Our patient, a 67-year-old man with a history of unremitting chronic sinusitis, was diagnosed with a pseudotumor of the orbit in 1996 after noticing blurry vision and a bulging left eye. He underwent radiation therapy, various medical treatments including corticosteroids, and chemotherapy, which were all ineffective in reducing the size of the tumor. Ultimately, the tumor was debulked.
The diagnosis rendered at that time was fibrosis and chronic inflammation. The subsequent clinical course was one of recurrence and intractable progressive growth over a 1- to 2-year period. As the many pathology interpretations did not indicate a malignant process but rather one of scar-like fibroplasia, he was managed with intermittent debulking. He underwent 5 more rounds of debulking, with the second to last one being an osteoplastic frontal sinusotomy performed in 2015.
The most recent brain radiographic images show a 4.2 x 2.9 x 4.1 cm retrobulbar mass causing left-sided proptosis that was inseparable from the optic nerve and ocular musculature (Figure 1). The most recent debulking specimen of presumed orbital pseudotumor was sent to our consultative dermatopathology practice for review. Of note, in 2015 prior to the most recent debulking, an asymptomatic cutaneous right cheek lesion was sampled, showing features consistent with granuloma faciale by the same consultant.
Light Microscopy
The specimen showed an obliterative tumefactive fibrosing process that had a distinct whorled pattern storiform morphology. In particular, the collagen bundles were of wider caliber, exhibiting a hyalinized appearance showing a concentric onion-skin pattern of fibroplasia around preexisting blood vessels. While the dominant morphology was one of patterned angiocentric fibrosis, there were foci of nodular angiocentric inflammation comprising lymphocytes, plasma cells, and neutrophils with supervening leukocytoclasia and evidence of vascular compromise. The latter was characterized by focal hemorrhage along with mural and luminal fibrin deposition (Figures 2A-F).
The material from the patient’s prior debulking procedures was available and showed a similar pattern of angiocentric storiform fibrosis. The findings were held to be diagnostic of eosinophilic angiocentric fibrosis (EAF) with coexisting granuloma faciale. Phenotypic studies conducted on the most recent debulking specimen revealed that the angiocentric infiltrate was predominated by a mixture of CD4+ T cells expressing GATA-3 and without staining for CXCR3 indicative of a Th2 T cell. In addition, in certain high power fields, there were more than 100 IgG4-positive plasma cells per high power field.
Discussion
EAF of the upper respiratory tract is a rare benign disorder of unknown etiology that is believed to represent a mucosal variant of granuloma faciale. Until 2003, only 14 cases of EAF had been described in the literature. The characteristic histologic finding of a perivascular inflammatory infiltrate of neutrophils, lymphocytes, and eosinophils with attendant mural and intraluminal fibrin deposition as well as onion-skin whirling of stromal fibrotic tissue are useful for making the histologic diagnosis of EAF.
Often and quite characteristically the dominant pattern is a pauci-inflammatory angiocentric fibrosing reaction without discernible vasculitic changes. Optimal treatment can be difficult as these cases respond poorly to oral medications. While the basis of the fibrosis is one that is undoubtedly cytokine driven with the initial lesion being a small vessel vasculitis, the condition responds poorly to medical treatment and surgical excision of the fibrotic tissue of EAF remains the most common modality used to treat anatomic obstruction.1
EAF represents a unique form of fibrosing small vessel vasculitis but is not associated with any systemic stigmata of vasculitis, although coexisting cutaneous chronic small vessel vasculitis can occur in these patients falling under the designation of granuloma faciale. The first documented case is attributed to Homes and Panje who reported a case in 1983 of so-called “intranasal granuloma faciale,” recognizing its similarity to the cutaneous entity of granuloma faciale.2 The latter is a form of chronic cutaneous confined vasculitis with the majority of cases localized to the face and manifesting a peculiar predilection to involve middle-aged men. Roberts and McCann subsequently introduced the term eosinophilic angiocentric fibrosis in 1985.3,4 Regarding the cutaneous equivalent namely granuloma faciale, this condition manifests as recurrent brown-red plaques on the forehead, cheeks, and ears with periods of relapses and partial remissions and in rare instances will coexist with EAF.5
Article continues on page 2
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Clinical demographics of EAF highlight several important patterns. There does not appear to be an obvious gender bias, which of course is in contradistinction to the gender bias that one sees in granuloma faciale. Patients tend to be in overall good health, but there appears to be a higher incidence of allergic and atopic disorders in patients with EAF than in the general population. The reported age at diagnosis ranges from 25 to 79 years, with a median of 49 years and a mean of 47 years. Patients often have a history of chronic symptoms; however, in some cases, the symptoms may be significant including recurrent epistaxis and persistent nasal stuffiness. As with our patient, the patients may be diagnosed as having chronic sinusitis. Given the supervening allergic history in a significant percent of patients, the diagnosis of chronic sinusitis is not unreasonable. Nonspecific mucosal thickening and submucosal fullness may be seen on physical examination, while a soft-tissue, polypoid mass may be detected on imaging.4,6 However, in some instances, the vasculitis results in a saddle nose deformity reflective of insidious tissue ischemia. Conversely in cases where there is excessive fibroplasias, a convex hook nose deformity may eventuate.
The 2 defining morphologic features of EAF are vasculitis and fibrosis. Two separate histologic phases reflect the temporal evolution of these lesions. Early lesions show an active necrotizing vasculitis affecting capillaries and venules with a prominence of eosinophils in an angiocentric array. The more advanced lesions show a characteristic laminated scalloped pattern of fibrosis with accentuation around chronically injured vessels. The vessels typically show an onion bulb-like pattern of laminated fibrosis, which can become very striking. Unlike classic cutaneous granuloma faciale, in EAF the vasculitic changes may be very subtle while the fibrosis is extensive.4
Other causes of extensive upper airway and orbital tumefactive fibrosis would encompass 2 principle entities, namely Erdheim-Chester disease and idiopathic fibrosis. Erdheim-Chester disease is a rare non-Langerhans’ cell histiocytosis. About half of those affected have extraskeletal manifestations, with extensive fibrosis involving the hypothalamus-pituitary axis, lung, heart, retroperitoneum, skin, liver kidneys, spleen, and orbit.7 Idiopathic fibrosis typically involves the retroperitoneum and mediastinum.8 However, involvement of the orbit has been described.8,9 Cases showing dominant involvement of the nasopharynx have not been described. Furthermore, neither condition has inherent vasculitis.
