ENDOCRINE SOCIETY
OXFORD
Severe Cholestatic Jaundice (Stauffer Syndrome) as a Rare Paraneoplastic Manifestation in Adrenocortical Carcinoma
Natia Murvelashvili,1.0 Patricio M Polanco,2 Sarah M. Khorsand,3 Jorge A. Marrero,4 Liwei Jia,5 Sasan Mirfakhraee, 1.0D Tobias Else, 6,[D Mouhammed Amir Habra,7 Suzanne Cole,8 and Oksana Hamidi1.DD
1Division of Endocrinology and Metabolism, UT Southwestern Medical Center, Dallas, Texas 75390, USA
2Division of Surgical Oncology, UT Southwestern Medical Center, Dallas, Texas 75390, USA
3Department of Anesthesiology and Pain Management, UT Southwestern Medical Center, Dallas, Texas 75390, USA
4Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA 5Department of Pathology, UT Southwestern Medical Center, Dallas, Texas 75390, USA
6Division Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan 48109, USA
“Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 8Division of Hematology and Oncology, UT Southwestern Medical Center, Dallas, Texas 75390, USA
Correspondence: Oksana Hamidi, DO, Division of Endocrinology and Metabolism, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA. Email: Oksana.Hamidi@UTSouthwestern.edu.
Abstract
Background: Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. While ACC can be associated with adrenal hormone excess syndromes, classic paraneoplastic syndromes are rarely seen. Stauffer syndrome, a paraneoplastic phenomenon characterized by reversible cholestasis in the absence of liver metastases, has been described with renal carcinoma and other malignancies but has not been previously reported in ACC.
Case Presentation: A 38-year-old man presented with emesis, painless jaundice, pruritus, and weight loss. Laboratory evaluation demonstrated elevated total bilirubin of 8.7 mg/dL (N < 1.3 mg/dL). Computed tomography revealed a 20.4-cm left adrenal mass without evidence of liver me- tastases. The patient’s condition deteriorated rapidly with progressive renal failure and worsening hyperbilirubinemia. The patient underwent left adrenalectomy, nephrectomy, ureterolysis, and wedge liver biopsy. Histopathology showed necrotic ACC with tumor invasion into the adrenal capsule, no lymphovascular invasion, uninvolved margins, and Ki-67 of 40%. Kidney parenchyma exhibited diffuse pigment casts. The liver spe- cimen contained diffuse bile deposits and minimal chronic inflammation in the portal tracts. He tested positive for the pathogenic variant of folliculin (FLCN) gene consistent with Birt-Hogg-Dube syndrome. Renal function recovered after surgery, and bilirubin level normalized after sev- eral weeks. Based on clinical presentation and absence of other etiologies, reversible cholestatic jaundice was attributed to Stauffer syndrome.
Conclusion: This is the first report of a unique presentation of paraneoplastic-related hyperbilirubinemia in the setting of ACC. While extremely rare, Stauffer syndrome should still be considered in differential diagnosis in patients with ACC with liver dysfunction and jaundice without evi- dence of liver metastases.
Keywords: adrenocortical carcinoma, Stauffer syndrome, jaundice, cholestasis, IL-6, liver failure, hyperbilirubinemia, paraneoplastic syndrome Abbreviations: ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; ALP, alkaline phosphatase; CT, computed tomography; DHEA-SO4, dehydroepiandrosterone sulfate; IL-6, interleukin-6; LFT, liver function test; RCC, renal cell carcinoma.
Adrenocortical carcinoma (ACC) is a rare and aggressive tumor arising from the adrenal cortex with an estimated an- nual incidence of 0.7 to 2 per million [1]. Women are more commonly affected than men [2]. ACC has bimodal age dis- tribution, with the first peak in childhood and a second peak in the fourth and fifth decade [2].
