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Stauffer’s syndrome: A comprehensive review and proposed updated diagnostic criteria
Urologic Oncology: Seminars and Original Investigations 36 (2018) 321–326
Review article
Stauffer’s syndrome: A comprehensive review and proposed updated diagnostic criteria Mário Fontes-Sousa, M.D.a,b,*, Helena Magalhães, M.D.a,b, Fernando Calais da Silva, M.D.b, Maria Joaquina Maurício, M.D.a,b a
Department of Medical Oncology, Portuguese Oncology Institute of Porto, Porto, Portugal b Portuguese Genitourinary Group (GPGU), Lisbon, Portugal
Received 12 November 2017; received in revised form 7 December 2017; accepted 28 January 2018
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. r 2018 Elsevier Inc. All rights reserved.
Keywords: Stauffer’s syndrome; Paraneoplastic disorders; Cholestasis; Renal cell carcinoma; Immuno-Oncology; IL-6
1. 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].
* Corresponding author. Tel.: þ351-225-084-000; fax: þ351-225-084-001. E-mail address: [email protected] (M. FontesSousa).
https://doi.org/10.1016/j.urolonc.2018.01.019 1078-1439/r 2018 Elsevier Inc. All rights reserved.
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].
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Table 1 Paraneoplastic intrahepatic cholestasis: clinical and analytical features of “classic” Staufffer’s syndrome and the described “variant” Clinical/analytical parameters
Stauffer’s syndrome classic description
Stauffer’s syndrome (jaundice) variant description
Alkaline phosphatase High High γ-Glutamyl transferase High High Albumin Low Low Erythrocyte sedimentation ratea High High α-2-globulin High High Platelets High High; thrombocytopenia described in one case [35] Prolongation of prothrombin time Present Present Hepatosplenomegaly Present Absent/present Hyperbilirrubin Absent Present Jaundice Absent Absent/present Urinary hyperpigmentation Absent Present Pruritus Absent Present Resolution after ressection of primary tumor Yes Yes Other clinical and analytical features may be present, but do not necessarily contribute to the syndrome’s definition: fever; flank pain; malaise; anorexia, weight loss; hypertension; hematuria; anemia or erythrocytosis, leukocytosis, phosphorous-calcium disorders, hypocholesterolemia, among others. a
In association with erythrocyte sedimentation rate, high C-reactive protein has also been described.
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].
2. Methods We conducted a bibliographical search for indexed medical journals at PubMed/Medline databases with the terms “Stauffer” or “Stauffer’s syndrome,” “paraneoplastic,” or “nonmetastatic intrahepatic cholestasis” (not limited
to renal cell carcinoma or “hypernephroma”) and related search terms, until August 31, 2017. 3. Results PubMed/Medline databases retrieved a total over 100 results, and after excluding duplicate entries, 65 were considered of interest and are herein reviewed. 4. Discussion We estimate that more than 100 cases documenting Stauffer’s syndrome have been reported worldwide since 1961, among case series and case reports. There is no apparent sex predominance. It has been suggested that RCC patients diagnosed with Stauffer’s syndrome may have a worse prognosis [13], but the evidence level is low. To our knowledge, no particular association with RCC histological subtypes has been made. Not surprisingly, most cases are of clear cell histology (the commonest RCC subtype), but others have been reported—including papillary [14] or sarcomatoid [15]. Interestingly, most of the recorded cases had a rightsided primary renal tumor [16], hinting a potential anatomical proximity role, but left-sided cases have also been recorded [4,17–20], so such assumption cannot be made. It should also be noted that liver metastization should be excluded, as it is estimated that more than one-third of RCC stage IV patients have liver metastasis [13] and this in itself can be a cause for cholestasis and should not be mistaken with Stauffer’s syndrome. After the initial description of the syndrome [3], it has since been associated with other malignancies (Table 2), notably solid tumors located intra-abdominally or pelvis, such as prostate cancer and bladder transitional cell carcinoma, leiomyosarcoma or ovarian dysgerminoma;
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Table 2 Cases reviewed best matched Stauffer’s syndrome and variants, regardless of primary tumor Malignancies in adults associated to Stauffer’s syndrome
Notable clinical features or observations
References (first author, year of publication, Ref.)
