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A 40-Year-Old Woman With Multiple Pulmonary Nodules40-Year-Old Woman With Multiple Pulmonary Nodules FREE TO VIEW

Kamonpun Ussavarungsi, MD; Andras Khoor, MD, PhD; Howard I. Jolles, MD; Isabel Mira-Avendano, MD
Author and Funding Information

From Pulmonary and Critical Care Medicine (Drs Ussavarungsi and Mira-Avendano), Laboratory Medicine and Pathology (Dr Khoor), and Diagnostic Radiology (Dr Jolles), Mayo Clinic, Jacksonville, FL.

CORRESPONDENCE TO: Kamonpun Ussavarungsi, MD, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: Ussavarungsi.Kamonpun@mayo.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(6):e198-e203. doi:10.1378/chest.14-0796
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A 40-year-old woman (a nonsmoker) with history of idiopathic thrombocytopenic purpura and a platelet count > 90,000 cells/μL without specific medication was referred to pulmonary clinic for evaluation of multiple pulmonary nodules. The patient presented to an outside hospital with fatigue, lack of energy, and dyspnea on exertion for 2 years. She denied fever, cough, chest pain, or weight loss. An initial chest radiograph showed bilateral multiple pulmonary nodules. A chest CT scan revealed multiple nodular lesions, varying in size, in all lobes of both lungs. There was no mediastinal lymphadenopathy or pleural effusion. There was no significant hypermetabolic activity on a subsequent fluorodeoxyglucose PET scan/CT scan, and there had been no significant change. She underwent CT scan-guided percutaneous transthoracic biopsy and bronchoscopy with transbronchial biopsies, all of which were inconclusive. An open lung biopsy was considered.

Figures in this Article

A physical examination revealed an alert and oriented patient without respiratory distress. Vital signs were normal except for a BMI of 34.7. Oxygen saturation was 99% on room air. Her overall exams were unremarkable.

Blood test results showed a hemoglobin value of 13.4 g/dL, hematocrit value of 41.5%, WBC count of 6,900 cells/μL, and a platelet count of 92,000 cells/μL. Her electrolytes, creatinine level, and liver function test results were normal. Her erythrocyte sedimentation rate was 7 mm/h (normal 0-29). Results on her serology panels were negative or normal, including antinuclear antibody (Ab), antineutrophil cytoplasmic Ab, rheumatoid factor, anti-double stranded (ds)-DNA Ab, Sm Ab, SS-A/SS-B Ab, ribonucleoprotein Ab, Scl-70 Ab, Jo 1 Ab. Her Aspergillus antigen test, fungal serologies, HIV enzyme-linked immunosorbent assay test, and TB skin test were negative.

A pulmonary function test showed no evidence of obstruction or restriction, normal inspiratory flow-volume loop, diffusion capacity, and negative methacholine challenge test. She had a normal ECG, echocardiography, and overnight oximetry.

A chest radiograph is shown in Figure 1, and chest CT scans without contrast are shown in Figures 2A-F. CT scan of the abdomen and pelvis was done as part of a malignancy workup, and it did not show any lymphadenopathy or intraabdominal mass. Esophagogastroduodenoscopy found reflux esophagitis, and colonoscopy showed only a hyperplastic rectal polyp.

Figure Jump LinkFigure 1 –  Chest radiograph demonstrating multiple nodular opacities in both lungs.Grahic Jump Location

Figure Jump LinkFigure 2 –  A-C, Chest CT scans without contrast revealed multiple nodular lesions in all lobes of both lungs, variably distributed from the central zone to the periphery (black arrows). The nodules varied in size from 1.1 to 2.0 cm, having sharp to mildly irregular margins. The majority of these nodules are subpleural and fissural in location, anatomically a perilymphatic distribution. D-F, Soft tissue window at the same level demonstrates mildly heterogeneous soft tissue density (white arrows). No lymphadenopathy. No pleural or pericardial effusions. G, Some lesions had an associated “feeding vessel sign,” correlating with a perivascular distribution seen on pathology (white arrow).Grahic Jump Location

The patient underwent right video-assisted thoracoscopy with wedge excision from the superior segment of the right lower lobe and the anterior segment of the right upper lobe. Two nodules were identified in the right lower lobe and one nodule was identified in the right upper lobe; the largest nodule measured 0.7 cm at its greatest dimension. Microscopically, well-circumscribed, densely fibrotic nodules with a lymphoid rim were seen (Fig 3A). Higher magnification revealed thick, hyalinized bands of collagen arranged in a whorled fashion. Collagen bundles were also layered around vessels (Fig 3B). Special stains for acid-fast bacilli and fungal organisms were negative.

