CASE-LETTER
Granulomatosis With Polyangiitis Accompanied by Manifestations of Ovarian and Cervical Lesions
G
ranulomatosis with polyangiitis is a vasculitis of unknown origin characterized by prominent involvement of the upper and lower respiratory tract and kidney. According to the American College of Rheumatology, granulomatosis with polyangiitis can be defined by 2 of the following criteria: nephritic urinary sediment, abnormal chest finding, nasal or oral inflammation or granulomatous inflammation on biopsy.1 Moreover, this disease has the potential to affect any organ system. In this report, a rare case of systemic granulomatosis with polyangiitis with primary manifestations involving the ovaries and cervix in a 58-year-old patient is described. The significance of this finding is discussed in relation to recent literature. A 58-year-old Chinese woman was hospitalized due to abnormal vaginal bleeding she experienced for 10 days in September 2012. Nine years before, the patient underwent a partial hysterectomy to treat uterine fibroids. A laparotomy revealed multiple inflammatory nodules on her abdominal wall, residual cervical thickening, bilateral ovarian cysts (1 3 2 3 2 cm3) with purulent spillage and adhesions between the ovaries and both the posterior lobe of the broad ligament and the intestinal tube. Pathological results showed that a large number of acute and chronic inflammatory cells had infiltrated the sample (Figure 1). In addition, granulomatous inflammation, multinucleated giant cells, massive cell necrosis and vasculitis were also observed (Figure 1). No acid-fast bacilli and fungi were found, and Periodic-Acid Schiff staining was negative. A lung x-ray obtained on day 1 did not show any abnormalities. However, an x-ray obtained 16 days later showed enhanced markings on the lungs and a patchy shadow in the upper quadrant of the right lung. On day 20, a computed tomography scan of the lung showed multiple nodular high-density shadows. However, the trachea and main bronchus were normal and enlarged lymph nodes were not observed in the mediastinum. On day 30, the patient presented to the Ophthalmology Department with a fever and nasal foreign matter. A nasal endoscopy was performed and extensive congestion and erosion in the nasal cavity were observed. Granulomatosis was suspected based on the levels of Protease-ANCA (PR3-ANCA) detected (200 RU/mL) in combination with positive detection of cytoplasmic neutrophil antibodies (cANCA) and antimitochondrial type 2 antibodies (ANA spectrum). The patient was also negative for tuberculosis antibodies. Therefore, the patient received 40 mg of methylprednisolone orally for the treatment of the granulomas. However, on day 32, the patient was admitted to the Department of Neurology with manifestations of barylalia, limited activity of the right limb and difficulty swallowing. The patient had a body temperature of 36.5°C, a blood pressure reading of 140/80 mm Hg, an anemic appearance and multiple ulcers present under the hard palate or tongue. The largest ulcer was 2 3 1 cm2. No abnormalities were detected during a cardiopulmonary and abdominal examination. Overall, the patient was conscious, exhibited barylalia, had difficulty lifting the bilateral soft palate, exhibited deviation of the uvula (left), had a weakened gag reflex, had reduced strength in the right upper limb muscle
352
(grade 3), showed an inability to form a fist and her right side was positive for both Chaddock’s and Babinski’s signs. Magnetic resonance imaging (MRI) of the head was performed on day 31, and patchy or dot-long T1 and T2 signals were observed in basal ganglia coronal sections obtained from both sides. Diffusion-weighted imaging of the bilateral thalamus and left corona radiata regions also revealed flake-like or dot-like strong signals. The patient subsequently received a daily oral dose of 100 mg aspirin. By day 36, the patient experienced double vision and left-sided central facial palsy. An MRI examination showed additional dot lesions present in the right basal ganglia compared with the MRI image obtained 5 days earlier. Computed tomography angiography of the head and neck showed mild stenosis of the bilateral common carotid arteries and the internal carotid artery. The right vertebral artery lumen also appeared to have a smaller diameter compared with the left side. No significant stenosis or filling defects were observed in the anterior, middle or posterior cerebral arteries on both sides. Furthermore, an ultrasonography did not reveal any defects in the major abdominal organs. Dyspnea occurred on day 37, and a lung x-ray showed multiple nodular shadows. Thus, a diagnosis of granulomatosis with polyangiitis was confirmed. The patient’s condition rapidly worsened on day 38, and the patient could not achieve a supine position. The patient’s heart rate reached 140 to 150 beats/min, and the patient received cardiac and diuretic therapy. On day 39, a positive fecal