurrences occurred 10 and 5 years after initial diagnosis, respectively. Further recurrences were noticed after complete remission of 9 and 10 years, respectively. They suggested malignant changes of ganglioneuroma to neuroblastoma and another recurrence after complete remission of late recurrence. In the collected cases, ages at death ranged from 11 to 22 years, with one exception. Recurrence during adolescence may be related to an alteration in immunologic surveillance due to the biologic maturation or due to the hormonal changes around this age. In any case, high incidence of late recurrence in patients with stage IV neuroblastoma points to the necessity for more serious follow-up beyond the time of puberty.
REFERENCES 1. Thomas PRM, Lee JY, Fineberg BB, et al: An analysis of neuroblastoma at a single institution. Cancer 53:2076-2082,1984 2. Bachmann KD: Das Neuroblastoma sympathicum: Khnik und prognose von 1030 Fallen. Z Kinderheik 86:710-724,1962 3. DeLorimier AA, Bragg KU, Linden G: Neurohlastoma in childhood. Am J Dis Child 118:441-450, 1969 4. Ringertz N, Lidholm SO: Mediastinal tumors and cysts. J Thorac Surg 31:458-487,1956 5. Horn RC, Koop CE, Kiesewetter WB: Neuroblastoma in childhood-Clinicopathologic study of forty-four cases. Lab Invest 5:106-119,1956 6. Hinton P, Buschke F: Neuroblastoma in children, 42 cases. Radio1 Clin Biol37:19-28,1968 7. Konrad PN, Singher LJ, Neerhout RC: Late death from neuroblastoma. J Pediatr 82:80-82, 1973
8. Richard MJS, Joo P, Gilbert EF: The rare problem of late recurrence in neuroblastoma. Cancer 38:1847-1853,1976 9. Jaffe N: Late death from neuroblastoma. J Pediatr 82:1904, 1973 10. Tess JDT, Nessi R: Late metastasis from neuroblastoma mimicking Ewing’s sarcoma. Pediatr Radio1 10:107-109,198O 11. Dannecker G, Leiding E, Treuner J, et al: Late recurrence of neuroblastoma. A reason for prolonged follow-up? Am J Pediatr Hematol Oncol5:271-274. 1983 12. Grosfeld JL, Baehner RL: Neuroblastoma; an analysis of 160 cases. World J Surg 4:29-38,198O 13. Cole WH: Efforts to explain spontaneous regression of cancer. J Surg Oncol17:201-209,198l
Hata, Fumiaki
Sasaki, Haruhiko
Naito, Hiromasa Takahashi, Sapporo, Japan
Tsutomu
Namieno,
and Junichi
Uchino
0 Recurrence in neuroblastoma more than 5 years after diagnosis is extremely rare. One case of neuroblastoma recurring 10 years after complete remission from disseminated neuroblastoma at the 5th month of life is reported. Twelve additional cases in the literature are reviewed. Despite the apparent rarity of this event, it should be considered that the patients with disseminated neuroblastoma induced to complete remission without definitive treatment have a potential for late recurrence and should be followed over long periods of time, especially during puberty. Copyright o 1991 by W.B. Saunders Company INDEX
WORDS:
Neuroblastoma,
late
recurrence.
EUROBLASTOMA is a biologically mysterious tumor in childhood. Spontaneous regression with histological and/or biologic maturation occasionally occurs with patients in stage IV-S. On the other hand, most of the tumors show widespread metastasis and have a poor prognosis. Two-year disease-free survival is considered highly predictive of therapeutic success with neuroblastoma. Recurrence more than 5 years after diagnosis is extremely rare. A lo-year-old girl experienced recurrence of neuroblastoma 10 years after complete remission. Based on a review of the literature, the late recurrence in neuroblastoma is discussed.