Figure Jump LinkFigure 3 –  A, Histologic sections of the right upper lobe lesion revealed a well-circumscribed, densely fibrotic nodule with a lymphoid rim at the interface (hematoxylin and eosin, original magnification × 4). B, At high magnification, the nodule was composed of thick collagen bundles, some of which were layered around vessels (hematoxylin and eosin, original magnification × 40).Grahic Jump Location
What is the diagnosis?
Diagnosis: Pulmonary hyalinizing granuloma
Clinical Discussion

Pulmonary hyalinizing granuloma (PHG) is a rare pulmonary condition that was first described by Engleman and colleagues in 1977. It is a benign process and consists of slowly enlarging parenchymal nodules. The two largest case series were from Engleman et al1 with 20 patients in 1977 and Yousem and Hochholzer2 with 24 patients in 1987.

The etiology and pathogenesis of this condition remain unknown. It was thought to represent the abnormal immune response to previous mycobacterial or fungal infection. PHG could be associated with an autoimmune process. Schlosnagle et al3 demonstrated autoantibodies, including antinuclear antibody, rheumatoid factor, antimicrosomal, antithyroglobulin, and anti-smooth muscle antibodies, as well as circulating immune complexes. In addition, 60% of the patients with serologic studies in the Yousem and Hochholzer2 series had evidence of autoimmune phenomena. PHG could be a fibrogenic host response to persistent antigenic stimuli or represent the end stage of infectious granulomas, autoimmune reactions, or burned-out inflammatory pseudotumors.

PHG is frequently associated with sclerosing mediastinitis and retroperitoneal fibrosis which may represent the same fibrotic-reactive process to triggers that include fungal organisms, TB bacilli, or other infectious agents, but the fibroinflammatory response could occur in the susceptible individuals. Lesions near the hilum have the potential to progress to sclerosing mediastinitis or sclerosing retroperitonitis.1,2

PHG has been previously reported to be associated with rheumatoid arthritis, multiple sclerosis, posterior uveitis, hemolytic anemia, Sjögren syndrome, primary biliary cirrhosis, and membranous glomerulonephritis.1-6 Associated lymphoproliferative disorders have also been reported, including lymphoma and Castleman disease.7,8 It has occurred in association with Morvan syndrome, which is thought to be autoimmune because of its association with antibodies to voltage-gated potassium channels and clinical response to plasmapheresis.9 PHG was reported in the patient with sarcoidosis and IgG4-related systemic sclerosing disease, which demonstrated increased serum IgG4 levels and elevated tissue IgG4-positive plasma cells in the PHG nodule.10 They shared the similar spectrum of manifestations, including sclerosing mediastinitis and retroperitoneal fibrosis, which might be explained from the same pathogenesis hypothesis. The Yousem and Hochholzer2 series mentioned that sclerosing inflammatory pseudotumors closely resemble PHG because four cases had lesions adjacent to PHG that were indistinguishable from inflammatory pseudotumors and plasma cell granuloma. The association between PHG and IgG4-related systemic sclerosing disease is yet to be determined. PHG may be a part of the spectrum of IgG4-related sclerosing disease or just represent the end stage of inflammatory pseudotumor.

The patient ages range from 19 to 77 years with a mean age in the mid-40s. There is no apparent racial or sex predilection. Symptoms are seen in 75% of patients with vague chest-related symptoms, such as dyspnea, cough, fatigue, and pleuritic chest pain being common. Twenty-five percent of the patients are symptomatic.1 Because imaging findings simulate malignancy, biopsy is required to establish the diagnosis. Most of the patients finally underwent open lung biopsy to obtain an adequate tissue.

Mean survival is unknown because of the limited patients, but the reported prognosis was excellent given the underlying benign process. There is no established treatment. Schlosnagle et al3 reported a case in which nodules did not change after prednisone trial, but corticosteroid responsiveness had been reported in a patient with laryngeal and subcutaneous involvement11 and in a patient with retroperitoneal fibrosis.5 The nodules regressed after increasing the dose of steroids in a case with chronic idiopathic thrombocytopenic purpura.12 Esme et al6 reported a case of PHG with posterior uveitis that mildly resolved with corticosteroid treatment, but there was no reduction in the size of the pulmonary lesions.

