CASE STUDY
A G-CSF-secreting adrenal carcinoma with rhabdoid-like differentiation causing leukocytosis
Emil Lou, Jeremy Goodwin, David N. Howell, John Hicks and L. Brett Caram
Background. A 57-year-old African American man presented to a tertiary care center with a 6-month history of fatigue and worsening abdominal pain. He had lost 9.1 kg in weight in the 3 months leading up to presentation, and described subjective fevers and night sweats for 1 month with a nonproductive cough and blurred vision for several weeks before presentation. He had chronic renal insufficiency, sleep apnea, hypertension, and peripheral vascular disease.
Investigations. Physical examination, complete blood count, peripheral blood smear, leukocyte alkaline phosphatase score, bone marrow biopsy, CT of the chest, abdomen, and pelvis, MRI of the abdomen and pelvis, measurement of plasma and urine metanephrines, 24 h urine testing for cortisol and 17-ketosteroids, measurement of serum granulocyte colony-stimulating factor (G-CSF) level, histopathologic examination and immunohistochemical staining of resected tumor.
Diagnosis. G-CSF-secreting adrenal carcinoma with rhabdoid-like differentiation.
Management. En bloc surgical resection of kidney, suprarenal mass and spleen was performed, followed by initiation of mitotane chemotherapy 3 months later.
Lou, E. et al. Nat. Rev. Urol. 6, 392-397 (2009); doi:10.1038/nrurol.2009.101
The case
Department of Internal Medicine, Division of Medical Oncology, Memorial Sloan- Kettering Cancer Center, New York, NY, USA (E. Lou). Department of Internal Medicine (J. Goodwin), Department of Pathology (D. N. Howell), Department of Infectious Disease (L. B. Caram), Duke University Medical Center, Durham, NC, USA. Department of Pathology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX, USA (J. Hicks).
Correspondence: E. Lou, Department of Medicine, 1275 York Avenue, New York, NY 10021, USA loue@mskcc.org
A 57-year-old African American man presented to a tertiary care center with a 6-month history of fatigue and lower abdominal pain. He had lost 9.1 kg in weight over the preceding 3 months, and experienced gradual worsening of left upper and lower quadrant abdomi- nal pain with early satiety despite adequate appetite. He described chronic renal insufficiency, sleep apnea, hypertension, and peripheral vascular disease. Review of systems was notable for subjective fevers and night sweats occurring on a regular basis for 1 month with a nonproductive cough and blurred vision for several weeks before presentation. He denied nausea, vomiting, melena, hematochezia, recent sick contacts or expo- sure to tuberculosis. His social history was notable for a 50-pack-year history of smoking cigarettes. Family history was unremarkable.
At presentation, the patient was afebrile with normal vital signs. Abdominal examination revealed no obvious palpable masses, tenderness, or splenomegaly. He had mild nontender hepatomegaly, an enlarged pros- tate on digital rectal examination, and his stool was guaiac negative.
Laboratory work-up on presentation was significant for a raised white blood cell count of 79.8 x 109/1, as compared to a level of 10.2 × 109/1 7 months previously (normal range 4.3-10.8 x 109/1). The differential count
was 91.9% granulocytes, 4.5% lymphocytes, and 3.4% monocytes. Hemoglobin and hematocrit were 119 g/l (normal range 124-149 g/l) and 3.62 (normal range 3.5-4.5), respectively, and platelet count was 469 × 109/1 (normal range 150-400 x 109/1). A peripheral blood smear revealed numerous mature polymorphonuclear cells, increased monocytes and numerous platelets with normal erythrocytes. The patient was admit- ted to a general medical ward within a few hours of presentation for further evaluation of the leukocytosis and abdominal pain. Upon admission, the patient was evaluated by a consultant hematologist, who raised concern for an occult solid malignancy, leukemoid reaction or chronic leukemia, such as chronic myelo- genous leukemia (CML). As the peripheral blood smear demonstrated numerous mature neutrophils without immature forms or myeloblasts, CML was deemed unlikely.
