DIAGNOSTIC DILEMMA Aimee K. Zaas, MD Thomas J. Marrie, MD, Section Editors
From Polyuria to Renal Mass: An Unexpected Link Frédéric Vandergheynst, MD,a Paraskevi Kazakou, MD, PhD,b Bruno Couturier, MD,a Nicolas Dumarey, MD,c Rose Ghanooni, MD,d Agnieszka Pozdzik, MD, PhD,e Sandrine Rorive, MD, PhD,f Daniel Van Gansbeke, MD,g Agnès Burniat, MD, PhDb a
Department of Internal Medicine, bDepartment of Endocrinology, cDepartment of Nuclear Medicine, dDepartment of Otorhinolaryngology, Department of Nephrology, fDepartment of Pathology, and gDepartment of Radiology, Erasme Hospital, Université Libre de Bruxelles, Belgium. e
PRESENTATION In February 2014, a 23-year-old woman presented to the Endocrinology Department with polydipsia and polyuria for 1 month. She also presented poor appetite but not loss of weight. In addition, she complained of predominant right retroorbital headaches in the context of a known chronic allergic rhinosinusitis. She had no visual complaints and her menstruation was regular. She took no medication on a regular basis. Her family history revealed type 2 diabetes in both parents and inflammatory polyarthritis in her father.
ASSESSMENT Physical examination of the patient was unremarkable except for obesity (body mass index 30.7 kg/m2) and small hyperpigmented macules on the back. No signs of Cushing’s syndrome such as buffalo neck, purple striae, or hypertension were evident. Nasal and sinus examination revealed chronic sinusitis. Initial blood analysis showed normal values of C-reactive protein, glycemia, electrolytes,
FV and PK have equally contributed to this work. Funding: None. Conflict of Interest: None. Authorship: FV, PK, and AB assessed and managed the patient. All authors had access to the data, contributed to the clinical diagnosis and to the redaction of the article. RG and DVG contributed to the clinical management of the patient. FV and PK contributed equally to this work. The patient’s written consent to publish was obtained. Requests for reprints should be addressed to Agnès Burniat, MD, PhD, Department of Endocrinology, Erasme Hospital, Université Libre de Bruxelles, Lennik Street 808, Brussels 1070, Belgium. E-mail address: [email protected]
0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.05.009
and renal function. A water deprivation test confirmed the suspected diagnosis of central diabetes insipidus, and treatment with intranasal desmopressin (10 mg twice a day) was started. Circulating levels of anterior pituitary hormones were normal. Magnetic resonance imaging of the pituitary showed a slightly enlarged gland (12.8 mm) with thickening of the pituitary stalk (3.9 mm) and loss of normal hyperintense T1-weighted signal of the posterior pituitary (Figure 1A and B). Chest radiograph was unremarkable. Cytological examination and tumor markers in serum and cerebrospinal fluid, including alpha fetoprotein and betahuman chorionic gonadotropin, were normal. Serum angiotensin-converting enzyme was not elevated, and antipituitary antibodies were negative. The tuberculin skin test and interferon-g release assay were also negative. Skin biopsy of the lesions on the back showed nonspecific chronic inflammatory changes with no argument for histiocytosis. Finally, [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) revealed hypermetabolism of the pituitary stalk, but also of the maxillary sinus, as well as a tumor-like lesion in the right kidney (Figure 2A). Renal contrast-enhanced ultrasonography (CEUS) confirmed the presence of the latter, measuring 2 cm in diameter. Given the association of sinusal and pituitary involvements, granulomatosis with polyangiitis was suspected. Antineutrophil cytoplasmic antibodies (ANCA) testing revealed elevated titers of anti-myeloperoxidase (anti-MPO) perinuclear ANCA (6.3 UI/mL, N < 3.5 UI/mL). However, histopathological examination of the maxillary sinus biopsy showed neither granulomatous inflammation nor vasculitis. Moreover, urinalysis and renal function were normal.