About 50% to 60% of patients with ACC have clin- ical manifestations of adrenal hormone excess [3, 4]. Hypercortisolism (Cushing syndrome) is the most common presentation in functional ACC. Other commonly produced hormones in patients with ACC are adrenal androgens result- ing in hirsutism and virilization in women. Hyperestrogenism with subsequent gynecomastia and testicular atrophy in men
and hyperaldosteronism leading to hypertension and hypokal- emia are very rare. Patients with nonfunctional tumors usu- ally present with nonspecific symptoms related to abdominal tumor mass effect. ACC can also be discovered incidentally on cross-sectional imaging performed for another reason, with 2% of adrenal incidentalomas being found to harbor ACC [5]. Approximately 25% to 30% of cases present with metastases at the time of initial diagnosis, most commonly spreading to lung, liver and bone [6-8]. Diagnosis is usually made by hormonal workup, abdominal cross-sectional im- aging, such as computed tomography (CT), magnetic reson- ance imaging), and 18F-fluorodeoxyglucose positron emission tomography, and histopathology. Complete surgical resection
with or without adjuvant therapies is the most important intervention in treating nonmetastatic ACC. The goal of treat- ment for patients with nonresectable disease is palliative ra- ther than curative.
Paraneoplastic syndrome in the setting of malignancy is characterized by a combination of clinical symptoms and signs caused by the remote effects of cancer, rather than by the direct invasion, compression of the tumor, or metastasis [9]. Paraneoplastic syndromes can manifest as neuropathy, polycythemia, thrombosis, malignant hypercalcemia, anemia, and liver dysfunction [10]. ACC-associated paraneoplastic syndromes are uncommon. Tumor-associated hypogly- cemia due to paraneoplastic secretion of insulin-like growth factor-2 (Anderson syndrome) [11, 12], hyperreninemic hyperaldosteronism [13], erythropoietin-associated polycy- themia, and leukocytosis due to chemokine release from the tumor [14] have been previously reported.
Stauffer syndrome is a paraneoplastic syndrome com- monly described in the setting of renal cell carcinoma (RCC), with the incidence ranging between 3 and 6% in patients with RCC [15, 16]. Stauffer syndrome was first described in 1961 by Herbert Stauffer as RCC, hypoalbuminemia, hypergammaglobulinemia, elevated alkaline phosphatase (ALP), and prolonged prothrombin time with normaliza- tion of liver function tests (LFTs) after tumor resection [17]. Stauffer syndrome is associated with poor prognosis [15, 16].
Although Stauffer syndrome is one of the most charac- teristic paraneoplastic syndromes associated with RCC, paraneoplastic hepatic dysfunction associated with ACC has not been previously reported. We describe a case of Stauffer syndrome in a patient with ACC presenting with severe cholestatic jaundice and liver dysfunction, with complete resolution of the clinical manifestations after surgical resec- tion of the tumor.
Case Presentation
A 38-year-old man with no significant medical history pre- sented to the hospital with nausea, vomiting, and painless jaundice associated with pruritus and a 100-pound (45-kg) unintentional weight loss. Laboratory workup showed ab- normal LFTs consistent with a cholestatic pattern (Table 1). Complete blood count, kidney function tests, coagulation tests, electrolytes, and thyroid function tests were normal. Workup for hepatitis was negative.
He underwent imaging, including CT of the abdomen and pelvis, which revealed a large, heterogeneous mass centered within the left adrenal region measuring 20.4 x 16.3 x 15.1 cm
| Analysis | Result | Reference range |
|---|---|---|
| Aspartate transaminase, U/L | 85 | 0-33 |
| Alanine transaminase, U/L | 79 | 10-49 |
| Alkaline phosphatase, U/L | 294 | 46-116 |
| Total bilirubin, mg/dL | 8.7 | 0.3-1.2 |
| Direct bilirubin, mg/dL | 7.0 | 0.0-0.3 |
| Indirect bilirubin, mg/dL | 1.7 | 0.2-1.0 |
with central necrosis concerning for ACC without evident liver metastases or intrahepatic or extrahepatic biliary ductal dilatation (Fig. 1). In addition, CT of the chest revealed a few subcentimeter bilateral pulmonary lesions concerning for lung metastases, and few perivascular nonspecific cystic spaces in lower lobes that can be seen in Birt-Hogg-Dube syndrome.
