Nonfunctioning Adrenocortical Carcinoma in Pediatric Acute Lymphoblastic Leukemia: A Case Report of a Rare Multiple Primaries Combination
Wafaa M. Rashed, MSc, BCNSP, ** Wael Zekri, MD,¿§ Madiha Awad, MD,§ Hala Taha, MD,§| Badr Abdalla, MD, and Ahmad S. Alfaar, MD*#
Summary: Childhood adrenocortical carcinoma (ACC) is a rare tumor and its association with acute lymphoblastic leukemia (ALL) is even rarer. One such case is discussed in this case report. A 3-year-old patient was concomitantly diagnosed with ALL and an initially nonmetastatic ACC. Management started by following the Total XV protocol without a window phase. Left adrenalec- tomy was conducted after the consolidation phase. Recurrence of a mass at the tumor bed was discovered at week 33 of the con- tinuation phase. Reexcision was conducted, followed by the administration of an ACC protocol including cisplatin, etoposide, and doxirubicin. Mitotane was added when a pulmonary meta- stasis was discovered and then stopped after the patient suffered from an arachnoid cyst and speech difficulties. The ALL protocol was resumed from week 34 of the continuation phase. Progression of pulmonary nodules was noted after week 45. A pulmonary metastectomy was performed. The ALL protocol was resumed up to week 51 with a good response as proven by assessment of minimal residual disease. A further recurrence was diagnosed at the abdominal tumor bed with a paravertebral mass and a pulmonary nodule. The patient was assigned to palliative treatment and died after a 32-month survival. Such rare associations need more extensive discussions of the best possible management in scientific literature.
Key Words: adrenocortical carcinoma, acute lymphoblastic leuke- mia, multiple primaries, childhood cancers
(J Pediatr Hematol Oncol 2017;39:150-152)
CASE REPORT
A 3-year-old boy was admitted to our hospital with fever, fatigue, sweat, and decreased activity. In addition, he was suffering from a right inguinal swelling with a history of progressive abdominal distension over 4 weeks. There was no family history of malignancy. The patient was fully immunized. The patient had developmental milestones consistent with his age, apart from delayed speech. Physical examination revealed a bilateral cervical, axillary, and inguinal lymph node (LN) enlargement (1.5x 1.5 cm, mobile discrete). Pelviabdominal examination showed no palpable masses with a spleen felt 3 to 4 cm and a liver 2 cm below the costal
Received for publication January 31, 2016; accepted September 30, 2016.
From the *Research Department; ¿ Pediatric Oncology Department; |Pathology Department, Children’s Cancer Hospital Egypt; §National Cancer Institute, Cairo University; (Cairo University Hospitals; ¡Armed Forces College of Medicine-Egypt (AFCM), Cairo, Egypt; and Charité-Universitätsmedizin Berlin, Berlin, Germany.
A.S.A. is supported by a grant from German Academic Exchange Service (DAAD) number 57147166. The remaining authors declare no conflict of interest.
Reprints: Ahmad S. Alfaar, MD, and Wafaa M. Rashed, MSc, BCNSP, Research Department, Children’s Cancer Hospital Egypt, Cairo 57357, Egypt (e-mails: ahmadsfar@gmail.com; wafaaanor@ gmail.com).
Copyright @ 2017 Wolters Kluwer Health, Inc. All rights reserved.
margin. Normal genitalia for age was observed. Abdominal ultra- sonography showed a 7×8cm left adrenal heterogenous mass compressing the left kidney. The liver was mildly enlarged to 13.8 cm in the right mid-clavicular line, with a smooth surface and homogenous parenchymal echogenicity. A 1.5cm right lobe peripheral subcapsular hypoechoic focal lesion was found. A small porta hepatis LN was seen, measuring about 6 x 13 mm. The spleen was enlarged to 13.5 cm in its long axis. Echocardiography showed normal left ventricular size and function with a fractional short- ening of 37% and an ejection fraction of 68%.