Angiocentric eosinophilic fibrosis is not typically associated with lethal midline granuloma-like lesions, although we have encountered cases showing extensive nasal fibrosis and obstruction as well as clinical features of lethal midline granuloma by virtue of the degree of destruction of the soft palate and uvula. The etiology of EAF remains elusive; however, there appears to be a higher incidence of allergic and atopic disorders consisting of asthma, drug allergy, environmental allergy, urticarial, or allergic rhinitis in patients with EAF than in the general population.10-12 A potential trigger (viral or drug) may evoke a type III hypersensitivity reaction; the tissue eosinophilia and extensive collagen synthesis suggests a Th2 dominant cytokine milieu.1
In addition, the patterned fibrosis is reminiscent of the laminated whorled fibroplasia seen in the setting of IgG4-positive sclerosing disease. This observation prompted the evaluation of these cases for the presence of IgG4-positive plasma cells in cases of EAF. Indeed there is at least a subset of cases of EAF that fulfill criteria to warrant categorization as a form of IgG4-related sclerosing disease, the latter encompassing a myriad of conditions characterized by the constellation of tumefactive fibroplasia with or without high serum IgG4 and increased numbers of IgG4-positive plasma cells on biopsy with an elevated IgG4-positive plasma cell to IgG4-positive plasma cell ratio in excess of 0.40. As with EAF, a significant percent of patients with IgG4 sclerosing disease have an allergic diathesis suggesting an interplay between what might be a Th2 dysregulatory state and a tendency for excessive production of polytypic IgG4-positive plasma cells. Recognizing the potential categorization of EAF as a form of IgG4-reactive sclerosing disease has critical therapeutic implications in regards to the administration of glucocorticoids and rituximab (Rituxan). One would expect a similar positive response as that noted in the setting of other forms of IgG4-reactive sclerosing disease.10
Mechanistically if one is to assume that EAF is part of IgG4-reactive sclerosing disease, then a Th2 dominant immune dysregulatory state could define a critical impetus to the disease process. The Th2 cytokines IL-4 and IL-10 are able to class switch plasma cells into producing IgG4, normally the least common of all immunoglobulins. In addition other Th2 cytokines, namely IL-13 and transforming growth factor-ß are potent fibrogenic cytokines. Hence, the fibrosis per se may not be specifically induced by the IgG4 but rather may be the sequelae of a dysregulated Th2 dominant microenvironment. If an abnormal Th2 immune response is a driving force behind this disorder, then IL-2-inducible kinase (ITK) becomes an important therapeutic target because its ablation would subvert Th2 immunity. Ibrutinib (Imbruvica) is a potent ITK inhibitor that could prove to be useful in the treatment of this disorder.
Treatment of EAF remains quite difficult. Oral corticosteroids, intralesional corticosteroids, as well as dapsone have been utilized for treatment with limited results. Local resection may result in progressive or persistent disease, as in our patient. There have been 2 reported cases where wide local excision in subglottic cases of EAF resulted in complete resolution of the disease.1,6 However, with the purported mechanisms involving T cells and IgG4-elaborating plasma cells, immunomodulatory drug therapy suppressing the Th2 response such as ibrutinab and potentially depleting B cells (ie, rituximab and glucocorticoids) defines a logical approach based on proposed pathogenetic mechanisms that underlie this condition. In our patient, the extent of Th2 T-cell infiltration along with the degree of IgG4-plasma cell infiltration would certainly suggest a combined biologic approach to prevent recurrence of this disease.
Dr Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY.
Disclosure: The authors report no relevant financial relationships.
References
1. Pereira EM, Millas I, Reis-Filho JS, Maeda SA, Franco M. Eosinophilic angiocentric fibrosis of the sinonasal tract: report on the clinicopathologic features of a case and review of the literature. Head Neck. 2002;24(3):307-311.
2. Holmes DK, Panje WR. Intranasal granuloma faciale. Am J Otolaryngol. 1983;4(3):184-186.
3. Roberts PF, McCann BG. Eosinophilic angiocentric fibrosis of the upper respiratory tract: a mucosal variant of granuloma faciale? A report of three cases. Histopathology. 1985;9(11):1217-1225.
4. Paun S, Lund VJ, Gallimore A. Nasal fibrosis: long-term follow up of four cases of eosinophilic angiocentric fibrosis. J Laryngol Otol. 2005;119(2):119-124.
5. LeBoit PE. Granuloma faciale: a diagnosis deserving of dignity. Am J Dermatopathol. 2002;24(5):440-443.
6. Burns BV, Roberts PF, De Carpentier J, Zarod AP. Eosinophilic angiocentric fibrosis affecting the nasal cavity. A mucosal variant of the skin lesion granuloma faciale. J Laryngol Otol. 2001;115(3):223-226.
7. Sheu SY, Wenzel RR, Kersting C, Merten R, Otterbach F, Schmid KW. Erdheim-Chester disease: case report with multisystemic manifestations including testes, thyroid, and lymph nodes, and a review of literature. J Clin Pathol. 2004;57(11):1225-1228.
8. McCarthy JM, White VA, Harris G, Simons KB, Kennerdell J, Rootman J. Idiopathic sclerosing inflammation of the orbit: immunohistologic analysis and comparison with retroperitoneal fibrosis. Mod Pathol. 1993;6(5):581-587.
9. Holodny AI, Kirsch CF, Hameed M, Sclar G. Tumefactive fibroinflammatory lesion of the neck with progressive invasion of the meninges, skull base, orbit, and brain. AJNR Am J Neuroradiol. 2001;22(5):876-879.
10. Deshpande V, Khosroshahi A, Nielsen GP, Hamilos DL, Stone JH. Eosinophilic angiocentric fibrosis is a form of IgG4-related systemic disease. Am J Surg Pathol. 2011;35(5):701-706.
11. Holsinger JM, Magro C, Allen C, Powell D, Agrawal A. Eosinophilic angiocentric fibrosis. J Otolaryngol Head Neck Surg. 2008;37(5):E155-E158.
12. Magro CM, Dyrsen M. Angiocentric lesions of the head and neck. Head Neck Pathol. 2008;2(2):116-130.
Our patient, a 67-year-old man with a history of unremitting chronic sinusitis, was diagnosed with a pseudotumor of the orbit in 1996 after noticing blurry vision and a bulging left eye. He underwent radiation therapy, various medical treatments including corticosteroids, and chemotherapy, which were all ineffective in reducing the size of the tumor. Ultimately, the tumor was debulked.