N
CASE
REPORT
A 5-month-old girl was referred for examination with an abdominal tumor and jaundice in June 1974 (Fig 1A). Laparotomy showed a retroperitoneal tumor sized 10 x 13 cm behind the head of the pancreas and four metastatic tumors in the right liver. Cholecystojejunostomy was performed. Biopsy specimen showed a neuroblastoma with rosette formation (Fig 2A). Radiation therapy was delivered to the whole abdomen in a dose of 800 rads and Vincristine and Cyclophosphamide therapy was continued weekly for 1 year. A second-look operation showed no tumor foci in the abdomen in July 1975. There was no evidence of disease until July 1984, when she had an adenopathy in the left submandibular region. The bone marrow aspiration showed neuroblastoma cells and levels of various cathecholamine in urine were markedly elevated. Computed tomography scan showed a retroperitoneal mass sized 11.8 x 8.8 x 9.0 cm behind the pancreas and multiple low-density lesions in the liver. Bone scintigram using 99mTc-MDP showed hot spots in the left frontal cranium and right iliac bone. Irradiation and combination chemotherapy with vincristine and cyclophosphamide were performed. However, hepatomegaly continued to grow (Fig 1B). Operative cannulation in the hepatic artery was performed on February 21, 1985. A tumor arising from the retroperitoneum behind the pancreas was shown, along with enlarged paraaortic lymph nodes. Histological examination showed a neuroblastoma JournalofPediatricSurgery,
Vol26,
No 12 (December),
1991: pp 1417-1419
Fig 1. diagnosis
Primary tumor and/or and (B) late recurrence
enlarged liver at the time of (A) initial are marked in the abdomen.
(Fig 2B). Chemotherapy was changed to administration of vincristine and adriamycin via the hepatic artery. No significant response was generated. Metastasis in the lung and various other sites developed. She died of intrathoracic and intraabdominal hemorrhage due to disseminated intravascular coagulopathy.
DISCUSSION
The main prognostic factors in neuroblastoma are the age of patients, the primary site, and the extent of the disease at the time of diagnosis.’ Only a 1.4%’ to From the First Department of Surgeq, Hokkaido University School of Medicine, Sapporo, Japan. Address reprint requests to Yoshinobu Hata, MD, The First Depatiment of Surgery, Hokkaido University School of Medicine, N15 W, 060 Sapporo, Japan. Copyright o 1991 by W B. Saunders Company 0022.3468/91/2612-0022$03.00/O 1417
1418
HATA
Fig 2. neurblasts,
Photomicrographs of (A) initial tumor mass and (B) liver occasionally occurring in rosette arrangement and lying
metastasis in a loose
4%3 death rate has been reported in patients with complete response for 24 months. Being disease free for 2 years after diagnosis was generally considered equivalent to cure. It is very rare for a patient surviving disease-free for longer than 5 years after diagnosis of neuroblastoma Table
C%ie NO. 1
Investigators Ringertz
2
Horn
3*
Hinton
4t
Hinton
5
Konrad
6
Konrad
7$
Jaffe’
et al4
et al5 et al6
et al’ et al’ et al’
8$
Richard
9
Tess et al”
IO 11 12 13
et al8
Dannecker et allI Dannecker et alli Dannecker et allI Present case
Age at Diagnosis
Sex
Stage
5yr
M
?
Primary Site
?
Epidural
2yr
M
?
Thorax and neck
10mo
F
III
Retroperitoneal with epidural extension
3yr Birth
M F
IV IV
Left adrenal Retroperi-
lyr
F
?
toneal lntrapelvic
7 yr
F
IV
Mediastinal
3mo
M
IVS
3yr
M
II
+w
tumor cells, x200).
resembling
to relapse. Twenty-four cases of late recurrences in neuroblastoma were collected by a review of the English language literature. Among them, 12 patients were well documented4-” (Table 1). Stage IV neuroblastoma was represented in 60% of the collected cases. Because the rate of the number of
1. Late Recurrence
Distant Metastasis
in late recurrenca showing pleomorphic bibrillar stroma (H&E, original magnification
ET AL
in Neuroblastoma
Surgery
Radiation
?
Biopsy
Chemotherapy
?
Age at Late Recurrence
Site of Late Recurrence
Distant Metastasis at Late Recurrence
15yr
Same as
+(?I +tw
Biopsy
f
-
?
primary ?
Biopsy
+
-
12yr
Same as
Age at Death 150r
16vr 14yr
-
16yr
primary
+ (8) +(BM)
?
Biopsy Biopsy
+ +
Biopsy
-
+U%BM)
-
13yr
+
IOyr
+
6 vr
? Mediastinal
+NB.E.P) +(B,BM)
13yr
Same as primary
+(B,BM)
11 yr
? ?
+(a) +m
22 yr
?
+PJ) +W=V4
20 yr
IOyr 22 yr 10yr 19yr
6 vr
Biopsy
+
Retroperi-
Excision
?
?
12yr
-
+(W
?
toneal Right adrenal
Excision
+
+
1Oyr
-
+EMhW)
?