Biochemical workup for the adrenal mass showed elevated dehydroepiandrosterone sulfate (DHEA-SO4) of 1764.2 µg/ dL (reference range, 34.5-568.9 µg/dL) and elevated estra- diol of 123 pg/mL (reference range, < 41 pg/mL) (Table 2). Although low testosterone level can be seen in acute illness, the patient had features of hypogonadism, such as gyneco- mastia and low libido. The patient underwent a liver biopsy, which showed chronic cholestasis with bile duct prolifer- ation, bile duct injury, canalicular bile plugs, and minimal centrilobular pericellular fibrosis on the trichrome stain con- cerning for primary sclerosis cholangitis or secondary chol- angitis process.
The patient’s condition deteriorated rapidly, and he devel- oped coagulopathy, altered mental status, progressive renal failure, hypoalbuminemia, hypergammaglobulinemia, and worsening cholestasis. Total bilirubin increased from 8.7 to 34.5 mg/dL (reference range, 0.2-1.3 mg/dL). He was started on continuous renal replacement therapy to optimize his renal function. Notably, his mental status and coagulopathy improved markedly with continuous renal replacement therapy. Hyperbilirubinemia was thought to be secondary to a paraneoplastic phenomenon from underlying presumed ACC and exposure to DHEA-SO4 causing downregulation of canicular biliary transport. He subsequently underwent exploratory laparotomy, en bloc left adrenalectomy with left nephrectomy, left ureterolysis, gastrojejunostomy tube placement, and wedge liver biopsy (Fig. 2A and 2B depict images of the resected specimen). Pathology confirmed a 20- cm mass consistent with necrotic ACC with tumor invasion into or through the adrenal capsule, no lymphovascular in- vasion identified, uninvolved margins, Ki-67 of 40%, and inhibin immunoreactivity. Kidney parenchyma showed dif- fuse pigment casts but no tumor invasion. A liver wedge resection demonstrated diffuse cholestasis with minimal chronic inflammation in the portal tracts and no evidence of metastasis (Fig. 3). Targeted DNA next-generation sequencing of the resected ACC Tempus xT assay con- sisting of 648 genes revealed FLCN c.1285dup, IDH2 c.5332C > T, PRKAR1A c.1074del, PDGFRB c.3282C > A, and concurrent transcriptomic analysis demonstrated vas- cular endothelial growth factor A overexpression. No al- terations of TP53, CTNNB1, MLH1, MSH2, MSH6, or PMS2 genes were detected. Microsatellite instability status was stable.
Postoperatively, hyperbilirubinemia resolved, and renal func- tion recovered (Fig. 4). Given resolution of the patient’s signs and symptoms after surgery and no evidence of recognizable hepatocellular or cholestatic conditions, reversible cholestasis was attributed to a paraneoplastic manifestation of ACC.
The patient underwent genetic testing and was found to have a FLCN gene pathogenic variant, consistent with Birt- Hogg-Dube syndrome, a rare, hereditary autosomal dom- inant disorder associated with cutaneous fibrofolliculomas, lung cysts, recurrent spontaneous pneumothoraces, and an increased risk of kidney cysts, benign tumors, and kidney cancer.
R
R
A
B
| Hormonal profile | Result | Reference range |
|---|---|---|
| Serum DHEA-SO4, µg/dL | 1764.2 | 34.5-568.9 |
| Plasma ACTH, pg/mL | 18 | 7-63 |
| Basal serum cortisol 8 am, mcg/dL | 18.30 | 4.80-19.50 |
| Serum androstenedione, ng/dL | 247 | 40-150 |
| Serum estradiol, pg/mL | 123 | < 41 |
| Serum testosterone, ng/dL | 237 | 240-871 |
| Plasma aldosterone concentration, ng/dL | 11 | ≤ 21 |
| PRA, ng/ml/h | 12 | 0.6-4.3 |
Abbreviations: ACTH, adrenocorticotropin; DHEA-SO 4, dehydroepiandrosterone sulfate; PRA, plasma renin activity.