Radiologic Discussion

Radiographic findings usually show randomly distributed nodules and masses. The nodules are usually bilateral, multiple, and multilobar, but solitary nodules are also reported in nearly one-third of patients.3 The lesions are usually well circumscribed, but can appear irregular with indistinct borders. Calcification and cavity are rarely seen. Size is variable and ranges from a few millimeters to 15 cm in diameter.1,13 In this patient (Fig 2G), some nodules were characterized as having a “feeding vessel sign,” which has been reported in association with pulmonary embolic phenomena, angioinvasive pulmonary aspergillosis, metastatic disease, and vasculitis.14 The relationship between the nodules and adjacent vessels can potentially indicate the underlying hematologic seeding of PHG.

The differential diagnosis is extensive and most commonly considered as either metastatic or primary malignancy. For the calcified masses, sarcomatous metastases, such as osteosarcoma, chondrosarcoma, and giant cell tumor, and carcinomatous metastases, including mucin-producing adenocarcinomas, thyroid cancer, and choriocarcinoma, should be considered. Other possibilities include infectious causes, such as Mycobacterium or fungal infection. The lesions are sometimes cavitary and misinterpreted as septic emboli. Noninfectious causes are vasculitis-related pulmonary nodules, sarcoidosis, amyloidosis, rheumatoid nodules, lymphomatoid granulomatosis, and plasma cell granuloma.1,2,13,15,16

Follow-up chest radiograph of most patients showed that the nodules grew slowly, with a doubling time of 2.5 years. The lesions rarely increased dramatically in size. In some patients, the nodules remained stable in size. The new lesions precipitated rebiopsy in three patients from the Yousem and Hochholzer series with histologic features that were similar to the original ones.1,2

Fludeoxyglucose PET scan/CT scan is a useful imaging tool to diagnose most pulmonary malignant lesions. One of the most common false-positive etiologies is granulomatous inflammation, such as sarcoidosis. Hypermetabolic activity can also be observed in patients with PHG.17

Pathologic Discussion

The pulmonary nodules were usually found within the lung parenchyma, but can be located subpleurally. Their appearance ranged from pearly white to waxy translucent. Microscopically, they were composed of homogeneous, pink, hyaline lamellae, usually surrounded by collections of plasma cells, lymphocytes, and histiocytes, which were found locally in a perivascular distribution. Eosinophils and giant cells were occasionally present. Foci of ischemic necrosis were common.1 Well-formed granulomas were not present, and special stains for acid-fast bacilli and fungi were negative. The Congo Red stain with polarization and crystal violet stain could be focally positive, but it could be separated from amyloidosis by electron microscopic study of the extracellular hyaline lamellae, which in PHG consisted of electron-dense, compact, homogeneous, amorphous material unlike the loosely and haphazardly arranged fibrillar amyloid.18 The routine histology can resemble pulmonary low-grade marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue-type lymphoma, but the immunohistochemical study will help differentiate mucosa-associated lymphoid tissue-type lymphoma from PHG or other inflammatory pseudotumors.

Clinical Progress

The patient tolerated the procedure well and was discharged in stable condition. There was no specific treatment given. The causes of dyspnea on exertion were multifactorial, including PHG itself, obesity, and decondition. PHG is frequently associated with sclerosing mediastinitis and retroperitoneal fibrosis, so the patient was advised to monitor her symptoms and have a follow-up chest radiograph.

We described a case of PHG, a rare clinico-radio-pathologic entity that should be in the differential diagnosis of multiple pulmonary nodules or masses. PHG may perhaps be associated with extrapulmonary manifestations. Based on the potential fibroinflammatory reaction triggered by the immunologic process, clinicians should consider and appropriately search for associated autoimmune conditions. Corticosteroid treatment may be tried, but there is no established effective treatment.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Engleman P, Liebow AA, Gmelich J, Friedman PJ. Pulmonary hyalinizing granuloma. Am Rev Respir Dis. 1977;115(6):997-1008. [PubMed]
 
Yousem SA, Hochholzer L. Pulmonary hyalinizing granuloma. Am J Clin Pathol. 1987;87(1):1-6. [PubMed]
 
Schlosnagle DC, Check IJ, Sewell CW, Plummer A, York RM, Hunter RL. Immunologic abnormalities in two patients with pulmonary hyalinizing granuloma. Am J Clin Pathol. 1982;78(2):231-235. [PubMed]
 
