Stauffer’s syndrome: A comprehensive review and proposed updated diagnostic criteria

Abstract

Background

Stauffer’s syndrome corresponds to a set of clinical and analytical changes of paraneoplastic nature firstly recognized more than 50 years ago, in association to renal cell carcinoma. A definitive review including universal diagnostic criteria and updated knowledge since the original description is lacking.

Basic procedures

The authors conducted a comprehensive bibliographical review and propose updated diagnostic criteria to standardize diagnosis for clinical practice purposes and avoid misclassification.

Main findings

Although having been described in association with renal cell carcinoma, the syndrome has been reported in correlation with other malignancies—either solid or hematological tumors. Additionally, a variant syndrome presenting with jaundice has also been characterized, but appears to have a similar clinical course to that of the classical Stauffer’s syndrome. Although often described as rare, it may be more frequent than previously recognized. Stauffer’s syndrome etiopathogenesis is still poorly understood, but immune mechanisms seem to play a role underscored by the malignancies to which the syndrome is associated, several of which having immunotherapy drugs approved for their treatment.

Principal conclusions

A set of diagnostic criteria should be used to simplify, broaden and standardized diagnosis, under the entity characterized by reversible paraneoplastic intrahepatic cholestasis. Clinicians should be aware of the syndrome, namely consider further investigation if a plausible cause for unexplained intrahepatic cholestasis in an otherwise healthy patient is not found. Even though no universal approach is available, investigation should be considered regarding metastatic disease after resection of a primary tumor which has revealed persistence or recurrence of symptoms.

Introduction

Remarkably, up to 20% of patients with renal cell carcinoma (RCC) have manifestations of paraneoplastic syndromes [1]. For a paraneoplastic syndrome diagnosis it is mandatory the existence of a malignancy, but the symptoms must not be caused by any mass effect such as direct tumor invasion or compression, or even metastasis [2].

Stauffer’s syndrome bears its name after Herbert Maurice Stauffer, an American gastroenterologist, who first described [3], in 1961, the 5 original cases that had common clinical and analytical features: diagnosis of hypernephroma, nowadays RCC; (mandatory) absence of liver metastasis; hypoalbuminemia; hypergammaglobulinemia; high alkaline phosphatase; prolonged thrombin time; and reversibility of changes after the removal of the primary tumor [3], [4] (Table 1). Bromsulphalein dye retention was also described, but has no current clinical use. Curiously, decades before, a correlation between the so-called hypernephroma and nonmetastatic hepatic disease was cunningly suggested [5].

Although reported in the literature as rare, its incidence is, in fact, unknown. Some of the most credible estimates place it around 15% of case series [6]; one study in which 7/102 (6.9%) of patients with renal carcinoma diagnosis presented with nonmetastatic hepatic dysfunction [7] and in those with persistence of hepatic changes there was an association with worse prognosis. In a bigger series, 48/365 (13.2%) of patients with RCC presented with elevated alkaline phosphatase plus another paraneoplastic features (for example, thrombocytosis) [8]—that could constitute Stauffer’s syndrome, even though this formal exploration was not made. In these patients, the paraneoplastic manifestations were not statistically different among stages and again, in general, their presence implied a worse prognosis [8].

The pathophysiology of the syndrome is still poorly understood. It was observed an association between higher levels of inflammatory interleukin-6 (IL-6) and paraneoplastic manifestations in RCC, including cholestasis, although a causal role is less established [9], [10]. Similar findings were reported in prostate cancer cases with paraneoplastic hepatic dysfunction [6], [11].

Autopsy studies revealed structural alterations, such as hepatic sinusoidal dilatation in association RCC, particularly occurring focally in the mid-zone of hepatic lobules notably without findings related to congestion of the central vein, endothelial damage, or hepatocellular necrosis [12]. It was stressed that the observed changes did not correlate directly to analytical dysfunction [12].