The diagnosis rendered at that time was fibrosis and chronic inflammation. The subsequent clinical course was one of recurrence and intractable progressive growth over a 1- to 2-year period. As the many pathology interpretations did not indicate a malignant process but rather one of scar-like fibroplasia, he was managed with intermittent debulking. He underwent 5 more rounds of debulking, with the second to last one being an osteoplastic frontal sinusotomy performed in 2015.
The most recent brain radiographic images show a 4.2 x 2.9 x 4.1 cm retrobulbar mass causing left-sided proptosis that was inseparable from the optic nerve and ocular musculature (Figure 1). The most recent debulking specimen of presumed orbital pseudotumor was sent to our consultative dermatopathology practice for review. Of note, in 2015 prior to the most recent debulking, an asymptomatic cutaneous right cheek lesion was sampled, showing features consistent with granuloma faciale by the same consultant.
Light Microscopy
The specimen showed an obliterative tumefactive fibrosing process that had a distinct whorled pattern storiform morphology. In particular, the collagen bundles were of wider caliber, exhibiting a hyalinized appearance showing a concentric onion-skin pattern of fibroplasia around preexisting blood vessels. While the dominant morphology was one of patterned angiocentric fibrosis, there were foci of nodular angiocentric inflammation comprising lymphocytes, plasma cells, and neutrophils with supervening leukocytoclasia and evidence of vascular compromise. The latter was characterized by focal hemorrhage along with mural and luminal fibrin deposition (Figures 2A-F).
The material from the patient’s prior debulking procedures was available and showed a similar pattern of angiocentric storiform fibrosis. The findings were held to be diagnostic of eosinophilic angiocentric fibrosis (EAF) with coexisting granuloma faciale. Phenotypic studies conducted on the most recent debulking specimen revealed that the angiocentric infiltrate was predominated by a mixture of CD4+ T cells expressing GATA-3 and without staining for CXCR3 indicative of a Th2 T cell. In addition, in certain high power fields, there were more than 100 IgG4-positive plasma cells per high power field.
Discussion
EAF of the upper respiratory tract is a rare benign disorder of unknown etiology that is believed to represent a mucosal variant of granuloma faciale. Until 2003, only 14 cases of EAF had been described in the literature. The characteristic histologic finding of a perivascular inflammatory infiltrate of neutrophils, lymphocytes, and eosinophils with attendant mural and intraluminal fibrin deposition as well as onion-skin whirling of stromal fibrotic tissue are useful for making the histologic diagnosis of EAF.
Often and quite characteristically the dominant pattern is a pauci-inflammatory angiocentric fibrosing reaction without discernible vasculitic changes. Optimal treatment can be difficult as these cases respond poorly to oral medications. While the basis of the fibrosis is one that is undoubtedly cytokine driven with the initial lesion being a small vessel vasculitis, the condition responds poorly to medical treatment and surgical excision of the fibrotic tissue of EAF remains the most common modality used to treat anatomic obstruction.1
EAF represents a unique form of fibrosing small vessel vasculitis but is not associated with any systemic stigmata of vasculitis, although coexisting cutaneous chronic small vessel vasculitis can occur in these patients falling under the designation of granuloma faciale. The first documented case is attributed to Homes and Panje who reported a case in 1983 of so-called “intranasal granuloma faciale,” recognizing its similarity to the cutaneous entity of granuloma faciale.2 The latter is a form of chronic cutaneous confined vasculitis with the majority of cases localized to the face and manifesting a peculiar predilection to involve middle-aged men. Roberts and McCann subsequently introduced the term eosinophilic angiocentric fibrosis in 1985.3,4 Regarding the cutaneous equivalent namely granuloma faciale, this condition manifests as recurrent brown-red plaques on the forehead, cheeks, and ears with periods of relapses and partial remissions and in rare instances will coexist with EAF.5
Clinical demographics of EAF highlight several important patterns. There does not appear to be an obvious gender bias, which of course is in contradistinction to the gender bias that one sees in granuloma faciale. Patients tend to be in overall good health, but there appears to be a higher incidence of allergic and atopic disorders in patients with EAF than in the general population. The reported age at diagnosis ranges from 25 to 79 years, with a median of 49 years and a mean of 47 years. Patients often have a history of chronic symptoms; however, in some cases, the symptoms may be significant including recurrent epistaxis and persistent nasal stuffiness. As with our patient, the patients may be diagnosed as having chronic sinusitis. Given the supervening allergic history in a significant percent of patients, the diagnosis of chronic sinusitis is not unreasonable. Nonspecific mucosal thickening and submucosal fullness may be seen on physical examination, while a soft-tissue, polypoid mass may be detected on imaging.4,6 However, in some instances, the vasculitis results in a saddle nose deformity reflective of insidious tissue ischemia. Conversely in cases where there is excessive fibroplasias, a convex hook nose deformity may eventuate.
The 2 defining morphologic features of EAF are vasculitis and fibrosis. Two separate histologic phases reflect the temporal evolution of these lesions. Early lesions show an active necrotizing vasculitis affecting capillaries and venules with a prominence of eosinophils in an angiocentric array. The more advanced lesions show a characteristic laminated scalloped pattern of fibrosis with accentuation around chronically injured vessels. The vessels typically show an onion bulb-like pattern of laminated fibrosis, which can become very striking. Unlike classic cutaneous granuloma faciale, in EAF the vasculitic changes may be very subtle while the fibrosis is extensive.4
Other causes of extensive upper airway and orbital tumefactive fibrosis would encompass 2 principle entities, namely Erdheim-Chester disease and idiopathic fibrosis. Erdheim-Chester disease is a rare non-Langerhans’ cell histiocytosis. About half of those affected have extraskeletal manifestations, with extensive fibrosis involving the hypothalamus-pituitary axis, lung, heart, retroperitoneum, skin, liver kidneys, spleen, and orbit.7 Idiopathic fibrosis typically involves the retroperitoneum and mediastinum.8 However, involvement of the orbit has been described.8,9 Cases showing dominant involvement of the nasopharynx have not been described. Furthermore, neither condition has inherent vasculitis.