occult blood test was obtained, and multiple subcutaneous congestion spots were observed on the ankles. The patient was then administered 1,000 mg methylprednisolone and 200 mg cyclophosphamide. Despite this, the patient’s condition did not improve. On day 43, the patient fell into a coma and died the following day. Granulomatosis with polyangiitis is a rare necrotizing granulomatous vasculitis characterized by the presence of c-ANCA involving the upper respiratory tract, lung and kidneys. The histological and pathological features include tissue necrosis, inflammatory granuloma and vasculitis. This report details an extremely rare case of granulomatosis with polyangiitis, which was complicated by multiple unusual manifestations involving the cervix, ovaries, lungs and nervous, digestive and cardiovascular systems. To date, only 6 cases of granulomatosis with polyangiitis and cervix involvement have been reported. In 5 cases, cervix lesions were observed during relapse. In the 6th case, the primary manifestation was menstrual bleeding caused by a uterine lesion.2–7 This case is the second to report a uterine lesion as a primary manifestation accompanied by ovary involvement. Pathological examinations showed extensive cervix vasculitis and ovarian necrosis, and the cervical lesion was differentiated from cervical cancer and tuberculosis. The differential diagnosis of granulomatosis with polyangiitis of the cervix includes squamous cell carcinoma, fungal infection, tuberculosis, sarcoidosis, systemic vasculitis (such as giant cell arteritis) and isolated vasculitis of the female genital tract. In a patient with cervical mucosal erosions, the abnormal cervix must be biopsied to exclude squamous cell carcinoma. Thus, a histologic distinction between squamous cell carcinoma and granulomatosis with polyangiitis is straightforward. Regarding fungal infections and tuberculosis, a purified protein derivative test, appropriate cultures and a chest x-ray can aid in the diagnosis. Sarcoidosis is a diagnosis of exclusion, while female genital tract involvement with giant cell arteritis is common.
The American Journal of the Medical Sciences
Volume 348, Number 4, October 2014
Case-Letter
FIGURE 1. Lesions observed in the ovaries and cervix. (A), Infiltration of perivascular inflammatory cells into the left ovary ([, multinucleated giant cells). (B), Infiltration of inflammatory vascular endothelial cells into the cervix ([, lymphocytes). (C), Inflammatory cell infiltration and tissue necrosis surrounding small blood vessels of the right ovary ([, necrotic tissue; B, small vessel lumens; O, small vessel wall) (hematoxylin and eosin staining, magnification 2003).
Giant cell arteritis involves vasculitis of small to medium arteries and most commonly affects the temporal arteries and extracranial branches of the aorta. Histologically, vasculitis is characterized by a concentric mixed inflammatory infiltrate composed of lymphocytes, histiocytes and multinucleated giant cells involving the media and adventitia. These patients generally present with fever, fatigue, weight loss and headache. However, isolated vasculitis of the female genital tract is a rare disease. The histologic features of this disease are similar to those of granulomatosis with polyangiitis, although positive c-ANCA in combination with systemic signs and symptoms of vasculitis support a diagnosis of granulomatosis with polyangiitis rather than isolated vasculitis. In the present case, the compromise of multiple organs and systems seemed to contribute to the rapid progression of granulomatosis with polyangiitis that was observed. Interestingly, however, there were no signs of kidney involvement detected. Renal granulomatosis with polyangiitis is a common condition, and these patients exhibit hematuria, proteinuria and cellular casts on urine cytology. Moreover, renal impairment manifests as acute kidney injury, chronic kidney disease or end-stage renal failure. In the present case, levels of creatinine and urea, as well as urinalysis, were checked several times. In each case, the results were normal. Schneider et al8 previously reported a patient who presented with necrotizing and granulomatous inflammation of the bronchi and vasculitis of the bronchial arteries and pulmonary vein without renal involvement. It remains unclear why an absence of kidney involvement was observed. In the present case, the absence of the typical triad of granulomatosis with polyangiitis symptoms, particularly the absence of renal involvement, potentially contributed to the delay in the diagnosis. Based on the diversity of manifestations that can be associated with granulomatosis with polyangiitis, misdiagnosis of this condition is common. Therefore, the goal of the present report was to illustrate rare manifestations of granulomatosis with polyangiitis that can develop to facilitate a definitive diagnosis as early as possible in future cases to improve patient prognosis.