Laboratory studies revealed normal adrenocortical hormone levels. In addition, the first total leukocyte count was 22.9x 103/ mcl. Bone marrow aspirate was infiltrated with numerous sheets of L1-type lymphoblasts representing 92% of the total population. Cytochemical staining with myeloperoxidase was negative, but Sudan black was positive. Bone marrow flow cytometry confirmed pre-B-cell acute lymphoblastic leukemia (ALL), and the DNA index was 1.0. The karyotype was 46XY [20], and the molecular results were negative for all translocations screened for precursor B-cells at the hospital [t(12;21), t(9;22), t(4,11), and t(1;19)]. Cere- brospinal fluid (CSF) showed no leukemia cells. The clinical deci- sion was to start treatment for the hematologic problem following ALL-Total XV study without a window phase.1 Treatment was composed of three phases: an induction phase followed by a con- solidation phase and finally a continuation phase. After 4 days of starting hematologic treatment, contrast-enhanced computed tomography (CECT) examination showed a huge globular rather defined heterogenously enhancing left suprarenal mass measuring 8×6×7cm at its maximum dimensions, showing central hypo- dense areas of cystic changes and tumor necrosis. The lesion’s anterior and lateral extensions reached the abdominal wall, while it pushed the left kidney downward and it abutted the inferior surface of the spleen superiorly with no evidence of invasion or infiltration of any of the mentioned structures. Five days later, a CT-guided biopsy of the left suprarenal mass showed nests and sheets of polyhedral cells having abundant granular eosinophilic cytoplasm and hyperchromatic oval nuclei. Nuclear pleomorphism was moderate, and mitosis was mild (3 per 50 high-power field). Focal areas of necrosis were noted. Immunostaining using the envision system and DAB chromogen revealed positive cytoplasmic staining for cytokeratin, vimentin, inhibin, and synaptophysin. Chromog- ranin and S100 were negative. The pathology report indicated a diagnosis of a left adrenal cortical neoplasm. Metastatic workup findings were normal, including that of a bone scan and a chest CT. Initial hepatic lesions disappeared, confirming the leukemic infil- trate nature. At day 42 of the induction phase of ALL treatment, the patient continued on the low-risk protocol and took 4 con- secutive courses of the consolidation phase with good tolerance. Left adrenalectomy was performed after the consolidation phase of ALL treatment (Fig. 1).
After adrenalectomy, the patient went on to the continuation phase of ALL treatment, showing a good response (Table 1). At week 33 of the continuation phase of ALL treatment, the patient developed a recurrence of the adrenocortical tumor that then showed a progressive course. A second operation, an abdominal exploration with a left nephrectomy, was carried out. Pathologic examination of the excised tissue revealed infiltration by sheets of
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vacuolated and eosinophilic granular cells having round to irreg- ular and occasionally multinucleated bizarre nuclei, with a vague sinusoidal pattern and desmoplastic fibrous bands. Capsule and perinephric and hilar fat were focally infiltrated by tumor cells. A focus of residual suprarenal tissue infiltration by tumor cells was evident. One of 3 excised hilar LNs was infiltrated. Vascular and ureteric margins were free.
The clinical decision was to target the adrenocortical carci- noma (ACC) with 6 cycles of CED (cisplatin/etoposide/doxor- ubicin)2 with follow-up using CT scanning. It was also decided to hold the ALL treatment. The patient received 3 cycles without mitotane. After the first cycle of ACC treatment, the chest CT revealed a metastatic pulmonary nodule. Before cycles 3 and 5 two other chest CTs revealed a stationary course of the pulmonary nodule. Starting from the fourth cycle, mitotane was added to the dose (Table 2).
Because of a newly developed speech abnormality before cycle 5, a CT of the brain was conducted, which showed a left temporal extra-axial CSF-containing arachnoid cyst measuring 18 × 29 mm, with mild supratentorial ventriculomegaly and cortical effacement, denoting early hydrocephalic changes. There was no evidence of metastatic deposits.
The patient finished 6 courses of ACC treatment. His speech difficulty was deemed related to the mitotane treatment3; it improved after mitotane discontinuation. The clinical decision after finishing the ACC treatment was to resume ALL treatment pro- tocol starting from week 34 of the continuation phase. A series of post-week 43 and 45 chest CTs showed an increase in size of the left pulmonary nodule, with a newly developed small nodule adherent to the previous one. There had been no instances of fungal chest infection or antifungal treatment. An abdominal CT showed a free operation bed. The patient was clinically well with no active problem. A CSF study at that time showed no leukemia cells.
A left pulmonary metastectomy operation, conducted 8 months after the second operation, revealed a yellowish necrotic nodule measuring 1.4x0.4cm, 0.5cm from the resected margin. The lung parenchyma was infiltrated by cohesive groups of pleo- morphic cells having abundant eosinophilic to clear cytoplasm and exhibiting evident necrosis and mitotic activity, including atypical forms, thus confirming metastatic behavior.