Angiocentric eosinophilic fibrosis is not typically associated with lethal midline granuloma-like lesions, although we have encountered cases showing extensive nasal fibrosis and obstruction as well as clinical features of lethal midline granuloma by virtue of the degree of destruction of the soft palate and uvula. The etiology of EAF remains elusive; however, there appears to be a higher incidence of allergic and atopic disorders consisting of asthma, drug allergy, environmental allergy, urticarial, or allergic rhinitis in patients with EAF than in the general population.10-12 A potential trigger (viral or drug) may evoke a type III hypersensitivity reaction; the tissue eosinophilia and extensive collagen synthesis suggests a Th2 dominant cytokine milieu.1
In addition, the patterned fibrosis is reminiscent of the laminated whorled fibroplasia seen in the setting of IgG4-positive sclerosing disease. This observation prompted the evaluation of these cases for the presence of IgG4-positive plasma cells in cases of EAF. Indeed there is at least a subset of cases of EAF that fulfill criteria to warrant categorization as a form of IgG4-related sclerosing disease, the latter encompassing a myriad of conditions characterized by the constellation of tumefactive fibroplasia with or without high serum IgG4 and increased numbers of IgG4-positive plasma cells on biopsy with an elevated IgG4-positive plasma cell to IgG4-positive plasma cell ratio in excess of 0.40. As with EAF, a significant percent of patients with IgG4 sclerosing disease have an allergic diathesis suggesting an interplay between what might be a Th2 dysregulatory state and a tendency for excessive production of polytypic IgG4-positive plasma cells. Recognizing the potential categorization of EAF as a form of IgG4-reactive sclerosing disease has critical therapeutic implications in regards to the administration of glucocorticoids and rituximab (Rituxan). One would expect a similar positive response as that noted in the setting of other forms of IgG4-reactive sclerosing disease.10
Mechanistically if one is to assume that EAF is part of IgG4-reactive sclerosing disease, then a Th2 dominant immune dysregulatory state could define a critical impetus to the disease process. The Th2 cytokines IL-4 and IL-10 are able to class switch plasma cells into producing IgG4, normally the least common of all immunoglobulins. In addition other Th2 cytokines, namely IL-13 and transforming growth factor-ß are potent fibrogenic cytokines. Hence, the fibrosis per se may not be specifically induced by the IgG4 but rather may be the sequelae of a dysregulated Th2 dominant microenvironment. If an abnormal Th2 immune response is a driving force behind this disorder, then IL-2-inducible kinase (ITK) becomes an important therapeutic target because its ablation would subvert Th2 immunity. Ibrutinib (Imbruvica) is a potent ITK inhibitor that could prove to be useful in the treatment of this disorder.
Treatment of EAF remains quite difficult. Oral corticosteroids, intralesional corticosteroids, as well as dapsone have been utilized for treatment with limited results. Local resection may result in progressive or persistent disease, as in our patient. There have been 2 reported cases where wide local excision in subglottic cases of EAF resulted in complete resolution of the disease.1,6 However, with the purported mechanisms involving T cells and IgG4-elaborating plasma cells, immunomodulatory drug therapy suppressing the Th2 response such as ibrutinab and potentially depleting B cells (ie, rituximab and glucocorticoids) defines a logical approach based on proposed pathogenetic mechanisms that underlie this condition. In our patient, the extent of Th2 T-cell infiltration along with the degree of IgG4-plasma cell infiltration would certainly suggest a combined biologic approach to prevent recurrence of this disease.
Dr Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY.
Disclosure: The authors report no relevant financial relationships.
References
1. Pereira EM, Millas I, Reis-Filho JS, Maeda SA, Franco M. Eosinophilic angiocentric fibrosis of the sinonasal tract: report on the clinicopathologic features of a case and review of the literature. Head Neck. 2002;24(3):307-311.
2. Holmes DK, Panje WR. Intranasal granuloma faciale. Am J Otolaryngol. 1983;4(3):184-186.
3. Roberts PF, McCann BG. Eosinophilic angiocentric fibrosis of the upper respiratory tract: a mucosal variant of granuloma faciale? A report of three cases. Histopathology. 1985;9(11):1217-1225.
4. Paun S, Lund VJ, Gallimore A. Nasal fibrosis: long-term follow up of four cases of eosinophilic angiocentric fibrosis. J Laryngol Otol. 2005;119(2):119-124.
5. LeBoit PE. Granuloma faciale: a diagnosis deserving of dignity. Am J Dermatopathol. 2002;24(5):440-443.
6. Burns BV, Roberts PF, De Carpentier J, Zarod AP. Eosinophilic angiocentric fibrosis affecting the nasal cavity. A mucosal variant of the skin lesion granuloma faciale. J Laryngol Otol. 2001;115(3):223-226.
7. Sheu SY, Wenzel RR, Kersting C, Merten R, Otterbach F, Schmid KW. Erdheim-Chester disease: case report with multisystemic manifestations including testes, thyroid, and lymph nodes, and a review of literature. J Clin Pathol. 2004;57(11):1225-1228.
8. McCarthy JM, White VA, Harris G, Simons KB, Kennerdell J, Rootman J. Idiopathic sclerosing inflammation of the orbit: immunohistologic analysis and comparison with retroperitoneal fibrosis. Mod Pathol. 1993;6(5):581-587.
9. Holodny AI, Kirsch CF, Hameed M, Sclar G. Tumefactive fibroinflammatory lesion of the neck with progressive invasion of the meninges, skull base, orbit, and brain. AJNR Am J Neuroradiol. 2001;22(5):876-879.
10. Deshpande V, Khosroshahi A, Nielsen GP, Hamilos DL, Stone JH. Eosinophilic angiocentric fibrosis is a form of IgG4-related systemic disease. Am J Surg Pathol. 2011;35(5):701-706.
11. Holsinger JM, Magro C, Allen C, Powell D, Agrawal A. Eosinophilic angiocentric fibrosis. J Otolaryngol Head Neck Surg. 2008;37(5):E155-E158.
12. Magro CM, Dyrsen M. Angiocentric lesions of the head and neck. Head Neck Pathol. 2008;2(2):116-130.
Our patient, a 67-year-old man with a history of unremitting chronic sinusitis, was diagnosed with a pseudotumor of the orbit in 1996 after noticing blurry vision and a bulging left eye. He underwent radiation therapy, various medical treatments including corticosteroids, and chemotherapy, which were all ineffective in reducing the size of the tumor. Ultimately, the tumor was debulked.
The diagnosis rendered at that time was fibrosis and chronic inflammation. The subsequent clinical course was one of recurrence and intractable progressive growth over a 1- to 2-year period. As the many pathology interpretations did not indicate a malignant process but rather one of scar-like fibroplasia, he was managed with intermittent debulking. He underwent 5 more rounds of debulking, with the second to last one being an osteoplastic frontal sinusotomy performed in 2015.