Renal cell carcinoma (RCC)
Described as the first manifestation of the RCC [24]
Stauffer 1961 [3] Walsh, 1968 [13] Souadjian, 1971 [4] Girmann, 1975 [43] Jacobi, 1976 [24] Jakse 1978 [53] Gallo, 1978 [44] Delpre, 1979 [26] Bischoff, 1979 [45] Giannotti, 1982 [46] Gil, 1995 [50] Kochetova, 1995 [51] Muñoz Vélez, 1999 [23] Steffens, 2003 [52] Yong, 2008 [14] Kranidiotis, 2009 [54] Kamiyama, 2011 [15] Küronya, 2014 [27] Takai, 2015 [25] Dourakis 1997 [29] Sarf, 2003 [30] Giannakos, 2005 [16] Morla 2006 [31] Mazokopakis, 2007 [17] Tomadoni, 2010 [20] Woldie, 2012 [18] Fernández, 2012 [19] Jangouk, 2014 [32] Akbulut, 2014 [33] Puga, 2015 [34] Ates, 2015 [35] Reddy, 1977 [59] Morís de la Tassa, 1991 [60] Cole, 2000 [56] Karakolios, 2003 [28] Koruk, 2004 [55] Shah, 2006 [61] Nguyen, 2011 [11] Kuramoto, 2013 [58] Hinostroza-Yanahuaya, 2013 [36] Okano, 2014 [57] Kato, 2014 [62] Sharara 1992 [63] Fraisse, 2001 [64] Bardia 2007 [38] Bal, 2009 [65] Saintigny, 2003 [66] Moreno-Palacios, 2011 [67] Yeh, 2015 [68] Harris, 2017 [39]
Liver function tests as biomarkers under sunitinib treatment [27] Stauffer’s syndrome variant
Prostate cancer
Soft tissue sarcomas
Bronchial adenocarcinoma Bladder urotelial carcinoma Ovarian dysgerminoma Pancreatic cancer Hematological malignancies
Thrombocytopenia described [35] Second most frequent urological malignancy (after renal cell carcinoma) to be associated to paraneoplastic syndromes; improvement with systemic therapy [28,55–[57]; variant syndrome described [58]
A case actually describes an intraabdominal abscess mimicking Stauffer syndrome diagnosed in the context of uterine leiomyosarcoma [38]
Hepatic abnormalities only after primary tumor removal and beginning with adjuvant drug induced hepatitis? Most Hodgkin disease, but also T-cell lymphoma
followed by thoracic location, such as bronchial adenocarcinoma. The syndrome has also been described in association with hematological malignancies [21,22], especially Hodgkin disease.
Watterson, 1989 [21] Yalçin, 1999 [22]
Classically, the symptoms and analytical changes that characterize the syndrome (Table 1) normalize after complete surgical removal of the primary tumor, being reversibility one of its fundamental characteristics. Unchanged or
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Table 3 Proposed diagnostic criteria for a broader paraneoplastic intrahepatic cholestasis syndrome, that would include both the classic and variant Stauffer’s syndrome, and updated with features described since the original characterization Histologically proven diagnosis of malignancy, most notably renal cell carcinoma Mandatory liver dysfunction or cholestasis, including prolonged thrombin time; jaundice, pruritus, or urinary hyperpigmentation may be present No evidence or suspicion of liver metastasis or mass effect on liver or biliary ducts, such as direct tumor or nodal disease with hepatic invasion or compression Hepatosplenomegaly may be present The alterations are reversible in nature, to be expected to normalize in the weeks to months after treatment to primary tumora In the metastasized setting (excluding liver) the alterations may be reversible by systemic therapyb Other causes of intrahepatic cholestasis should be excluded. Liver biopsy may be necessary for accurate differential diagnosisc a Maintaining hepatic dysfunction features should prompt differential diagnosis or workup for occult disease. Also, these changes can be present at diagnosis (sometimes the first clinical feature), at persistence or recurrence of disease or at metastization (liver not included). b Monitorization of disease response by hepatic parameters fluctuations should not be regarded as standard, as they may not be reliable biomarkers and can be influenced by many factors. c There are no known liver pathological pathognomonic changes associated to the syndrome.