Discussion
We describe the first reported case of Stauffer syndrome in a patient with ACC presenting with severe cholestatic jaun- dice and subsequent normalization of LFTs following surgical resection of the tumor. Clinical presentation and laboratory and radiographic evaluation were consistent with Stauffer syndrome, a reversible cholestasis in the absence of tumor in- vasion or compression, or liver metastases [16, 17]. Stauffer syndrome is characterized by elevated ALP, erythrocyte sedi- mentation rate, a-2-globulin, and y-glutamyl transferase; thrombocytosis; prolongation of prothrombin time; low al- bumin; and hepatosplenomegaly in the absence of liver me- tastasis. It has been classically associated with large RCC [18, 19], although it has also been reported in patients with ma- lignant lymphoproliferative diseases [20], pancreatic cancer [21], and prostate cancer [22-24]. Jaundice can be caused by several hepatocellular conditions such as neoplasms, meta- bolic or hereditary disorders, systemic disorders, infections, toxins, and immunologic causes, which should be excluded in patients with cholestatic jaundice [25]. Estrogen-induced cholestasis is common among the cholestasis syndromes. Still, the degree of hyperbilirubinemia with only modest elevation of estradiol level in our patient was discordant and unlikely to be the etiology.
The pathophysiology of Stauffer syndrome is not fully understood. Prior reports suggest that in the setting of RCC, Stauffer syndrome can result from inhibition of suramin by the neoplastic cells. Suramin inhibits the binding of growth
factors (eg, epidermal growth factor, platelet-derived growth factor, tumor growth factor-ß) to their receptors and thus counters the ability of these factors to stimulate growth of tumor cells in vitro [26]. In addition, interleukin-6 (IL-6), a multifunctional cytokine produced by various lymphoid and nonlymphoid cells, is reported to be secreted by RCC cell lines and has been implicated as a possible pathogenic factor in RCC with Stauffer syndrome [27]. Elevations of serum IL-6 are associated with paraneoplastic manifestations frequently seen in patients with RCC, including anemia, thrombocytosis, decreased albumin, and elevated ALP [27]. The IL-6/Janus- activated kinase 1 (JAK1) pathway promotes cancer immune evasion through phosphorylation of programmed cell death ligand 1 (PD-L1) (Tyr 112) [28]. Treatment with anti-IL-6 monoclonal antibody leads to improvement in most biochem- ical abnormalities in these patients [28].
The molecular pathogenesis of ACCs is poorly understood. Most cases are sporadic but can rarely be associated with her- editary syndromes. Our patient had a genetic test revealing a heterozygous, germline pathogenic variant in the FLCN gene at c.1285dup (p.His429Profs*27). He was diagnosed with Birt-Hogg-Dube syndrome, a rare, autosomal domin- ant inherited disorder [29]. Individuals with Birt-Hogg-Dube syndrome have an increased risk for various cutaneous lesions, pulmonary cysts, spontaneous pneumothorax, and renal tu- mors. There is no known association between cholestatic jaundice or paraneoplastic liver dysfunction and Birt-Hogg- Dube syndrome. On resolution of jaundice, it was noted that the patient had pathognomonic cutaneous lesions described with Birt-Hogg-Dube syndrome. Kidney pathology was nega- tive for malignancy. However, CT of the chest demonstrated a few perivascular, elongated, perifissural, or duplicated cystic spaces in the lower lobes of the lungs. While ACC is not a classic finding, there are a few case reports of oncocytic ad- renal tumors in individuals with of Birt-Hogg-Dube syndrome [30, 31]. The severity and presence of symptoms can vary substantially among affected individuals, even within the same family.