+
-
16yr
Left adrenal
+
15yr
+
1Oyr
Retroperitoneal Retroperi-
Left adrenal
+IH.D)
lyr
F
II
11 mo
M
IV
?
+(E)
Biopsy
8mo
M
IV
Mediastinal
+W)
Biopsy
5mo
F
IV
Retroperitoneal
+(H)
Biopsy
Abbreviations: B, bone; EM, bone marrow; H, liver; D, skin; E, orbit; *Ten years later a spinal fusion, incidental finding of ganglioneuroma. tFive years later, Ganglioneuroma of vertebra. *Two times of late recurrence.
+
toneal N, lymph
node;
P, lung.
?
16yr
+(N)
15yr
+(B,BM,H)
11 yr
LATE
RECURRENCE
1419
IN NEUROBLASTOMA
long-term survivors in stage IV neuroblastoma to all survivors is only 8.0’ to 15.4,” its incidence is very high. The possibility of late recurrence in survivors of stage IV neuroblastoma is very important and merits due consideration. The primary sites were too diverse to categorize in these patients. Two cases with bone metastasis were noted; Grosfeld and Baehner” cited that long-term disease-free survival with bone metastasis was uncommon and late recurrence may be possible in these cases. Among the stage IV patients with bone metastases, three were treated by irradiation only. Moreover, two were treated with chemotherapy only. However, the effective doses were not always applied. They seemed to be regarded as spontaneous regression. Our patient was also considered to have spontaneous regression.13 Spontaneous regression of the disease may have the potential to cause late recurrence. In the collected cases, all but two patients with stage II underwent biopsy only. Grosfeld and Baehner” reported that there were no long-term survivors
without complete resection; therefore, complete remission in 11 patients is a very rare outcome. In the two cases reported by Hinton and Buschke,6 ganglioneuroblastomas developed 5 years after remission and became disseminated neuroblastoma several years after this recurrence. In the two cases reported by Jaffe’ and Richard et al,* recurrences occurred 10 and 5 years after initial diagnosis, respectively. Further recurrences were noticed after complete remission of 9 and 10 years, respectively. They suggested malignant changes of ganglioneuroma to neuroblastoma and another recurrence after complete remission of late recurrence. In the collected cases, ages at death ranged from 11 to 22 years, with one exception. Recurrence during adolescence may be related to an alteration in immunologic surveillance due to the biologic maturation or due to the hormonal changes around this age. In any case, high incidence of late recurrence in patients with stage IV neuroblastoma points to the necessity for more serious follow-up beyond the time of puberty.
REFERENCES 1. Thomas PRM, Lee JY, Fineberg BB, et al: An analysis of neuroblastoma at a single institution. Cancer 53:2076-2082,1984 2. Bachmann KD: Das Neuroblastoma sympathicum: Khnik und prognose von 1030 Fallen. Z Kinderheik 86:710-724,1962 3. DeLorimier AA, Bragg KU, Linden G: Neurohlastoma in childhood. Am J Dis Child 118:441-450, 1969 4. Ringertz N, Lidholm SO: Mediastinal tumors and cysts. J Thorac Surg 31:458-487,1956 5. Horn RC, Koop CE, Kiesewetter WB: Neuroblastoma in childhood-Clinicopathologic study of forty-four cases. Lab Invest 5:106-119,1956 6. Hinton P, Buschke F: Neuroblastoma in children, 42 cases. Radio1 Clin Biol37:19-28,1968 7. Konrad PN, Singher LJ, Neerhout RC: Late death from neuroblastoma. J Pediatr 82:80-82, 1973
8. Richard MJS, Joo P, Gilbert EF: The rare problem of late recurrence in neuroblastoma. Cancer 38:1847-1853,1976 9. Jaffe N: Late death from neuroblastoma. J Pediatr 82:1904, 1973 10. Tess JDT, Nessi R: Late metastasis from neuroblastoma mimicking Ewing’s sarcoma. Pediatr Radio1 10:107-109,198O 11. Dannecker G, Leiding E, Treuner J, et al: Late recurrence of neuroblastoma. A reason for prolonged follow-up? Am J Pediatr Hematol Oncol5:271-274. 1983 12. Grosfeld JL, Baehner RL: Neuroblastoma; an analysis of 160 cases. World J Surg 4:29-38,198O 13. Cole WH: Efforts to explain spontaneous regression of cancer. J Surg Oncol17:201-209,198l