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Figure 1 Pituitary magnetic resonance imaging study. (A) Gadolinium-enhanced coronal T1-weighted image (March 2014). Slightly enlarged pituitary gland (12.8 mm; solid arrow) and thickened stalk (3.9 mm; dotted arrow). (B) Sagittal T1-weighted image (March 2014). Loss of the normal hyperintense signal of the posterior pituitary (solid arrow). (C) Gadolinium-enhanced coronal T1-weighted image (March 2015). Normalization of pituitary size (solid arrow) and stalk width (dotted arrow). (D) Sagittal T1-weighted image (March 2015). Persistent loss of the normal posterior lobe T1 hyperintensity (solid arrow).
At that time, renal mass was not easily accessible to safe percutaneous ultrasound-guided biopsy. Hence, close clinical and radiological follow-up was proposed.
DIAGNOSIS Six months later, the patient developed pain in the right flank and in the cervical and lumbar spine. Further blood testing demonstrated elevation of C-reactive protein (110 mg/L). Elevated titers of anti-MPO ANCA were confirmed. CEUS showed progression of the right renal mass, which had doubled in size (4.3 cm), and suspected new lesions in the left kidney. This was confirmed by 18 F-FDG PET/CT (Figure 2B). Despite progression of the renal lesions, urinary sediment and renal function remained normal. Fortunately, at this time point, the larger size of the right renal tumor allowed safe percutaneous biopsy. Histopathological examination of the biopsy specimen revealed severe necrotizing granulomatous tubulointerstitial nephritis and extracapillary glomerulonephritis, confirming the diagnosis of granulomatosis with polyangiitis (Figure 3).
Pituitary involvement is an uncommon complication of granulomatosis with polyangiitis, with about 30 patients reported in literature.1-3 When it occurs, central diabetes insipidus usually follows rather than precedes lung and kidney involvement. In a recent monocentric series on granulomatosis with polyangiitis-related pituitary diseases, the most frequent endocrine dysfunctions were secondary hypogonadism and diabetes insipidus. All patients had abnormal pituitary imaging.4 Granulomatous renal inflammatory pseudotumor is even more rare, with only 16 cases described. These pseudotumoral lesions have only exceptionally been identified by 18 F-FDG PET/CT5 and never by CEUS.
MANAGEMENT Considering the young age of the patient, in order to avoid cyclophosphamide-induced ovarian failure, treatment with rituximab (375 mg/m2 once weekly during 4 weeks) was initiated. Prednisolone was started in parallel and continued with progressive stepwise dose reduction.
Vandergheynst et al
From Polyuria to Renal Mass: An Unexpected Link
3
Figure 2 [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). (A) Hypermetabolic lesion in the right kidney (March 2014). (B) Expansion of the lesion in the right kidney and appearance of new lesions in the left kidney (September 2014).
Ultrasonographic controls performed 5 and 13 weeks after the last rituximab administration demonstrated disappearance of renal tumors. Additionally, magnetic resonance imaging control 5 months later showed a return of normal pituitary size and stalk width, but a persistent loss of the normal posterior lobe T1 hyperintensity (Figure 1C and D). Unfortunately, central diabetes insipidus persisted. Inflammatory parameters and anti-MPO ANCA titer returned to normal range and polyarthralgia improved. Most of the reported cases of renal inflammatory pseudotumors related to granulomatosis with polyangiitis have been treated surgically or, less frequently, by classical immunosuppression (cyclophosphamide and steroids).5,6 Our patient experienced rapid and complete renal response to rituximab. The persistence of diabetes insipidus could be related to irreversible damage, although longer follow-up is required considering the positive evolution of pituitary imaging. In the Mayo Clinic series,
reversibility of diabetes insipidus was noted in 67% of cases.4 In conclusion, granulomatosis with polyangiitis should be considered in the differential diagnosis of central diabetes insipidus on the one hand, and of renal mass lesions on the other. The key role of 18F-FDG PET/CT in the diagnosis work-up presented here is consistent with emerging data on the benefit of this examination in the assessment of granulomatosis with polyangiitis, especially in atypical presentations.7,8 Rapid recognition of granulomatosis with polyangiitis as the cause of diabetes insipidus and initiation of treatment could minimize the risk of irreversible damage. In renal mass-like lesions, establishing the diagnosis of granulomatosis with polyangiitis could prevent unnecessary nephrectomy. To our knowledge this is the first case combining central diabetes insipidus and subsequent bilateral renal pseudotumors in the setting of granulomatosis with polyangiitis.