Ó 2014 Lippincott Williams & Wilkins
*Shan-Ji Nan, Wen-Yu Li, Cheng-Bi Xu, Chun-Ling Song,
MD MD MD MD
Department of Neurology Second Hospital of Jilin University Changchun, China *E-mail: [email protected] The authors have no financial or other conflicts of interest to disclose. ACKNOWLEDGMENTS The authors thank Medjaden Bioscience Limited for assistance in the preparation of this article. REFERENCES 1. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990;33:1101–7. 2. Malamou-Mitsi VD, Pappa LS, Paraskevaidis E, et al. Uterine cervical involvement in a patient with Wegener’s granulomatosis. Am J Med 2000;109:74–5. 3. Stone JH, Millward CL, Criswell LA. Two genitourinary manifestations of Wegener’s granulomatosis. J Rheumatol 1997;24:1846–8. 4. Ahson GZ, Parkin DE, Gulliford C, et al. A rare case of postmenopausal bleeding due to Wegener’s granulomatosis. Acta Obstet Gynecol Scand 2002;81:1086–7. 5. Bean SM, Conner MG. Wegener’s granulomatosis of the uterine cervix: a case report and review of the literature. Int J Gynecol Pathol 2007;26:95–8. 6. Maina WC, Crocker SG, Scott D, et al. Postmenopausal bleeding due to cervical involvement with Wegener’s granulomatosis. J Obstet Gynaecol 2009;29:167–9. 7. Mukherjee S, Al-Utayem W, Bergin L, et al. Wegener’s granulomatosis presenting as intermenstrual bleeding. J Obstet Gynaecol 2011;31:191–2. 8. Schneider P, Grone J, Braun J, et al. Wegener’s granulomatosis presenting as necrosis of the left mainstem bronchus. Asian Cardiovasc Thorac Ann 2002;10:277–9.
353
Granulomatosis With Polyangiitis Accompanied by Manifestations of Ovarian and Cervical Lesions
G
ranulomatosis with polyangiitis is a vasculitis of unknown origin characterized by prominent involvement of the upper and lower respiratory tract and kidney. According to the American College of Rheumatology, granulomatosis with polyangiitis can be defined by 2 of the following criteria: nephritic urinary sediment, abnormal chest finding, nasal or oral inflammation or granulomatous inflammation on biopsy.1 Moreover, this disease has the potential to affect any organ system. In this report, a rare case of systemic granulomatosis with polyangiitis with primary manifestations involving the ovaries and cervix in a 58-year-old patient is described. The significance of this finding is discussed in relation to recent literature. A 58-year-old Chinese woman was hospitalized due to abnormal vaginal bleeding she experienced for 10 days in September 2012. Nine years before, the patient underwent a partial hysterectomy to treat uterine fibroids. A laparotomy revealed multiple inflammatory nodules on her abdominal wall, residual cervical thickening, bilateral ovarian cysts (1 3 2 3 2 cm3) with purulent spillage and adhesions between the ovaries and both the posterior lobe of the broad ligament and the intestinal tube. Pathological results showed that a large number of acute and chronic inflammatory cells had infiltrated the sample (Figure 1). In addition, granulomatous inflammation, multinucleated giant cells, massive cell necrosis and vasculitis were also observed (Figure 1). No acid-fast bacilli and fungi were found, and Periodic-Acid Schiff staining was negative. A lung x-ray obtained on day 1 did not show any abnormalities. However, an x-ray obtained 16 days later showed enhanced markings on the lungs and a patchy shadow in the upper quadrant of the right lung. On day 20, a computed tomography scan of the lung showed multiple nodular high-density shadows. However, the trachea and main bronchus were normal and enlarged lymph nodes were not observed in the mediastinum. On day 30, the patient presented to the Ophthalmology Department with a fever and nasal foreign matter. A nasal endoscopy was performed and extensive congestion and erosion in the nasal cavity were observed. Granulomatosis was suspected based on the levels of Protease-ANCA (PR3-ANCA) detected (200 RU/mL) in combination with positive detection of cytoplasmic neutrophil antibodies (cANCA) and antimitochondrial type 2 antibodies (ANA spectrum). The patient was also negative for tuberculosis antibodies. Therefore, the patient received 40 mg of methylprednisolone orally for the treatment of the granulomas. However, on day 32, the patient was admitted to the Department of Neurology with manifestations of barylalia, limited activity of the right limb and difficulty swallowing. The patient had a body temperature of 36.5°C, a blood pressure reading of 140/80 mm Hg, an anemic appearance and multiple ulcers present under the hard palate or tongue. The largest ulcer was 2 3 1 cm2. No abnormalities were detected during a cardiopulmonary and abdominal examination. Overall, the patient was conscious, exhibited barylalia, had difficulty lifting the bilateral soft palate, exhibited deviation of the uvula (left), had a weakened gag reflex, had reduced strength in the right upper limb muscle