The patient’s leukocyte alkaline phosphatase score was elevated at 352 (normal range 20-100), consis- tent with a leukemoid reaction. Bone marrow biopsy revealed marked myeloid hyperplasia without evidence of increased myeloblasts or islands of immature myeloid cells. CT of the chest, abdomen, and pelvis revealed a large 5.5 x 5.5 cm heterogeneously enhancing, left supra- renal mass. The exact site of origin of the mass could not be determined. Also noted on CT were a thickening of the gastric fundus adjacent to the suprarenal mass, and a 2.8 cm heterogeneous, peripherally enhancing
mass within the medial segment of the left lobe of the liver. MRI of the abdomen did not identify the origin of the suprarenal mass. The hepatic mass was character- ized by MRI as a 3 x 3 cm low T1 signal, moderately high T2 signal lesion that demonstrated peripheral enhancement relative to adjacent hepatic parenchyma on delayed images (Figure 1). On the basis of these findings, the hepatic lesion was thought likely to be a hypervascular metastasis. To assess whether the supra- renal mass was a functioning adrenal tumor, plasma and urine metanephrines were measured and 24h urine was tested for cortisol and 17-ketosteroids. The results of these tests were within normal limits. Granulocyte colony-stimulating factor (G-CSF) overexpression by the suprarenal tumor was explored by measurement of serum G-CSF, which was found to be markedly increased at 688.2 pg/ml (upper limit of normal 39.1 pg/ml), indicating paraneoplastic leukocytosis.
An en bloc resection of the left kidney, large supra- renal mass, and spleen was performed by a urologic surgeon 2 months after initial presentation, with no noted complications. A band of fibrous tissue separating the kidney from the suprarenal mass was noted. The mass was abutting the spleen, but did not invade it. Surgical margins were considered to be negative by a pathologist. Histopathologic examina- tion revealed the tumor was composed of large nests and aggregates of rhabdoid-like tumor cells without glandular or squamous differentiation (Figure 2a,b). Abundant tumor necrosis was present. Clear cell fea- tures, typical of conventional renal cell carcinoma, were absent. No direct contiguity of the tumor with the adjacent kidney was demonstrated histologically. A few islands of entrapped adrenal gland tissue were present in a single tissue section of the submitted tumor. Immunohistochemical staining of the tumor cells for CD10 was positive (Figure 2c). Pancytokeratin staining had a globular, perinuclear pattern in many tumor cells (Figure 2d), and there was diffuse cytoplasmic staining for vimentin in most of the tumor cells. Strong reactiv- ity was also seen with immunohistochemical staining for G-CSF (Figure 2e). Immunohistochemical stain- ing for epithelial membrane antigen, chromogranin, synaptophysin, calretinin, inhibin, renal cell carci- noma antigen, cytokeratins 5/6 and 7, MART-1, CD30, CD45, and CD138 was either negative or nonspecific. Electron microscopy showed rhabdoid tumor cells with focal cytoplasmic collections of intermediate filaments and occasional perinuclear tonofilament bundles (Figure 2f), a feature probably related to the globular staining identified for pancytokeratin and often associated with rhabdoid tumors. However, sub- sequent immunostaining for SMARCB1 (SWI/SNF- related matrix-associated actin-dependent regulator of chromatin subfamily B member 1) was strongly posi- tive in a nuclear pattern, indicating that the mass was not a primary rhabdoid tumor. In the context of the above results, the tumor was most likely to be an adrenal
carcinoma with secondary rhabdoid-like differentiation; secondary rhabdoid-like cells have the histopathologic and ultrastructural features of primary rhabdoid tumor cells but lack the SMARCB1 mutational deletion.
Immediately before resection of the tumor, the patient’s white blood cell count had reached 163 x 109/1. At hos- pital discharge 5 days after complete surgical resection of the tumor, the patient’s white blood cell count had decreased to 15 × 109/1 and his plasma G-CSF level had returned to normal (Figure 3).