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Figure 3 Histopathological examination of the renal biopsy specimen revealed granulomatous inflammation with multinucleated giant cells, extra-capillary proliferation and fibrinoid necrosis which confirmed the diagnosis of granulomatosis with polyangiitis.
References 1. Young TY, Li JYZ, Amato L, et al. Pituitary involvement in Wegener’s granulomatosis. Pituitary. 2008;11:77-84. 2. Cunnington JR, Ramesh J, Zammit Y, Scott D, Isaacs J. Diabetes insipidus as a complication of Wegener’s granulomatosis and its treatment with biologic agents. Int J Rheumatol. 2009;2009:346136. 3. Tenorio Jimenez C, Montalvo Valdivieso A, López Gallardo GL, Mcgowan B. Pituitary involvement in Wegener’s granulomatosis: unusual biochemical findings and severe malnutrition. BMJ Case Rep. 2011 Nov 7. http://dx.doi.org/10.1136/bcr.02.2011.3850. 4. Kapoor E, Cartin-Ceba R, Specks U, Leavitt J, Erickson B, Erickson D. Pituitary dysfunction in granulomatosis with polyangiitis: the Mayo Clinic experience. J Clin Endocrinol Metab. 2014;99:3988-3994.
5. Vandergheynst F, Dumarey N, Cogan E. Relapse of an inflammatory pseudotumor associated with Wegener’s granulomatosis. Acta Clinica Belgica. 2010;65:429-431. 6. Vandergheynst F, Van Gansbeke D, Cogan E. Wegener’s granulomatosis masquerading as a renal cancer: a case report and review of the literature. Clin Exp Rheumatol. 2006;24: 584-586. 7. Soussan M, Abisror N, Abas S, et al. FDG-PET/CT in patients with ANCA-associated vasculitis: case-series and literature review. Autoimmun Rev. 2014;13:125-131. 8. Kemna MJ, Vandergheynst F, Vöö S, et al. Positron Emission Tomography scanning in Anti-Neutrophil Cytoplasmic AntibodiesAssociated Vasculitis. Medicine (Baltimore). 2015;94(20):e747.
From Polyuria to Renal Mass: An Unexpected Link Frédéric Vandergheynst, MD,a Paraskevi Kazakou, MD, PhD,b Bruno Couturier, MD,a Nicolas Dumarey, MD,c Rose Ghanooni, MD,d Agnieszka Pozdzik, MD, PhD,e Sandrine Rorive, MD, PhD,f Daniel Van Gansbeke, MD,g Agnès Burniat, MD, PhDb a
Department of Internal Medicine, bDepartment of Endocrinology, cDepartment of Nuclear Medicine, dDepartment of Otorhinolaryngology, Department of Nephrology, fDepartment of Pathology, and gDepartment of Radiology, Erasme Hospital, Université Libre de Bruxelles, Belgium. e
PRESENTATION In February 2014, a 23-year-old woman presented to the Endocrinology Department with polydipsia and polyuria for 1 month. She also presented poor appetite but not loss of weight. In addition, she complained of predominant right retroorbital headaches in the context of a known chronic allergic rhinosinusitis. She had no visual complaints and her menstruation was regular. She took no medication on a regular basis. Her family history revealed type 2 diabetes in both parents and inflammatory polyarthritis in her father.