John PG, Rahman J, Payne CB. Pulmonary hyalinizing granuloma: an unusual association with multiple sclerosis. South Med J. 1995;88(10):1076-1077. [CrossRef] [PubMed]
 
Hashimoto S, Fujii W, Takahashi T, et al. Pulmonary hyalinizing granuloma with hydronephrosis. Intern Med. 2002;41(6):463-466. [CrossRef] [PubMed]
 
Esme H, Ermis SS, Fidan F, Unlu M, Dilek FH. A case of pulmonary hyalinizing granuloma associated with posterior uveitis. Tohoku J Exp Med. 2004;204(1):93-97. [CrossRef] [PubMed]
 
Atagi S, Sakatani M, Akira M, Yamamoto S, Ueda E. Pulmonary hyalinizing granuloma with Castleman’s disease. Intern Med. 1994;33(11):689-691. [CrossRef] [PubMed]
 
Kojima M, Nakamura S, Ban S, et al. Primary pulmonary low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type with prominent hyalinosis. A case report. Pathol Res Pract. 2002;198(10):685-688. [CrossRef] [PubMed]
 
Winger DI, Spiegler P, Trow TK, et al. Radiology-Pathology Conference: pulmonary hyalinizing granuloma associated with lupus-like anticoagulant and Morvan’s syndrome. Clin Imaging. 2007;31(4):264-268. [CrossRef] [PubMed]
 
Chapman EM, Gown A, Mazziotta R, Churg A. Pulmonary hyalinizing granuloma with associated elevation in serum and tissue IgG4 occurring in a patient with a history of sarcoidosis. Am J Surg Pathol. 2012;36(5):774-778. [CrossRef] [PubMed]
 
Shinohara T, Kaneko T, Miyazawa N, et al. Pulmonary hyalinizing granuloma with laryngeal and subcutaneous involvement: report of a case successfully treated with glucocorticoids. Intern Med. 2004;43(1):69-73. [CrossRef] [PubMed]
 
Satti MB, Batouk AA, Abdelaziz MM, Ahmad MF, Abdelaal MA. Pulmonary hyalinizing granuloma. Bilateral pulmonary nodules associated with chronic idiopathic thrombocytopenic purpura. Saudi Med J. 2005;26(9):1459-1463. [PubMed]
 
Shibata Y, Kobayashi T, Hattori Y, et al. High-resolution CT findings in pulmonary hyalinizing granuloma. J Thorac Imaging. 2007;22(4):374-377. [CrossRef] [PubMed]
 
Haaga JR, Dogra VS, Forsting M, Gilkeson RC, Ha HK, Sundaram M. CT and MRI of the Whole Body.5th ed. Philadelphia, PA: Mosby Elsevier; 2009:868-870.
 
Chalaoui J, Grégoire P, Sylvestre J, Lefebvre R, Amyot R. Pulmonary hyalinizing granuloma: a cause of pulmonary nodules. Radiology. 1984;152(1):23-26. [CrossRef] [PubMed]
 
Ikard RW. Pulmonary hyalinizing granuloma. Chest. 1988;93(4):871-872. [CrossRef] [PubMed]
 
Lien CT, Yang CJ, Yang SF, Chou SH, Huang MS. Pulmonary hyalinizing granuloma mimicking multiple lung metastases: report of fluorodeoxyglucose positron emission findings. J Thorac Imaging. 2010;25(2):W36-W39. [PubMed]
 
Guccion JG, Rohatgi PK, Saini N. Pulmonary hyalinizing granuloma. Electron microscopic and immunologic studies. Chest. 1984;85(4):571-573. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Chest radiograph demonstrating multiple nodular opacities in both lungs.Grahic Jump Location
Figure Jump LinkFigure 2 –  A-C, Chest CT scans without contrast revealed multiple nodular lesions in all lobes of both lungs, variably distributed from the central zone to the periphery (black arrows). The nodules varied in size from 1.1 to 2.0 cm, having sharp to mildly irregular margins. The majority of these nodules are subpleural and fissural in location, anatomically a perilymphatic distribution. D-F, Soft tissue window at the same level demonstrates mildly heterogeneous soft tissue density (white arrows). No lymphadenopathy. No pleural or pericardial effusions. G, Some lesions had an associated “feeding vessel sign,” correlating with a perivascular distribution seen on pathology (white arrow).Grahic Jump Location
Figure Jump LinkFigure 3 –  A, Histologic sections of the right upper lobe lesion revealed a well-circumscribed, densely fibrotic nodule with a lymphoid rim at the interface (hematoxylin and eosin, original magnification × 4). B, At high magnification, the nodule was composed of thick collagen bundles, some of which were layered around vessels (hematoxylin and eosin, original magnification × 40).Grahic Jump Location