The ALL treatment protocol continued until week 51 with a good response as evidenced by minimal residual disease (MRD) results (Table 2). A follow-up CT showed the operative bed having a left paravertebral fairly defined hypodense lesion measuring about 2.5×2.2cm, seen as a likely recurrence, with a left basal pulmonary nodule and consolidation. The clinical decision was to start palliative chemotherapy (6-Mercaptopurine [50 mg/m2] and methotrexate [20 mg/m2]). A CT-guided biopsy to confirm recur- rence was not possible, because of the inaccessibility of the lesion.
| Treatment Phase | Bone Marrow (%) | MRD (%) |
|---|---|---|
| Induction phase | ||
| Day 15 | 4 | 0.31 |
| Day 42 | 0 | < 0.01 |
| Continuation phase | ||
| Week 7 | 0 | < 0.01 |
| Week 17 | 0 | < 0.01 |
| Week 48 | 1 | < 0.01 |
ALL indicates acute lymphoblastic leukemia; MRD, minimal residual disease.
| Drug | Dose |
|---|---|
| Mitotane | 4 g/m2 PO 4 times a day |
| Cisplatin | 50 mg/m2/dose IV over 6h day 1 and 2 |
| Etoposide | 100 mg/m2/dose IV over 1 h on days 1, 2, and 3. |
| Doxorubicin | 25 mg/m2/dose IV over 1 h on days 4 and 5 |
Five months later, no bone metastases were detected during a 99mTc-MDP bone scan, and MRD was < 0.01%. Palliative che- motherapy continued for 6 months after which the patient suffered from epistaxis and rectum bleeding. He was on supportive care for 4 months when he finally passed away. The overall survival of this patient was 31.73 months.
DISCUSSION
Although ALL is the most common childhood leuke- mia, simultaneous occurrence of ALL with ACC in a child is rare. Li-Fraumeni syndrome is an autosomal dominant hereditary disease characterized by affection of multiple primary tumors with TP53 mutations.4 6 A few case reports have attributed concomitant occurrence of leukemia and ACC to Li-Fraumeni syndrome.7 The most recent of these reports indicated that the patient died 13 months after diagnosis. Other reports showed incidences of ALL with other solid tumors.8,9 Unfortunately, we could not examine TP53 in our patient, nor in his family.
The strategy of treatment of our case was based on the use of an institutional 3-year standard ALL protocol, while also managing the ACC. A complete tumor resection was the cornerstone of the ACC treatment plan,10 but the clinical decision was to delay surgery after the consolidation phase of ALL treatment so as to be sure that the patient was in complete remission. The patient’s response to ALL treatment was very successful, as evident by successive MRD results during treatment (Table 1). This patient was classified as a low-risk ALL patient. Such a classification is usually characterized by excellent survival.1 Despite the promising response to ALL treatment, a challenge to the treatment was that the adrenocortical tumor prognosis remained unclear. Recent evidence builds the prognosis of ACC on 3 pillars: staging, resection status, and grading (both Ki67 and mitotic count).10 Beuschlein et al11 con- cluded that Ki67 is the most important prognostic factor for recurrence after complete resection.
A second challenge to the treatment of this case was the recurrence of ACC during the course of ALL treatment. The clinical decision was to stop ALL treatment and con- duct a left nephrectomy, and to follow that with 6 cycles of combined CED chemotherapy. A third challenge was lung metastasis after the first cycle. Mitotane was thus added, being the only officially approved drug for metastatic ACC.10 Follow-up chest CT initially showed a stationary course; however, upon resuming ALL treatment, an ever- increasing size of the pulmonary nodule led to a decision to conduct a left pulmonary metastectomy. Recurrence led to a decision to administer palliative treatment.
Throughout this patient’s treatment, the management strategy was decided by a multidisciplinary team that took many factors into consideration. Adrenalectomy was con- sidered only after the induction and consolidation phases of ALL to avoid central nervous system relapse. Notably, 6- Mp/MTX was not administered during the 17-day lapa- rotomy and postlaparotomy recovery period. During this
period the patient had a nasogastric tube. We then resumed the treatment after these 17 days. The decision then was to target the recurrent ACC with CED and mitotane, recog- nizing the case as one of recurrent ACC of bad prognosis with an under-control leukemic disease (MRD < 0.01%). It was realized that etoposide and doxorubicin, both used in ACC treatment, would also be effective against leukemic blasts.
Despite all efforts to effectively navigate through challenges met and move forward both treatment strategies, the aggressiveness of ACC had the upper hand.
ACC in childhood is a rare disease12 and its prognosis is disappointing. Collaborative efforts are needed to iden- tify the etiology of the disease and find more promising combination drugs with optimum outcome.
ACKNOWLEDGMENT
The authors would like to thank Dr Mohamed-Ismail Y. Rakha for revising the manuscript.
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