Mitotane chemotherapy was begun 3 months after surgery, taken orally at a dose of 500 mg daily, increas- ing to 1 g daily after 7 days. The patient was also started on prednisone 5 mg daily to keep his mitotane level at 14-25 µg/ml. The hematology-oncology consultancy team planned to add either streptozocin or a combina- tion of etoposide, doxorubicin and cisplatin to the chemotherapy regimen once hepatic metastasis was confirmed by biopsy. MRI of the abdomen 2 months after surgery showed no change in the size of the liver lesion. A liver biopsy was planned, but could not be performed owing to the patient’s rising white blood cell count and associated morbidity. Unfortunately, the patient tolerated mitotane poorly, suffering from nausea, vomiting and malaise (grade I-II) that started within weeks of initiation of chemotherapy, and was initially controlled with metoclopramide 10 mg three times a day and omeprazole 20 mg daily. In addition, the tumor displayed a poor response to treatment, as noted by a rapid rise in peripheral white blood cell count (Figure 3). The patient’s mitotane dose was increased to 2 g daily 4.5 months after surgery, and further increased to 2.5 g daily 3 weeks later, in response to his rising white blood cell count. At this dose, the patient experienced severe nausea (grade III) and was hospitalized as a result. Repeat MRI of the abdomen, performed 5 months after surgery, confirmed tumor recurrence and identified a further mass in the left hemiabdomen abutting the left psoas muscle that demonstrated partial enhancement. The hypervascular
a
b
C
d
e
f
n
liver mass was also noted to be ill-defined and enlarg- ing. The patient’s white blood cell count reached a maximum value of 181 × 109/1 6 months after surgery. The patient’s condition continued to deteriorate owing to adverse effects from the mitotane treatment,
and 6 months after surgery he demonstrated severe nausea and vomiting (grade II-III), constitutional symptoms and clinical decompensation. The patient chose to initiate hospice care 7 months after the initial surgery, and died 1 month later.
CASE STUDY
Discussion of diagnosis
G-CSF is a 19 kDa polypeptide that induces the prolifera- tion and maturation of neutrophils. Few case reports have associated solid tumors with ectopic production of G-CSF, resulting in paraneoplastic leukocytosis. Most G-CSF-secreting tumors are urological malig- nancies, such as renal cell carcinoma,1-3 but tumors involving the thyroid, lung, mesothelium, stomach and gallbladder have also been reported.3-10 G-CSF over- production and its effect on tumor progression have not been well characterized. Some authors have postu- lated that paraneoplastic G-CSF production portends a poor prognosis due to the role of G-CSF as an autocrine growth stimulator, leading to aggressive tumor growth and proliferation.11
We present the case of a 57-year-old man with marked leukocytosis caused by a G-CSF-secreting retroperito- neal suprarenal tumor with rhabdoid-like differ- entiation. The tumor was established as the source of leukocytosis by the return of the serum G-CSF level and white blood cell counts to normal following resection of the primary tumor, and the immunohistochemical detection of G-CSF expression in tumor tissue. A rapidly rising, extremely high white blood cell count heralded tumor recurrence, thus making serum white cell count and G-CSF level markers for recurrent disease in this patient.
The site of origin of the tumor could not be deter- mined with complete confidence. Grossly, it seemed to have replaced the adrenal gland and was distinctly separated from the adjacent kidney by a fibrous capsule, suggesting adrenal origin. The tumor also lacked clear cell features which typify the most common form of renal cell carcinoma. However, its immunophenotype, including coexpression of cytokeratins, vimentin, and CD10, is more typical of carcinoma of renal origin rather than adrenal origin. In addition, G-CSF-secreting tumors reported in the literature are most often of urothelial or renal cell origin. These findings, and the inability to define the precise tissue of origin, made diagnosis difficult.
The initial evaluation of this patient suggested a retro- peritoneal rhabdoid tumor. Case reports of rhabdoid tumors in adults have previously been described, 12-15 but evidence of rhabdoid tumors of adrenal origin is limited.16,17 At the molecular level, the common link between rhabdoid tumors of the kidney, brain, and soft tissues is mutation or deletion of the tumor suppressor gene SMARCB1 (INI1), which is criti- cal to rhabdoid tumor formation. Both alleles of the SMARCB1 gene are inactivated in >85% of rhab- doid tumors.18 Immunohistochemical staining of the resected tumor for SMARCB1 proved important, as positive nuclear staining excluded primary rhabdoid tumor, despite histopathologic and ultrastructural evidence of rhabdoid differentiation. Thus, the tumor most likely represented an adrenal carcinoma with rhabdoid-like differentiation.