Conclusion
Our case highlights a unique presentation of ACC with a re- versible cholestatic jaundice variant of Stauffer syndrome. To the best of our knowledge, Stauffer syndrome has not been previously reported in ACC, and it should be con- sidered as a cause of cholestatic jaundice in ACC as part of a paraneoplastic syndrome of rare pathogenesis.
A
B
A
B
300
AST (U/L)
Surgery
ALT (U/L)
250
Upper limit of normal level
200
150
100
50
0
0
2
4
6
8
10
12
14
16
Weeks after initial presentation
Author Contributions
All authors made substantial contributions through drafting of the manuscript or revisions, and all authors read and ap- proved the final manuscript.
40
Total bilirubin (mg/dL)
Upper limit of normal level
35
30
25
Surgery
20
15
10
5
0
0
2
4
6
8
10
12
14
16
Weeks after initial presentation
Disclosures
O.H. reports research collaboration with Mayo Clinic and advisory board participation with Corcept Therapeutics, Novo Nordisk, and Recordati Rare Diseases, Inc, outside
the submitted work. The remaining authors have nothing to disclose.
Data Availability
Not applicable.
References
1. Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical car- cinoma. J Clin Endocrinol Metab. 2013;98(12):4551-4564. doi:10.1210/jc.2013-3020
2. Wajchenberg BL, Albergaria Pereira MA, Medonca BB, et al. Adrenocortical carcinoma: clinical and laboratory observa- tions. Cancer. 2000;88(4):711-736. doi:10.1002/(SICI)1097- 0142(20000215)88:4<711:AID-CNCR1>3.0.CO;2-W
3. Berruti A, Fassnacht M, Haak H, et al. Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer. Eur Urol. 2014;65(4):832-838.doi:10.1016/j. eururo.2013.11.006
4. Fassnacht M, Allolio B. Clinical management of adrenocortical car- cinoma. Best Pract Res Clin Endocrinol Metab. 2009;23(2):273- 289. doi:10.1016/j.beem.2008.10.008
5. Ebbehoj A, Li D, Kaur RJ, et al. Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population-based cohort study. Lancet Diabetes Endocrinol. 2020;8(11):894-902. doi:10.1016/ S2213-8587(20)30314-4
6. Abiven G, Coste J, Groussin L, et al. Clinical and biological fea- tures in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab. 2006;91(7):2650-2655. doi:10.1210/ jc.2005-2730
7. Luton JP, Cerdas S, Billaud L, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane ther- apy. N Engl J Med. 1990;322(17):1195-1201. doi:10.1056/ NEJM199004263221705
8. Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evalu- ation and treatment. J Urol. 2003;169(1):5-11. doi:10.1097/01. ju.0000030148.59051.35
9. Hong MK, Kong J, Namdarian B, et al. Paraneoplastic syndromes in prostate cancer. Nat Rev Urol. 2010;7(12):681-692. doi:10.1038/ nrurol.2010.186
10. Gold PJ, Fefer A, Thompson JA. Paraneoplastic manifestations of renal cell carcinoma. Semin Urol Oncol 1996;14(4):216-222.
11. Ishikura K, Takamura T, Takeshita Y, et al. Cushing’s syndrome and big IGF-II associated hypoglycaemia in a patient with adrenocortical carcinoma. BMJ Case Rep. 2010;2010:bcr0720092100. doi:10.1136/bcr.07.2009.2100
12. Kim SW, Lee SE, Oh YL, Kim S, Park SH, Kim JH. Nonislet cell tumor hypoglycemia in a patient with adrenal cortical carcinoma. Case Rep Endocrinol 2016;2016:1-4. doi:10.1155/2016/5731417
13. Yamanaka K, Iitaka M, Inaba M, Morita T, Sasano H, Katayama S. A case of renin-producing adrenocortical cancer. Endocr J. 2000;47(2):119-125. doi:10.1507/endocrj.47.119
14. Schteingart DE, Giordano TJ, Benitez RS, et al. Overexpression of CXC chemokines by an adrenocortical carcinoma: a novel
clinical syndrome. J Clin Endocrinol Metab. 2001;86(8):3968- 3974. doi: 10.1210/jcem.86.8.7780
15. Boxer RJ, Waisman J, Lieber MM, Mampaso FM, Skinner DG. Non- metastatic hepatic dysfunction associated with renal carcinoma. J Urol. 1978;119(4):468-471. doi:10.1016/S0022-5347(17)57519-9
16. Sharma N, Darr U, Darr A, Sood G. Stauffer syndrome: a com- prehensive review of the icteric variant of the syndrome. Cureus. 2019;11(10):e6032. doi:10.7759/cureus.6032
17. Fontes-Sousa M, Magalhães H, Calais da Silva F, Maurício MJ. Stauffer’s syndrome: a comprehensive review and proposed updated diagnostic criteria. Urol Oncol. 2018;36(7):321-326. doi:10.1016/j.urolonc.2018.01.019
18. Song S, Hartnett D, Tan S, Hart J, Jeremiah J. The great imposter: a confusing case of a rare renal cell carcinoma. R I Med J (2013). 2020;103(10):35-37.