The most recent brain radiographic images show a 4.2 x 2.9 x 4.1 cm retrobulbar mass causing left-sided proptosis that was inseparable from the optic nerve and ocular musculature (Figure 1). The most recent debulking specimen of presumed orbital pseudotumor was sent to our consultative dermatopathology practice for review. Of note, in 2015 prior to the most recent debulking, an asymptomatic cutaneous right cheek lesion was sampled, showing features consistent with granuloma faciale by the same consultant.
Light Microscopy
The specimen showed an obliterative tumefactive fibrosing process that had a distinct whorled pattern storiform morphology. In particular, the collagen bundles were of wider caliber, exhibiting a hyalinized appearance showing a concentric onion-skin pattern of fibroplasia around preexisting blood vessels. While the dominant morphology was one of patterned angiocentric fibrosis, there were foci of nodular angiocentric inflammation comprising lymphocytes, plasma cells, and neutrophils with supervening leukocytoclasia and evidence of vascular compromise. The latter was characterized by focal hemorrhage along with mural and luminal fibrin deposition (Figures 2A-F).
The material from the patient’s prior debulking procedures was available and showed a similar pattern of angiocentric storiform fibrosis. The findings were held to be diagnostic of eosinophilic angiocentric fibrosis (EAF) with coexisting granuloma faciale. Phenotypic studies conducted on the most recent debulking specimen revealed that the angiocentric infiltrate was predominated by a mixture of CD4+ T cells expressing GATA-3 and without staining for CXCR3 indicative of a Th2 T cell. In addition, in certain high power fields, there were more than 100 IgG4-positive plasma cells per high power field.
Discussion
EAF of the upper respiratory tract is a rare benign disorder of unknown etiology that is believed to represent a mucosal variant of granuloma faciale. Until 2003, only 14 cases of EAF had been described in the literature. The characteristic histologic finding of a perivascular inflammatory infiltrate of neutrophils, lymphocytes, and eosinophils with attendant mural and intraluminal fibrin deposition as well as onion-skin whirling of stromal fibrotic tissue are useful for making the histologic diagnosis of EAF.
Often and quite characteristically the dominant pattern is a pauci-inflammatory angiocentric fibrosing reaction without discernible vasculitic changes. Optimal treatment can be difficult as these cases respond poorly to oral medications. While the basis of the fibrosis is one that is undoubtedly cytokine driven with the initial lesion being a small vessel vasculitis, the condition responds poorly to medical treatment and surgical excision of the fibrotic tissue of EAF remains the most common modality used to treat anatomic obstruction.1
EAF represents a unique form of fibrosing small vessel vasculitis but is not associated with any systemic stigmata of vasculitis, although coexisting cutaneous chronic small vessel vasculitis can occur in these patients falling under the designation of granuloma faciale. The first documented case is attributed to Homes and Panje who reported a case in 1983 of so-called “intranasal granuloma faciale,” recognizing its similarity to the cutaneous entity of granuloma faciale.2 The latter is a form of chronic cutaneous confined vasculitis with the majority of cases localized to the face and manifesting a peculiar predilection to involve middle-aged men. Roberts and McCann subsequently introduced the term eosinophilic angiocentric fibrosis in 1985.3,4 Regarding the cutaneous equivalent namely granuloma faciale, this condition manifests as recurrent brown-red plaques on the forehead, cheeks, and ears with periods of relapses and partial remissions and in rare instances will coexist with EAF.5
,
Our patient, a 67-year-old man with a history of unremitting chronic sinusitis, was diagnosed with a pseudotumor of the orbit in 1996 after noticing blurry vision and a bulging left eye. He underwent radiation therapy, various medical treatments including corticosteroids, and chemotherapy, which were all ineffective in reducing the size of the tumor. Ultimately, the tumor was debulked.
The diagnosis rendered at that time was fibrosis and chronic inflammation. The subsequent clinical course was one of recurrence and intractable progressive growth over a 1- to 2-year period. As the many pathology interpretations did not indicate a malignant process but rather one of scar-like fibroplasia, he was managed with intermittent debulking. He underwent 5 more rounds of debulking, with the second to last one being an osteoplastic frontal sinusotomy performed in 2015.
The most recent brain radiographic images show a 4.2 x 2.9 x 4.1 cm retrobulbar mass causing left-sided proptosis that was inseparable from the optic nerve and ocular musculature (Figure 1). The most recent debulking specimen of presumed orbital pseudotumor was sent to our consultative dermatopathology practice for review. Of note, in 2015 prior to the most recent debulking, an asymptomatic cutaneous right cheek lesion was sampled, showing features consistent with granuloma faciale by the same consultant.
Light Microscopy
The specimen showed an obliterative tumefactive fibrosing process that had a distinct whorled pattern storiform morphology. In particular, the collagen bundles were of wider caliber, exhibiting a hyalinized appearance showing a concentric onion-skin pattern of fibroplasia around preexisting blood vessels. While the dominant morphology was one of patterned angiocentric fibrosis, there were foci of nodular angiocentric inflammation comprising lymphocytes, plasma cells, and neutrophils with supervening leukocytoclasia and evidence of vascular compromise. The latter was characterized by focal hemorrhage along with mural and luminal fibrin deposition (Figures 2A-F).
The material from the patient’s prior debulking procedures was available and showed a similar pattern of angiocentric storiform fibrosis. The findings were held to be diagnostic of eosinophilic angiocentric fibrosis (EAF) with coexisting granuloma faciale. Phenotypic studies conducted on the most recent debulking specimen revealed that the angiocentric infiltrate was predominated by a mixture of CD4+ T cells expressing GATA-3 and without staining for CXCR3 indicative of a Th2 T cell. In addition, in certain high power fields, there were more than 100 IgG4-positive plasma cells per high power field.
Discussion
EAF of the upper respiratory tract is a rare benign disorder of unknown etiology that is believed to represent a mucosal variant of granuloma faciale. Until 2003, only 14 cases of EAF had been described in the literature. The characteristic histologic finding of a perivascular inflammatory infiltrate of neutrophils, lymphocytes, and eosinophils with attendant mural and intraluminal fibrin deposition as well as onion-skin whirling of stromal fibrotic tissue are useful for making the histologic diagnosis of EAF.