Tables

References

Engleman P, Liebow AA, Gmelich J, Friedman PJ. Pulmonary hyalinizing granuloma. Am Rev Respir Dis. 1977;115(6):997-1008. [PubMed]
 
Yousem SA, Hochholzer L. Pulmonary hyalinizing granuloma. Am J Clin Pathol. 1987;87(1):1-6. [PubMed]
 
Schlosnagle DC, Check IJ, Sewell CW, Plummer A, York RM, Hunter RL. Immunologic abnormalities in two patients with pulmonary hyalinizing granuloma. Am J Clin Pathol. 1982;78(2):231-235. [PubMed]
 
John PG, Rahman J, Payne CB. Pulmonary hyalinizing granuloma: an unusual association with multiple sclerosis. South Med J. 1995;88(10):1076-1077. [CrossRef] [PubMed]
 
Hashimoto S, Fujii W, Takahashi T, et al. Pulmonary hyalinizing granuloma with hydronephrosis. Intern Med. 2002;41(6):463-466. [CrossRef] [PubMed]
 
Esme H, Ermis SS, Fidan F, Unlu M, Dilek FH. A case of pulmonary hyalinizing granuloma associated with posterior uveitis. Tohoku J Exp Med. 2004;204(1):93-97. [CrossRef] [PubMed]
 
Atagi S, Sakatani M, Akira M, Yamamoto S, Ueda E. Pulmonary hyalinizing granuloma with Castleman’s disease. Intern Med. 1994;33(11):689-691. [CrossRef] [PubMed]
 
Kojima M, Nakamura S, Ban S, et al. Primary pulmonary low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type with prominent hyalinosis. A case report. Pathol Res Pract. 2002;198(10):685-688. [CrossRef] [PubMed]
 
Winger DI, Spiegler P, Trow TK, et al. Radiology-Pathology Conference: pulmonary hyalinizing granuloma associated with lupus-like anticoagulant and Morvan’s syndrome. Clin Imaging. 2007;31(4):264-268. [CrossRef] [PubMed]
 
Chapman EM, Gown A, Mazziotta R, Churg A. Pulmonary hyalinizing granuloma with associated elevation in serum and tissue IgG4 occurring in a patient with a history of sarcoidosis. Am J Surg Pathol. 2012;36(5):774-778. [CrossRef] [PubMed]
 
Shinohara T, Kaneko T, Miyazawa N, et al. Pulmonary hyalinizing granuloma with laryngeal and subcutaneous involvement: report of a case successfully treated with glucocorticoids. Intern Med. 2004;43(1):69-73. [CrossRef] [PubMed]
 
Satti MB, Batouk AA, Abdelaziz MM, Ahmad MF, Abdelaal MA. Pulmonary hyalinizing granuloma. Bilateral pulmonary nodules associated with chronic idiopathic thrombocytopenic purpura. Saudi Med J. 2005;26(9):1459-1463. [PubMed]
 
Shibata Y, Kobayashi T, Hattori Y, et al. High-resolution CT findings in pulmonary hyalinizing granuloma. J Thorac Imaging. 2007;22(4):374-377. [CrossRef] [PubMed]
 
Haaga JR, Dogra VS, Forsting M, Gilkeson RC, Ha HK, Sundaram M. CT and MRI of the Whole Body.5th ed. Philadelphia, PA: Mosby Elsevier; 2009:868-870.
 
Chalaoui J, Grégoire P, Sylvestre J, Lefebvre R, Amyot R. Pulmonary hyalinizing granuloma: a cause of pulmonary nodules. Radiology. 1984;152(1):23-26. [CrossRef] [PubMed]
 
Ikard RW. Pulmonary hyalinizing granuloma. Chest. 1988;93(4):871-872. [CrossRef] [PubMed]
 
Lien CT, Yang CJ, Yang SF, Chou SH, Huang MS. Pulmonary hyalinizing granuloma mimicking multiple lung metastases: report of fluorodeoxyglucose positron emission findings. J Thorac Imaging. 2010;25(2):W36-W39. [PubMed]
 
Guccion JG, Rohatgi PK, Saini N. Pulmonary hyalinizing granuloma. Electron microscopic and immunologic studies. Chest. 1984;85(4):571-573. [CrossRef] [PubMed]
 
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