19. Tanous B, Alsaud A, Mahmoud KE, Yassin MA. A rare presenta- tion of Stauffer’s syndrome associated with renal cell carcinoma. Case Rep Oncol. 2020;13(2):742-746. doi:10.1159/000508039
20. Watterson J, Priest JR. Jaundice as a paraneoplastic phenomenon in a T-cell lymphoma. Gastroenterology. 1989;97(5):1319-1322. doi:10.1016/0016-5085(89)91706-x
21. Harris D, Saif MW. Stauffer’s syndrome in pancreatic cancer: first case report. Cureus. 2017;9(5):e1230. doi:10.7759/cureus.1230
22. Bhangoo MS, Cheng B, Botta GP, Thorson P, Kosty MP. Reversible intrahepatic cholestasis in metastatic prostate cancer: an un- common paraneoplastic syndrome. Mol Clin Oncol. 2018;8(4): 609-612. doi:10.3892/mco.2018.1564
23. Gökçen P, Gökçen K, Çakmak E, Gökçe G. Paraneoplastic hyperbilirubinemia in metastatic prostate cancer and review of the current literature. Turk J Urol. 2019;45(1):70-72. doi:10.5152/ tud.2018.52059
24. Romašovs A, Puķītis A, Mokricka V, Frolovaa E. Stauffer’s syn- drome in patient with metastatic prostate cancer. Case Rep Urol. 2019;2019:1-3. doi: 10.1155/2019/9745301
25. John S, Pratt DS. Jaundice. In: Jameson JL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. McGraw-Hill Education; 2018.
26. Chang SY, Yu DS, Sherwood ER, Kozlowski JM, Lee C. Inhibitory effects of suramin on a human renal cell carcinoma line, causing nephrogenic hepatic dysfunction. J Urol. 1992;147(4): 1147-1150. doi:10.1016/s0022-5347(17)37505-5
27. Walther MM, Johnson B, Culley D, et al. Serum interleukin-6 levels in metastatic renal cell carcinoma before treatment with inter- leukin-2 correlates with paraneoplastic syndromes but not patient survival. J Urol. 1998;159(3):718-722.
28. Chan LC, Li CW, Xia W, et al. IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion. J Clin Invest. 2019;129(8):3324-3338.
29. Daccord C, Good JM, Morren MA, Bonny O, Hohl D, Lazor R. Birt-Hogg-Dubé syndrome. Eur Respir Rev. 2020;29:200042. doi:10.1183/16000617.0042-2020
30. Raymond VM, Long JM, Everett JN, et al. An oncocytic ad- renal tumour in a patient with Birt-Hogg-Dubé syndrome. Clin Endocrinol (Oxf). 2014;80(6):925-927. doi:10.1111/cen.12292
31. Ramsingh J, Watson C. Oncocytoma of the adrenal gland in Birt-Hogg-Dube syndrome. BMJ Case Rep. 2018;2018:1-3. doi:10.1136/bcr-2018-224283