Often and quite characteristically the dominant pattern is a pauci-inflammatory angiocentric fibrosing reaction without discernible vasculitic changes. Optimal treatment can be difficult as these cases respond poorly to oral medications. While the basis of the fibrosis is one that is undoubtedly cytokine driven with the initial lesion being a small vessel vasculitis, the condition responds poorly to medical treatment and surgical excision of the fibrotic tissue of EAF remains the most common modality used to treat anatomic obstruction.1
EAF represents a unique form of fibrosing small vessel vasculitis but is not associated with any systemic stigmata of vasculitis, although coexisting cutaneous chronic small vessel vasculitis can occur in these patients falling under the designation of granuloma faciale. The first documented case is attributed to Homes and Panje who reported a case in 1983 of so-called “intranasal granuloma faciale,” recognizing its similarity to the cutaneous entity of granuloma faciale.2 The latter is a form of chronic cutaneous confined vasculitis with the majority of cases localized to the face and manifesting a peculiar predilection to involve middle-aged men. Roberts and McCann subsequently introduced the term eosinophilic angiocentric fibrosis in 1985.3,4 Regarding the cutaneous equivalent namely granuloma faciale, this condition manifests as recurrent brown-red plaques on the forehead, cheeks, and ears with periods of relapses and partial remissions and in rare instances will coexist with EAF.5
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Clinical demographics of EAF highlight several important patterns. There does not appear to be an obvious gender bias, which of course is in contradistinction to the gender bias that one sees in granuloma faciale. Patients tend to be in overall good health, but there appears to be a higher incidence of allergic and atopic disorders in patients with EAF than in the general population. The reported age at diagnosis ranges from 25 to 79 years, with a median of 49 years and a mean of 47 years. Patients often have a history of chronic symptoms; however, in some cases, the symptoms may be significant including recurrent epistaxis and persistent nasal stuffiness. As with our patient, the patients may be diagnosed as having chronic sinusitis. Given the supervening allergic history in a significant percent of patients, the diagnosis of chronic sinusitis is not unreasonable. Nonspecific mucosal thickening and submucosal fullness may be seen on physical examination, while a soft-tissue, polypoid mass may be detected on imaging.4,6 However, in some instances, the vasculitis results in a saddle nose deformity reflective of insidious tissue ischemia. Conversely in cases where there is excessive fibroplasias, a convex hook nose deformity may eventuate.
The 2 defining morphologic features of EAF are vasculitis and fibrosis. Two separate histologic phases reflect the temporal evolution of these lesions. Early lesions show an active necrotizing vasculitis affecting capillaries and venules with a prominence of eosinophils in an angiocentric array. The more advanced lesions show a characteristic laminated scalloped pattern of fibrosis with accentuation around chronically injured vessels. The vessels typically show an onion bulb-like pattern of laminated fibrosis, which can become very striking. Unlike classic cutaneous granuloma faciale, in EAF the vasculitic changes may be very subtle while the fibrosis is extensive.4
Other causes of extensive upper airway and orbital tumefactive fibrosis would encompass 2 principle entities, namely Erdheim-Chester disease and idiopathic fibrosis. Erdheim-Chester disease is a rare non-Langerhans’ cell histiocytosis. About half of those affected have extraskeletal manifestations, with extensive fibrosis involving the hypothalamus-pituitary axis, lung, heart, retroperitoneum, skin, liver kidneys, spleen, and orbit.7 Idiopathic fibrosis typically involves the retroperitoneum and mediastinum.8 However, involvement of the orbit has been described.8,9 Cases showing dominant involvement of the nasopharynx have not been described. Furthermore, neither condition has inherent vasculitis.
Angiocentric eosinophilic fibrosis is not typically associated with lethal midline granuloma-like lesions, although we have encountered cases showing extensive nasal fibrosis and obstruction as well as clinical features of lethal midline granuloma by virtue of the degree of destruction of the soft palate and uvula. The etiology of EAF remains elusive; however, there appears to be a higher incidence of allergic and atopic disorders consisting of asthma, drug allergy, environmental allergy, urticarial, or allergic rhinitis in patients with EAF than in the general population.10-12 A potential trigger (viral or drug) may evoke a type III hypersensitivity reaction; the tissue eosinophilia and extensive collagen synthesis suggests a Th2 dominant cytokine milieu.1
In addition, the patterned fibrosis is reminiscent of the laminated whorled fibroplasia seen in the setting of IgG4-positive sclerosing disease. This observation prompted the evaluation of these cases for the presence of IgG4-positive plasma cells in cases of EAF. Indeed there is at least a subset of cases of EAF that fulfill criteria to warrant categorization as a form of IgG4-related sclerosing disease, the latter encompassing a myriad of conditions characterized by the constellation of tumefactive fibroplasia with or without high serum IgG4 and increased numbers of IgG4-positive plasma cells on biopsy with an elevated IgG4-positive plasma cell to IgG4-positive plasma cell ratio in excess of 0.40. As with EAF, a significant percent of patients with IgG4 sclerosing disease have an allergic diathesis suggesting an interplay between what might be a Th2 dysregulatory state and a tendency for excessive production of polytypic IgG4-positive plasma cells. Recognizing the potential categorization of EAF as a form of IgG4-reactive sclerosing disease has critical therapeutic implications in regards to the administration of glucocorticoids and rituximab (Rituxan). One would expect a similar positive response as that noted in the setting of other forms of IgG4-reactive sclerosing disease.10
Mechanistically if one is to assume that EAF is part of IgG4-reactive sclerosing disease, then a Th2 dominant immune dysregulatory state could define a critical impetus to the disease process. The Th2 cytokines IL-4 and IL-10 are able to class switch plasma cells into producing IgG4, normally the least common of all immunoglobulins. In addition other Th2 cytokines, namely IL-13 and transforming growth factor-ß are potent fibrogenic cytokines. Hence, the fibrosis per se may not be specifically induced by the IgG4 but rather may be the sequelae of a dysregulated Th2 dominant microenvironment. If an abnormal Th2 immune response is a driving force behind this disorder, then IL-2-inducible kinase (ITK) becomes an important therapeutic target because its ablation would subvert Th2 immunity. Ibrutinib (Imbruvica) is a potent ITK inhibitor that could prove to be useful in the treatment of this disorder.
Treatment of EAF remains quite difficult. Oral corticosteroids, intralesional corticosteroids, as well as dapsone have been utilized for treatment with limited results. Local resection may result in progressive or persistent disease, as in our patient. There have been 2 reported cases where wide local excision in subglottic cases of EAF resulted in complete resolution of the disease.1,6 However, with the purported mechanisms involving T cells and IgG4-elaborating plasma cells, immunomodulatory drug therapy suppressing the Th2 response such as ibrutinab and potentially depleting B cells (ie, rituximab and glucocorticoids) defines a logical approach based on proposed pathogenetic mechanisms that underlie this condition. In our patient, the extent of Th2 T-cell infiltration along with the degree of IgG4-plasma cell infiltration would certainly suggest a combined biologic approach to prevent recurrence of this disease.