worsened liver function tests after the removal of the primary renal tumor has been reported [7,23] and is frequently associated to worse prognosis [24], as it could be related to persistence of disease or metastasis, for instance [24,25]. On the other hand, it was at some point hypothesized that the hepatic changes could be explained by clinically occult liver metastasis that would regress after surgery to the primary tumor, but there is no pertinent evidence that could support such claims [13]. From a practical standpoint, the liver dysfunction could imply a higher surgical bleeding risk but it should not be regarded as a formal contra-indication to surgery per se, especially with curative intent, and this problematic has been explored elsewhere [19,26]. Also, under systemic treatment in the non-hepatic metastatic setting normalization can be observed and has been suggested to correlate to disease control in both kidney and prostate cancer [27,28]. A variant syndrome was later described [16–20,29–35]. Although fulfilling the “classical” criteria (nonjaundice), the patients additionally presented with jaundice or pruritus (Table 1). This “variant” syndrome has not been known to have different etiology, therapeutic or prognostic outcomes, so one can find it to be clinically redundant. Of note, several published cases may not fulfill the general syndrome’s criteria [36–39], albeit being reported as such. Other depictions, associated for instance with benign kidney disease [40], infection [38], or even with no neoplasia diagnosis at all [41] have also been published. Naturally, Stauffer’s syndrome should not be confused with iatrogenic or drug induced cholestasis [39,41,42]. The treatment is based on disease control (removal of primary tumor or systemic oncological treatment) otherwise it is essentially symptomatic. Therefore, considering the knowledge accumulated since the original description over 50 years ago, we propose the use of a broader designation, such as paraneoplastic intrahepatic cholestasis, to integrate nonrenal cell cancer malignancies and Stauffer’s syndrome “variant” features thus broading the diagnostic spectrum and avoiding misclassifications, by using standardized and updated diagnostic criteria (Table 3).
Curiously, in recent years, immune check-point inhibitors have shown efficacy and have been approved for treatment in almost every tumor in which Stauffer’s syndrome has been associated with, such as RCC, bladder cancer, lung cancer, or even Hodgkin disease (notable exception of melanoma and head and neck cancers), which may correlate to the immune-mediated mechanisms that are thought to be involved with the syndrome’s pathophysiology, most likely beyond IL-6. One anecdotal case reports a complete response of lung metastasis after radical nephrectomy followed by interferon-alpha therapy in a patient with RCC with Stauffer’s syndrome [15], but so much remains to be understood between the interplay of immune-mediated paraneoplastic manifestations and immunotherapy. Worth to mention is that while reviewing the literature on this topic we observed how it heavily relies on case reports, many incomplete or published in non-English languages, making it particularly challenging to critically evaluate them [15,27,30,43–52].
5. Conclusions The differential diagnosis of intrahepatic cholestasis is broad, and includes primary liver disease (metabolism/alcohol or drug related, neoplasia, and infection) or systemic (infection and neoplasia) and warrants investigation procedures. Although described as rare, if one considers the largest series, Stauffer’s syndrome may be more common than usually realized. It has also been reported in some cases as the first and/or the most prominent systemic clinical manifestation of paraneoplastic disease, convincingly associated to several different types of tumors. In addition, a variant syndrome has been characterized, presenting with hyperbilirubinemia, jaundice or pruritus, as opposed to Stauffer’s original description, probably representing a wider range of liver dysfunction, although appearing to have a similar clinical course to that of the classical syndrome. We propose an updated set of criteria to simplify, broaden and standardize diagnosis, under the entity characterized by reversible paraneoplastic intrahepatic cholestasis.
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Clinicians should be aware of this syndrome, namely consider further investigation if a plausible cause is not found for unexplained intrahepatic cholestasis in an otherwise healthy patient or even consider investigation of metastatic disease after resection of a primary tumor with persistence or recurrence of the syndrome’s clinical and analytical features. Even today, much remains to be understood, especially considering the immune-mediated phenomena that seem to have a fundamental role in the syndrome’s etiopathogenesis.