250
Day 7
Day 58
G-CSF:
G-CSF:
688.2 pg/ml
23.1 pg/ml
200
Day 56
White blood cell concentration
Tumor
excision
150
100
50
0
0
25
50
75
100
125
150
175
200
225
250
275
300
Time since admission (days)
Treatment and management
Currently, no proven standard of treatment exists for rhabdoid tumors, although various combinations of standard chemotherapy drugs have been reported. The combination of vincristine, cyclophosphamide, and doxorubicin alternating with cisplatin and etoposide has been used to treat a rhabdoid tumor of the adrenal gland in a pediatric patient, who received only one cycle before succumbing to disease.16 One patient with advanced- stage rhabdoid tumor of the ovary received adjuvant ifosfamide, epirubicin and cisplatin, with an apparent complete response after two cycles. She received two further cycles before experiencing lymph node recur- rence; further treatment with ifosfamide and cisplatin for three cycles resulted in stable disease 18 months after surgery.19 The role of increased levels of vascular endothelial growth factor (VEGF) and increased angio- genesis in adrenal tumors has been explored;20 the VEGF inhibitor bevacizumab has been used in at least one case of rhabdoid tumor, in a man with extrarenal rhabdoid tumor of the pelvis and retroperitoneum who failed systemic chemotherapy with ifosfamide, liposomal doxorubicin, paclitaxel and cisplatin. The patient then received two treatments of bevacizumab before suc- cumbing to total organ failure.21 In addition, targeting cell-cycle effectors downstream of SMARCB1, such as cyclin D1, may provide a novel treatment for this rare and incurable disease.18 The use of histone deacetylase inhibitors to induce expression of the cell cycle inhibitor CDKN1C (a downstream target of SMARCB1; deleted in rhabdoid tumors) is also being explored.22
As a result of the diagnostic difficulties in the present patient, the decision was made to apply standard-of-care treatment for adrenocortical carcinoma. Specifically, en bloc surgical resection was performed, and followed 3 months later by mitotane with plans to include combina- tion chemotherapy in the adjuvant setting. Consideration was given to administering mitotane with streptozocin,
CASE STUDY
depending on whether liver biopsy confirmed the lesion as metastatic; patients with demonstrated metastases had poorer prognosis in a phase II trial.23 The combina- tion of doxorubicin, etoposide and vincristine with daily mitotane was considered, although significant adverse effects of this regimen have been reported.24 However, after taking mitotane for over 3 months the patient was unable to tolerate further chemotherapy. His poor ability to tolerate single-agent therapy meant that he was not a suitable candidate for more-aggressive therapy. Further avenues were not explored at the patient’s request.
Mitotane, a synthetic derivative of the insecticide dichlorodiphenyltrichloroethane (DDT), is the only drug approved by the FDA for treatment of adrenocortical carcinoma.25,26 The efficacy and administration of mito- tane in the treatment of this disease is controversial, in part due to the rarity of adrenocortical carcinoma and the lack of randomized controlled trials. Mitotane is selective for normal adrenocortical cells, as well as those secret- ing excess cortisol, via a mechanism of mitochondrial hydroxylation involving the P-450 enzymes.27 Because of the poor capability of human adrenal cells to metabolize this drug to its active form, clinical responses have been poor, with tumor responses as low as 23%.27 Mitotane might not be a cytotoxic drug, and is unable to kill resid- ual cells after surgery. Rather, its role might be in delaying cell proliferation and time to recurrence and progression of disease.25 In addition, owing to significant drug-related toxicity, drug doses are usually reduced during the course
of treatment, which requires determination of serum mitotane concentrations to assess bioavailability.26,27
A retrospective analysis of 177 German and Italian patients demonstrated that adjuvant mitotane prolonged recurrence-free survival by as much as 32 months, with dose reduction necessary in only 13% of patients.26 This study, however, is limited by its retrospective nature and possible selection bias. Generally, the consensus is that this drug should be started immediately after surgery and that caution should be taken to avoid gastrointestinal and neurologic toxicities associated with high doses.26,28-32 Adjuvant radiation therapy has also been explored in this setting, with decreased local recurrence at 5 years, but no difference in disease-free or overall survival.33
Conclusions
Herein, we present a case of a patient with an adrenal carcinoma with rhabdoid-like differentiation and with high circulating serum levels of G-CSF that resulted in a paraneoplastic leukocytosis. This case presented several diagnostic and treatment challenges, and illustrates the difficulty in diagnosing and treating rare tumors, even in the setting of expert evaluation and diagnostic resources. These unusual malignancies present chal- lenges to pathologists, surgeons and oncologists alike. Compounding the morbidity of the reported patient was the aberrant ectopic production of G-CSF, which portends a poor prognosis in what was already a rare, aggressive, and difficult-to-treat malignancy.
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Acknowledgments
The authors gratefully acknowledge and thank Dr Diana McNeill, the Departments of Medicine and Pathology, and the Internal Medicine Residency Program, Duke University Medical Center, Durham, NC for their kind support in the evaluation and publication of this case.