Dr Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY.
Disclosure: The authors report no relevant financial relationships.
References
1. Pereira EM, Millas I, Reis-Filho JS, Maeda SA, Franco M. Eosinophilic angiocentric fibrosis of the sinonasal tract: report on the clinicopathologic features of a case and review of the literature. Head Neck. 2002;24(3):307-311.
2. Holmes DK, Panje WR. Intranasal granuloma faciale. Am J Otolaryngol. 1983;4(3):184-186.
3. Roberts PF, McCann BG. Eosinophilic angiocentric fibrosis of the upper respiratory tract: a mucosal variant of granuloma faciale? A report of three cases. Histopathology. 1985;9(11):1217-1225.
4. Paun S, Lund VJ, Gallimore A. Nasal fibrosis: long-term follow up of four cases of eosinophilic angiocentric fibrosis. J Laryngol Otol. 2005;119(2):119-124.
5. LeBoit PE. Granuloma faciale: a diagnosis deserving of dignity. Am J Dermatopathol. 2002;24(5):440-443.
6. Burns BV, Roberts PF, De Carpentier J, Zarod AP. Eosinophilic angiocentric fibrosis affecting the nasal cavity. A mucosal variant of the skin lesion granuloma faciale. J Laryngol Otol. 2001;115(3):223-226.
7. Sheu SY, Wenzel RR, Kersting C, Merten R, Otterbach F, Schmid KW. Erdheim-Chester disease: case report with multisystemic manifestations including testes, thyroid, and lymph nodes, and a review of literature. J Clin Pathol. 2004;57(11):1225-1228.
8. McCarthy JM, White VA, Harris G, Simons KB, Kennerdell J, Rootman J. Idiopathic sclerosing inflammation of the orbit: immunohistologic analysis and comparison with retroperitoneal fibrosis. Mod Pathol. 1993;6(5):581-587.
9. Holodny AI, Kirsch CF, Hameed M, Sclar G. Tumefactive fibroinflammatory lesion of the neck with progressive invasion of the meninges, skull base, orbit, and brain. AJNR Am J Neuroradiol. 2001;22(5):876-879.
10. Deshpande V, Khosroshahi A, Nielsen GP, Hamilos DL, Stone JH. Eosinophilic angiocentric fibrosis is a form of IgG4-related systemic disease. Am J Surg Pathol. 2011;35(5):701-706.
11. Holsinger JM, Magro C, Allen C, Powell D, Agrawal A. Eosinophilic angiocentric fibrosis. J Otolaryngol Head Neck Surg. 2008;37(5):E155-E158.
12. Magro CM, Dyrsen M. Angiocentric lesions of the head and neck. Head Neck Pathol. 2008;2(2):116-130.
Our patient, a 67-year-old man with a history of unremitting chronic sinusitis, was diagnosed with a pseudotumor of the orbit in 1996 after noticing blurry vision and a bulging left eye. He underwent radiation therapy, various medical treatments including corticosteroids, and chemotherapy, which were all ineffective in reducing the size of the tumor. Ultimately, the tumor was debulked.
The diagnosis rendered at that time was fibrosis and chronic inflammation. The subsequent clinical course was one of recurrence and intractable progressive growth over a 1- to 2-year period. As the many pathology interpretations did not indicate a malignant process but rather one of scar-like fibroplasia, he was managed with intermittent debulking. He underwent 5 more rounds of debulking, with the second to last one being an osteoplastic frontal sinusotomy performed in 2015.
The most recent brain radiographic images show a 4.2 x 2.9 x 4.1 cm retrobulbar mass causing left-sided proptosis that was inseparable from the optic nerve and ocular musculature (Figure 1). The most recent debulking specimen of presumed orbital pseudotumor was sent to our consultative dermatopathology practice for review. Of note, in 2015 prior to the most recent debulking, an asymptomatic cutaneous right cheek lesion was sampled, showing features consistent with granuloma faciale by the same consultant.
Light Microscopy
The specimen showed an obliterative tumefactive fibrosing process that had a distinct whorled pattern storiform morphology. In particular, the collagen bundles were of wider caliber, exhibiting a hyalinized appearance showing a concentric onion-skin pattern of fibroplasia around preexisting blood vessels. While the dominant morphology was one of patterned angiocentric fibrosis, there were foci of nodular angiocentric inflammation comprising lymphocytes, plasma cells, and neutrophils with supervening leukocytoclasia and evidence of vascular compromise. The latter was characterized by focal hemorrhage along with mural and luminal fibrin deposition (Figures 2A-F).
The material from the patient’s prior debulking procedures was available and showed a similar pattern of angiocentric storiform fibrosis. The findings were held to be diagnostic of eosinophilic angiocentric fibrosis (EAF) with coexisting granuloma faciale. Phenotypic studies conducted on the most recent debulking specimen revealed that the angiocentric infiltrate was predominated by a mixture of CD4+ T cells expressing GATA-3 and without staining for CXCR3 indicative of a Th2 T cell. In addition, in certain high power fields, there were more than 100 IgG4-positive plasma cells per high power field.
Discussion
EAF of the upper respiratory tract is a rare benign disorder of unknown etiology that is believed to represent a mucosal variant of granuloma faciale. Until 2003, only 14 cases of EAF had been described in the literature. The characteristic histologic finding of a perivascular inflammatory infiltrate of neutrophils, lymphocytes, and eosinophils with attendant mural and intraluminal fibrin deposition as well as onion-skin whirling of stromal fibrotic tissue are useful for making the histologic diagnosis of EAF.