ASSESSMENT Physical examination of the patient was unremarkable except for obesity (body mass index 30.7 kg/m2) and small hyperpigmented macules on the back. No signs of Cushing’s syndrome such as buffalo neck, purple striae, or hypertension were evident. Nasal and sinus examination revealed chronic sinusitis. Initial blood analysis showed normal values of C-reactive protein, glycemia, electrolytes,
FV and PK have equally contributed to this work. Funding: None. Conflict of Interest: None. Authorship: FV, PK, and AB assessed and managed the patient. All authors had access to the data, contributed to the clinical diagnosis and to the redaction of the article. RG and DVG contributed to the clinical management of the patient. FV and PK contributed equally to this work. The patient’s written consent to publish was obtained. Requests for reprints should be addressed to Agnès Burniat, MD, PhD, Department of Endocrinology, Erasme Hospital, Université Libre de Bruxelles, Lennik Street 808, Brussels 1070, Belgium. E-mail address: [email protected]
0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.05.009
and renal function. A water deprivation test confirmed the suspected diagnosis of central diabetes insipidus, and treatment with intranasal desmopressin (10 mg twice a day) was started. Circulating levels of anterior pituitary hormones were normal. Magnetic resonance imaging of the pituitary showed a slightly enlarged gland (12.8 mm) with thickening of the pituitary stalk (3.9 mm) and loss of normal hyperintense T1-weighted signal of the posterior pituitary (Figure 1A and B). Chest radiograph was unremarkable. Cytological examination and tumor markers in serum and cerebrospinal fluid, including alpha fetoprotein and betahuman chorionic gonadotropin, were normal. Serum angiotensin-converting enzyme was not elevated, and antipituitary antibodies were negative. The tuberculin skin test and interferon-g release assay were also negative. Skin biopsy of the lesions on the back showed nonspecific chronic inflammatory changes with no argument for histiocytosis. Finally, [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) revealed hypermetabolism of the pituitary stalk, but also of the maxillary sinus, as well as a tumor-like lesion in the right kidney (Figure 2A). Renal contrast-enhanced ultrasonography (CEUS) confirmed the presence of the latter, measuring 2 cm in diameter. Given the association of sinusal and pituitary involvements, granulomatosis with polyangiitis was suspected. Antineutrophil cytoplasmic antibodies (ANCA) testing revealed elevated titers of anti-myeloperoxidase (anti-MPO) perinuclear ANCA (6.3 UI/mL, N < 3.5 UI/mL). However, histopathological examination of the maxillary sinus biopsy showed neither granulomatous inflammation nor vasculitis. Moreover, urinalysis and renal function were normal.
2
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-
2015
Figure 1 Pituitary magnetic resonance imaging study. (A) Gadolinium-enhanced coronal T1-weighted image (March 2014). Slightly enlarged pituitary gland (12.8 mm; solid arrow) and thickened stalk (3.9 mm; dotted arrow). (B) Sagittal T1-weighted image (March 2014). Loss of the normal hyperintense signal of the posterior pituitary (solid arrow). (C) Gadolinium-enhanced coronal T1-weighted image (March 2015). Normalization of pituitary size (solid arrow) and stalk width (dotted arrow). (D) Sagittal T1-weighted image (March 2015). Persistent loss of the normal posterior lobe T1 hyperintensity (solid arrow).
At that time, renal mass was not easily accessible to safe percutaneous ultrasound-guided biopsy. Hence, close clinical and radiological follow-up was proposed.
DIAGNOSIS Six months later, the patient developed pain in the right flank and in the cervical and lumbar spine. Further blood testing demonstrated elevation of C-reactive protein (110 mg/L). Elevated titers of anti-MPO ANCA were confirmed. CEUS showed progression of the right renal mass, which had doubled in size (4.3 cm), and suspected new lesions in the left kidney. This was confirmed by 18 F-FDG PET/CT (Figure 2B). Despite progression of the renal lesions, urinary sediment and renal function remained normal. Fortunately, at this time point, the larger size of the right renal tumor allowed safe percutaneous biopsy. Histopathological examination of the biopsy specimen revealed severe necrotizing granulomatous tubulointerstitial nephritis and extracapillary glomerulonephritis, confirming the diagnosis of granulomatosis with polyangiitis (Figure 3).
Pituitary involvement is an uncommon complication of granulomatosis with polyangiitis, with about 30 patients reported in literature.1-3 When it occurs, central diabetes insipidus usually follows rather than precedes lung and kidney involvement. In a recent monocentric series on granulomatosis with polyangiitis-related pituitary diseases, the most frequent endocrine dysfunctions were secondary hypogonadism and diabetes insipidus. All patients had abnormal pituitary imaging.4 Granulomatous renal inflammatory pseudotumor is even more rare, with only 16 cases described. These pseudotumoral lesions have only exceptionally been identified by 18 F-FDG PET/CT5 and never by CEUS.
MANAGEMENT Considering the young age of the patient, in order to avoid cyclophosphamide-induced ovarian failure, treatment with rituximab (375 mg/m2 once weekly during 4 weeks) was initiated. Prednisolone was started in parallel and continued with progressive stepwise dose reduction.