352
(grade 3), showed an inability to form a fist and her right side was positive for both Chaddock’s and Babinski’s signs. Magnetic resonance imaging (MRI) of the head was performed on day 31, and patchy or dot-long T1 and T2 signals were observed in basal ganglia coronal sections obtained from both sides. Diffusion-weighted imaging of the bilateral thalamus and left corona radiata regions also revealed flake-like or dot-like strong signals. The patient subsequently received a daily oral dose of 100 mg aspirin. By day 36, the patient experienced double vision and left-sided central facial palsy. An MRI examination showed additional dot lesions present in the right basal ganglia compared with the MRI image obtained 5 days earlier. Computed tomography angiography of the head and neck showed mild stenosis of the bilateral common carotid arteries and the internal carotid artery. The right vertebral artery lumen also appeared to have a smaller diameter compared with the left side. No significant stenosis or filling defects were observed in the anterior, middle or posterior cerebral arteries on both sides. Furthermore, an ultrasonography did not reveal any defects in the major abdominal organs. Dyspnea occurred on day 37, and a lung x-ray showed multiple nodular shadows. Thus, a diagnosis of granulomatosis with polyangiitis was confirmed. The patient’s condition rapidly worsened on day 38, and the patient could not achieve a supine position. The patient’s heart rate reached 140 to 150 beats/min, and the patient received cardiac and diuretic therapy. On day 39, a positive fecal occult blood test was obtained, and multiple subcutaneous congestion spots were observed on the ankles. The patient was then administered 1,000 mg methylprednisolone and 200 mg cyclophosphamide. Despite this, the patient’s condition did not improve. On day 43, the patient fell into a coma and died the following day. Granulomatosis with polyangiitis is a rare necrotizing granulomatous vasculitis characterized by the presence of c-ANCA involving the upper respiratory tract, lung and kidneys. The histological and pathological features include tissue necrosis, inflammatory granuloma and vasculitis. This report details an extremely rare case of granulomatosis with polyangiitis, which was complicated by multiple unusual manifestations involving the cervix, ovaries, lungs and nervous, digestive and cardiovascular systems. To date, only 6 cases of granulomatosis with polyangiitis and cervix involvement have been reported. In 5 cases, cervix lesions were observed during relapse. In the 6th case, the primary manifestation was menstrual bleeding caused by a uterine lesion.2–7 This case is the second to report a uterine lesion as a primary manifestation accompanied by ovary involvement. Pathological examinations showed extensive cervix vasculitis and ovarian necrosis, and the cervical lesion was differentiated from cervical cancer and tuberculosis. The differential diagnosis of granulomatosis with polyangiitis of the cervix includes squamous cell carcinoma, fungal infection, tuberculosis, sarcoidosis, systemic vasculitis (such as giant cell arteritis) and isolated vasculitis of the female genital tract. In a patient with cervical mucosal erosions, the abnormal cervix must be biopsied to exclude squamous cell carcinoma. Thus, a histologic distinction between squamous cell carcinoma and granulomatosis with polyangiitis is straightforward. Regarding fungal infections and tuberculosis, a purified protein derivative test, appropriate cultures and a chest x-ray can aid in the diagnosis. Sarcoidosis is a diagnosis of exclusion, while female genital tract involvement with giant cell arteritis is common.