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Acknowledegements To Gabriel Gonçalves Fagundes for proof-reading the article.
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Review article
Stauffer’s syndrome: A comprehensive review and proposed updated diagnostic criteria Mário Fontes-Sousa, M.D.a,b,*, Helena Magalhães, M.D.a,b, Fernando Calais da Silva, M.D.b, Maria Joaquina Maurício, M.D.a,b a
Department of Medical Oncology, Portuguese Oncology Institute of Porto, Porto, Portugal b Portuguese Genitourinary Group (GPGU), Lisbon, Portugal
Received 12 November 2017; received in revised form 7 December 2017; accepted 28 January 2018
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. r 2018 Elsevier Inc. All rights reserved.
Keywords: Stauffer’s syndrome; Paraneoplastic disorders; Cholestasis; Renal cell carcinoma; Immuno-Oncology; IL-6
1. 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].
* Corresponding author. Tel.: þ351-225-084-000; fax: þ351-225-084-001. E-mail address: [email protected] (M. FontesSousa).
https://doi.org/10.1016/j.urolonc.2018.01.019 1078-1439/r 2018 Elsevier Inc. All rights reserved.
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].
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Table 1 Paraneoplastic intrahepatic cholestasis: clinical and analytical features of “classic” Staufffer’s syndrome and the described “variant” Clinical/analytical parameters
Stauffer’s syndrome classic description
Stauffer’s syndrome (jaundice) variant description
Alkaline phosphatase High High γ-Glutamyl transferase High High Albumin Low Low Erythrocyte sedimentation ratea High High α-2-globulin High High Platelets High High; thrombocytopenia described in one case [35] Prolongation of prothrombin time Present Present Hepatosplenomegaly Present Absent/present Hyperbilirrubin Absent Present Jaundice Absent Absent/present Urinary hyperpigmentation Absent Present Pruritus Absent Present Resolution after ressection of primary tumor Yes Yes Other clinical and analytical features may be present, but do not necessarily contribute to the syndrome’s definition: fever; flank pain; malaise; anorexia, weight loss; hypertension; hematuria; anemia or erythrocytosis, leukocytosis, phosphorous-calcium disorders, hypocholesterolemia, among others. a
In association with erythrocyte sedimentation rate, high C-reactive protein has also been described.
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].
2. Methods We conducted a bibliographical search for indexed medical journals at PubMed/Medline databases with the terms “Stauffer” or “Stauffer’s syndrome,” “paraneoplastic,” or “nonmetastatic intrahepatic cholestasis” (not limited
to renal cell carcinoma or “hypernephroma”) and related search terms, until August 31, 2017. 3. Results PubMed/Medline databases retrieved a total over 100 results, and after excluding duplicate entries, 65 were considered of interest and are herein reviewed. 4. Discussion We estimate that more than 100 cases documenting Stauffer’s syndrome have been reported worldwide since 1961, among case series and case reports. There is no apparent sex predominance. It has been suggested that RCC patients diagnosed with Stauffer’s syndrome may have a worse prognosis [13], but the evidence level is low. To our knowledge, no particular association with RCC histological subtypes has been made. Not surprisingly, most cases are of clear cell histology (the commonest RCC subtype), but others have been reported—including papillary [14] or sarcomatoid [15]. Interestingly, most of the recorded cases had a rightsided primary renal tumor [16], hinting a potential anatomical proximity role, but left-sided cases have also been recorded [4,17–20], so such assumption cannot be made. It should also be noted that liver metastization should be excluded, as it is estimated that more than one-third of RCC stage IV patients have liver metastasis [13] and this in itself can be a cause for cholestasis and should not be mistaken with Stauffer’s syndrome. After the initial description of the syndrome [3], it has since been associated with other malignancies (Table 2), notably solid tumors located intra-abdominally or pelvis, such as prostate cancer and bladder transitional cell carcinoma, leiomyosarcoma or ovarian dysgerminoma;
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Table 2 Cases reviewed best matched Stauffer’s syndrome and variants, regardless of primary tumor Malignancies in adults associated to Stauffer’s syndrome
Notable clinical features or observations
References (first author, year of publication, Ref.)