Vandergheynst et al
From Polyuria to Renal Mass: An Unexpected Link
3
Figure 2 [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). (A) Hypermetabolic lesion in the right kidney (March 2014). (B) Expansion of the lesion in the right kidney and appearance of new lesions in the left kidney (September 2014).
Ultrasonographic controls performed 5 and 13 weeks after the last rituximab administration demonstrated disappearance of renal tumors. Additionally, magnetic resonance imaging control 5 months later showed a return of normal pituitary size and stalk width, but a persistent loss of the normal posterior lobe T1 hyperintensity (Figure 1C and D). Unfortunately, central diabetes insipidus persisted. Inflammatory parameters and anti-MPO ANCA titer returned to normal range and polyarthralgia improved. Most of the reported cases of renal inflammatory pseudotumors related to granulomatosis with polyangiitis have been treated surgically or, less frequently, by classical immunosuppression (cyclophosphamide and steroids).5,6 Our patient experienced rapid and complete renal response to rituximab. The persistence of diabetes insipidus could be related to irreversible damage, although longer follow-up is required considering the positive evolution of pituitary imaging. In the Mayo Clinic series,
reversibility of diabetes insipidus was noted in 67% of cases.4 In conclusion, granulomatosis with polyangiitis should be considered in the differential diagnosis of central diabetes insipidus on the one hand, and of renal mass lesions on the other. The key role of 18F-FDG PET/CT in the diagnosis work-up presented here is consistent with emerging data on the benefit of this examination in the assessment of granulomatosis with polyangiitis, especially in atypical presentations.7,8 Rapid recognition of granulomatosis with polyangiitis as the cause of diabetes insipidus and initiation of treatment could minimize the risk of irreversible damage. In renal mass-like lesions, establishing the diagnosis of granulomatosis with polyangiitis could prevent unnecessary nephrectomy. To our knowledge this is the first case combining central diabetes insipidus and subsequent bilateral renal pseudotumors in the setting of granulomatosis with polyangiitis.
4
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-
2015
Figure 3 Histopathological examination of the renal biopsy specimen revealed granulomatous inflammation with multinucleated giant cells, extra-capillary proliferation and fibrinoid necrosis which confirmed the diagnosis of granulomatosis with polyangiitis.
References 1. Young TY, Li JYZ, Amato L, et al. Pituitary involvement in Wegener’s granulomatosis. Pituitary. 2008;11:77-84. 2. Cunnington JR, Ramesh J, Zammit Y, Scott D, Isaacs J. Diabetes insipidus as a complication of Wegener’s granulomatosis and its treatment with biologic agents. Int J Rheumatol. 2009;2009:346136. 3. Tenorio Jimenez C, Montalvo Valdivieso A, López Gallardo GL, Mcgowan B. Pituitary involvement in Wegener’s granulomatosis: unusual biochemical findings and severe malnutrition. BMJ Case Rep. 2011 Nov 7. http://dx.doi.org/10.1136/bcr.02.2011.3850. 4. Kapoor E, Cartin-Ceba R, Specks U, Leavitt J, Erickson B, Erickson D. Pituitary dysfunction in granulomatosis with polyangiitis: the Mayo Clinic experience. J Clin Endocrinol Metab. 2014;99:3988-3994.
5. Vandergheynst F, Dumarey N, Cogan E. Relapse of an inflammatory pseudotumor associated with Wegener’s granulomatosis. Acta Clinica Belgica. 2010;65:429-431. 6. Vandergheynst F, Van Gansbeke D, Cogan E. Wegener’s granulomatosis masquerading as a renal cancer: a case report and review of the literature. Clin Exp Rheumatol. 2006;24: 584-586. 7. Soussan M, Abisror N, Abas S, et al. FDG-PET/CT in patients with ANCA-associated vasculitis: case-series and literature review. Autoimmun Rev. 2014;13:125-131. 8. Kemna MJ, Vandergheynst F, Vöö S, et al. Positron Emission Tomography scanning in Anti-Neutrophil Cytoplasmic AntibodiesAssociated Vasculitis. Medicine (Baltimore). 2015;94(20):e747.