The American Journal of the Medical Sciences
Volume 348, Number 4, October 2014
Case-Letter
FIGURE 1. Lesions observed in the ovaries and cervix. (A), Infiltration of perivascular inflammatory cells into the left ovary ([, multinucleated giant cells). (B), Infiltration of inflammatory vascular endothelial cells into the cervix ([, lymphocytes). (C), Inflammatory cell infiltration and tissue necrosis surrounding small blood vessels of the right ovary ([, necrotic tissue; B, small vessel lumens; O, small vessel wall) (hematoxylin and eosin staining, magnification 2003).
Giant cell arteritis involves vasculitis of small to medium arteries and most commonly affects the temporal arteries and extracranial branches of the aorta. Histologically, vasculitis is characterized by a concentric mixed inflammatory infiltrate composed of lymphocytes, histiocytes and multinucleated giant cells involving the media and adventitia. These patients generally present with fever, fatigue, weight loss and headache. However, isolated vasculitis of the female genital tract is a rare disease. The histologic features of this disease are similar to those of granulomatosis with polyangiitis, although positive c-ANCA in combination with systemic signs and symptoms of vasculitis support a diagnosis of granulomatosis with polyangiitis rather than isolated vasculitis. In the present case, the compromise of multiple organs and systems seemed to contribute to the rapid progression of granulomatosis with polyangiitis that was observed. Interestingly, however, there were no signs of kidney involvement detected. Renal granulomatosis with polyangiitis is a common condition, and these patients exhibit hematuria, proteinuria and cellular casts on urine cytology. Moreover, renal impairment manifests as acute kidney injury, chronic kidney disease or end-stage renal failure. In the present case, levels of creatinine and urea, as well as urinalysis, were checked several times. In each case, the results were normal. Schneider et al8 previously reported a patient who presented with necrotizing and granulomatous inflammation of the bronchi and vasculitis of the bronchial arteries and pulmonary vein without renal involvement. It remains unclear why an absence of kidney involvement was observed. In the present case, the absence of the typical triad of granulomatosis with polyangiitis symptoms, particularly the absence of renal involvement, potentially contributed to the delay in the diagnosis. Based on the diversity of manifestations that can be associated with granulomatosis with polyangiitis, misdiagnosis of this condition is common. Therefore, the goal of the present report was to illustrate rare manifestations of granulomatosis with polyangiitis that can develop to facilitate a definitive diagnosis as early as possible in future cases to improve patient prognosis.
Ó 2014 Lippincott Williams & Wilkins
*Shan-Ji Nan, Wen-Yu Li, Cheng-Bi Xu, Chun-Ling Song,
MD MD MD MD
Department of Neurology Second Hospital of Jilin University Changchun, China *E-mail: [email protected] The authors have no financial or other conflicts of interest to disclose. ACKNOWLEDGMENTS The authors thank Medjaden Bioscience Limited for assistance in the preparation of this article. REFERENCES 1. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990;33:1101–7. 2. Malamou-Mitsi VD, Pappa LS, Paraskevaidis E, et al. Uterine cervical involvement in a patient with Wegener’s granulomatosis. Am J Med 2000;109:74–5. 3. Stone JH, Millward CL, Criswell LA. Two genitourinary manifestations of Wegener’s granulomatosis. J Rheumatol 1997;24:1846–8. 4. Ahson GZ, Parkin DE, Gulliford C, et al. A rare case of postmenopausal bleeding due to Wegener’s granulomatosis. Acta Obstet Gynecol Scand 2002;81:1086–7. 5. Bean SM, Conner MG. Wegener’s granulomatosis of the uterine cervix: a case report and review of the literature. Int J Gynecol Pathol 2007;26:95–8. 6. Maina WC, Crocker SG, Scott D, et al. Postmenopausal bleeding due to cervical involvement with Wegener’s granulomatosis. J Obstet Gynaecol 2009;29:167–9. 7. Mukherjee S, Al-Utayem W, Bergin L, et al. Wegener’s granulomatosis presenting as intermenstrual bleeding. J Obstet Gynaecol 2011;31:191–2. 8. Schneider P, Grone J, Braun J, et al. Wegener’s granulomatosis presenting as necrosis of the left mainstem bronchus. Asian Cardiovasc Thorac Ann 2002;10:277–9.
353