Renal cell carcinoma (RCC)
Described as the first manifestation of the RCC [24]
Stauffer 1961 [3] Walsh, 1968 [13] Souadjian, 1971 [4] Girmann, 1975 [43] Jacobi, 1976 [24] Jakse 1978 [53] Gallo, 1978 [44] Delpre, 1979 [26] Bischoff, 1979 [45] Giannotti, 1982 [46] Gil, 1995 [50] Kochetova, 1995 [51] Muñoz Vélez, 1999 [23] Steffens, 2003 [52] Yong, 2008 [14] Kranidiotis, 2009 [54] Kamiyama, 2011 [15] Küronya, 2014 [27] Takai, 2015 [25] Dourakis 1997 [29] Sarf, 2003 [30] Giannakos, 2005 [16] Morla 2006 [31] Mazokopakis, 2007 [17] Tomadoni, 2010 [20] Woldie, 2012 [18] Fernández, 2012 [19] Jangouk, 2014 [32] Akbulut, 2014 [33] Puga, 2015 [34] Ates, 2015 [35] Reddy, 1977 [59] Morís de la Tassa, 1991 [60] Cole, 2000 [56] Karakolios, 2003 [28] Koruk, 2004 [55] Shah, 2006 [61] Nguyen, 2011 [11] Kuramoto, 2013 [58] Hinostroza-Yanahuaya, 2013 [36] Okano, 2014 [57] Kato, 2014 [62] Sharara 1992 [63] Fraisse, 2001 [64] Bardia 2007 [38] Bal, 2009 [65] Saintigny, 2003 [66] Moreno-Palacios, 2011 [67] Yeh, 2015 [68] Harris, 2017 [39]
Liver function tests as biomarkers under sunitinib treatment [27] Stauffer’s syndrome variant
Prostate cancer
Soft tissue sarcomas
Bronchial adenocarcinoma Bladder urotelial carcinoma Ovarian dysgerminoma Pancreatic cancer Hematological malignancies
Thrombocytopenia described [35] Second most frequent urological malignancy (after renal cell carcinoma) to be associated to paraneoplastic syndromes; improvement with systemic therapy [28,55–[57]; variant syndrome described [58]
A case actually describes an intraabdominal abscess mimicking Stauffer syndrome diagnosed in the context of uterine leiomyosarcoma [38]
Hepatic abnormalities only after primary tumor removal and beginning with adjuvant drug induced hepatitis? Most Hodgkin disease, but also T-cell lymphoma
followed by thoracic location, such as bronchial adenocarcinoma. The syndrome has also been described in association with hematological malignancies [21,22], especially Hodgkin disease.
Watterson, 1989 [21] Yalçin, 1999 [22]
Classically, the symptoms and analytical changes that characterize the syndrome (Table 1) normalize after complete surgical removal of the primary tumor, being reversibility one of its fundamental characteristics. Unchanged or
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Table 3 Proposed diagnostic criteria for a broader paraneoplastic intrahepatic cholestasis syndrome, that would include both the classic and variant Stauffer’s syndrome, and updated with features described since the original characterization Histologically proven diagnosis of malignancy, most notably renal cell carcinoma Mandatory liver dysfunction or cholestasis, including prolonged thrombin time; jaundice, pruritus, or urinary hyperpigmentation may be present No evidence or suspicion of liver metastasis or mass effect on liver or biliary ducts, such as direct tumor or nodal disease with hepatic invasion or compression Hepatosplenomegaly may be present The alterations are reversible in nature, to be expected to normalize in the weeks to months after treatment to primary tumora In the metastasized setting (excluding liver) the alterations may be reversible by systemic therapyb Other causes of intrahepatic cholestasis should be excluded. Liver biopsy may be necessary for accurate differential diagnosisc a Maintaining hepatic dysfunction features should prompt differential diagnosis or workup for occult disease. Also, these changes can be present at diagnosis (sometimes the first clinical feature), at persistence or recurrence of disease or at metastization (liver not included). b Monitorization of disease response by hepatic parameters fluctuations should not be regarded as standard, as they may not be reliable biomarkers and can be influenced by many factors. c There are no known liver pathological pathognomonic changes associated to the syndrome.
worsened liver function tests after the removal of the primary renal tumor has been reported [7,23] and is frequently associated to worse prognosis [24], as it could be related to persistence of disease or metastasis, for instance [24,25]. On the other hand, it was at some point hypothesized that the hepatic changes could be explained by clinically occult liver metastasis that would regress after surgery to the primary tumor, but there is no pertinent evidence that could support such claims [13]. From a practical standpoint, the liver dysfunction could imply a higher surgical bleeding risk but it should not be regarded as a formal contra-indication to surgery per se, especially with curative intent, and this problematic has been explored elsewhere [19,26]. Also, under systemic treatment in the non-hepatic metastatic setting normalization can be observed and has been suggested to correlate to disease control in both kidney and prostate cancer [27,28]. A variant syndrome was later described [16–20,29–35]. Although fulfilling the “classical” criteria (nonjaundice), the patients additionally presented with jaundice or pruritus (Table 1). This “variant” syndrome has not been known to have different etiology, therapeutic or prognostic outcomes, so one can find it to be clinically redundant. Of note, several published cases may not fulfill the general syndrome’s criteria [36–39], albeit being reported as such. Other depictions, associated for instance with benign kidney disease [40], infection [38], or even with no neoplasia diagnosis at all [41] have also been published. Naturally, Stauffer’s syndrome should not be confused with iatrogenic or drug induced cholestasis [39,41,42]. The treatment is based on disease control (removal of primary tumor or systemic oncological treatment) otherwise it is essentially symptomatic. Therefore, considering the knowledge accumulated since the original description over 50 years ago, we propose the use of a broader designation, such as paraneoplastic intrahepatic cholestasis, to integrate nonrenal cell cancer malignancies and Stauffer’s syndrome “variant” features thus broading the diagnostic spectrum and avoiding misclassifications, by using standardized and updated diagnostic criteria (Table 3).
Curiously, in recent years, immune check-point inhibitors have shown efficacy and have been approved for treatment in almost every tumor in which Stauffer’s syndrome has been associated with, such as RCC, bladder cancer, lung cancer, or even Hodgkin disease (notable exception of melanoma and head and neck cancers), which may correlate to the immune-mediated mechanisms that are thought to be involved with the syndrome’s pathophysiology, most likely beyond IL-6. One anecdotal case reports a complete response of lung metastasis after radical nephrectomy followed by interferon-alpha therapy in a patient with RCC with Stauffer’s syndrome [15], but so much remains to be understood between the interplay of immune-mediated paraneoplastic manifestations and immunotherapy. Worth to mention is that while reviewing the literature on this topic we observed how it heavily relies on case reports, many incomplete or published in non-English languages, making it particularly challenging to critically evaluate them [15,27,30,43–52].
5. Conclusions The differential diagnosis of intrahepatic cholestasis is broad, and includes primary liver disease (metabolism/alcohol or drug related, neoplasia, and infection) or systemic (infection and neoplasia) and warrants investigation procedures. Although described as rare, if one considers the largest series, Stauffer’s syndrome may be more common than usually realized. It has also been reported in some cases as the first and/or the most prominent systemic clinical manifestation of paraneoplastic disease, convincingly associated to several different types of tumors. In addition, a variant syndrome has been characterized, presenting with hyperbilirubinemia, jaundice or pruritus, as opposed to Stauffer’s original description, probably representing a wider range of liver dysfunction, although appearing to have a similar clinical course to that of the classical syndrome. We propose an updated set of criteria to simplify, broaden and standardize diagnosis, under the entity characterized by reversible paraneoplastic intrahepatic cholestasis.
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Clinicians should be aware of this syndrome, namely consider further investigation if a plausible cause is not found for unexplained intrahepatic cholestasis in an otherwise healthy patient or even consider investigation of metastatic disease after resection of a primary tumor with persistence or recurrence of the syndrome’s clinical and analytical features. Even today, much remains to be understood, especially considering the immune-mediated phenomena that seem to have a fundamental role in the syndrome’s etiopathogenesis.
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Acknowledegements To Gabriel Gonçalves Fagundes for proof-reading the article.
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