Often and quite characteristically the dominant pattern is a pauci-inflammatory angiocentric fibrosing reaction without discernible vasculitic changes. Optimal treatment can be difficult as these cases respond poorly to oral medications. While the basis of the fibrosis is one that is undoubtedly cytokine driven with the initial lesion being a small vessel vasculitis, the condition responds poorly to medical treatment and surgical excision of the fibrotic tissue of EAF remains the most common modality used to treat anatomic obstruction.1
EAF represents a unique form of fibrosing small vessel vasculitis but is not associated with any systemic stigmata of vasculitis, although coexisting cutaneous chronic small vessel vasculitis can occur in these patients falling under the designation of granuloma faciale. The first documented case is attributed to Homes and Panje who reported a case in 1983 of so-called “intranasal granuloma faciale,” recognizing its similarity to the cutaneous entity of granuloma faciale.2 The latter is a form of chronic cutaneous confined vasculitis with the majority of cases localized to the face and manifesting a peculiar predilection to involve middle-aged men. Roberts and McCann subsequently introduced the term eosinophilic angiocentric fibrosis in 1985.3,4 Regarding the cutaneous equivalent namely granuloma faciale, this condition manifests as recurrent brown-red plaques on the forehead, cheeks, and ears with periods of relapses and partial remissions and in rare instances will coexist with EAF.5
Clinical demographics of EAF highlight several important patterns. There does not appear to be an obvious gender bias, which of course is in contradistinction to the gender bias that one sees in granuloma faciale. Patients tend to be in overall good health, but there appears to be a higher incidence of allergic and atopic disorders in patients with EAF than in the general population. The reported age at diagnosis ranges from 25 to 79 years, with a median of 49 years and a mean of 47 years. Patients often have a history of chronic symptoms; however, in some cases, the symptoms may be significant including recurrent epistaxis and persistent nasal stuffiness. As with our patient, the patients may be diagnosed as having chronic sinusitis. Given the supervening allergic history in a significant percent of patients, the diagnosis of chronic sinusitis is not unreasonable. Nonspecific mucosal thickening and submucosal fullness may be seen on physical examination, while a soft-tissue, polypoid mass may be detected on imaging.4,6 However, in some instances, the vasculitis results in a saddle nose deformity reflective of insidious tissue ischemia. Conversely in cases where there is excessive fibroplasias, a convex hook nose deformity may eventuate.
The 2 defining morphologic features of EAF are vasculitis and fibrosis. Two separate histologic phases reflect the temporal evolution of these lesions. Early lesions show an active necrotizing vasculitis affecting capillaries and venules with a prominence of eosinophils in an angiocentric array. The more advanced lesions show a characteristic laminated scalloped pattern of fibrosis with accentuation around chronically injured vessels. The vessels typically show an onion bulb-like pattern of laminated fibrosis, which can become very striking. Unlike classic cutaneous granuloma faciale, in EAF the vasculitic changes may be very subtle while the fibrosis is extensive.4
Other causes of extensive upper airway and orbital tumefactive fibrosis would encompass 2 principle entities, namely Erdheim-Chester disease and idiopathic fibrosis. Erdheim-Chester disease is a rare non-Langerhans’ cell histiocytosis. About half of those affected have extraskeletal manifestations, with extensive fibrosis involving the hypothalamus-pituitary axis, lung, heart, retroperitoneum, skin, liver kidneys, spleen, and orbit.7 Idiopathic fibrosis typically involves the retroperitoneum and mediastinum.8 However, involvement of the orbit has been described.8,9 Cases showing dominant involvement of the nasopharynx have not been described. Furthermore, neither condition has inherent vasculitis.
Angiocentric eosinophilic fibrosis is not typically associated with lethal midline granuloma-like lesions, although we have encountered cases showing extensive nasal fibrosis and obstruction as well as clinical features of lethal midline granuloma by virtue of the degree of destruction of the soft palate and uvula. The etiology of EAF remains elusive; however, there appears to be a higher incidence of allergic and atopic disorders consisting of asthma, drug allergy, environmental allergy, urticarial, or allergic rhinitis in patients with EAF than in the general population.10-12 A potential trigger (viral or drug) may evoke a type III hypersensitivity reaction; the tissue eosinophilia and extensive collagen synthesis suggests a Th2 dominant cytokine milieu.1
In addition, the patterned fibrosis is reminiscent of the laminated whorled fibroplasia seen in the setting of IgG4-positive sclerosing disease. This observation prompted the evaluation of these cases for the presence of IgG4-positive plasma cells in cases of EAF. Indeed there is at least a subset of cases of EAF that fulfill criteria to warrant categorization as a form of IgG4-related sclerosing disease, the latter encompassing a myriad of conditions characterized by the constellation of tumefactive fibroplasia with or without high serum IgG4 and increased numbers of IgG4-positive plasma cells on biopsy with an elevated IgG4-positive plasma cell to IgG4-positive plasma cell ratio in excess of 0.40. As with EAF, a significant percent of patients with IgG4 sclerosing disease have an allergic diathesis suggesting an interplay between what might be a Th2 dysregulatory state and a tendency for excessive production of polytypic IgG4-positive plasma cells. Recognizing the potential categorization of EAF as a form of IgG4-reactive sclerosing disease has critical therapeutic implications in regards to the administration of glucocorticoids and rituximab (Rituxan). One would expect a similar positive response as that noted in the setting of other forms of IgG4-reactive sclerosing disease.10
Mechanistically if one is to assume that EAF is part of IgG4-reactive sclerosing disease, then a Th2 dominant immune dysregulatory state could define a critical impetus to the disease process. The Th2 cytokines IL-4 and IL-10 are able to class switch plasma cells into producing IgG4, normally the least common of all immunoglobulins. In addition other Th2 cytokines, namely IL-13 and transforming growth factor-ß are potent fibrogenic cytokines. Hence, the fibrosis per se may not be specifically induced by the IgG4 but rather may be the sequelae of a dysregulated Th2 dominant microenvironment. If an abnormal Th2 immune response is a driving force behind this disorder, then IL-2-inducible kinase (ITK) becomes an important therapeutic target because its ablation would subvert Th2 immunity. Ibrutinib (Imbruvica) is a potent ITK inhibitor that could prove to be useful in the treatment of this disorder.
Treatment of EAF remains quite difficult. Oral corticosteroids, intralesional corticosteroids, as well as dapsone have been utilized for treatment with limited results. Local resection may result in progressive or persistent disease, as in our patient. There have been 2 reported cases where wide local excision in subglottic cases of EAF resulted in complete resolution of the disease.1,6 However, with the purported mechanisms involving T cells and IgG4-elaborating plasma cells, immunomodulatory drug therapy suppressing the Th2 response such as ibrutinab and potentially depleting B cells (ie, rituximab and glucocorticoids) defines a logical approach based on proposed pathogenetic mechanisms that underlie this condition. In our patient, the extent of Th2 T-cell infiltration along with the degree of IgG4-plasma cell infiltration would certainly suggest a combined biologic approach to prevent recurrence of this disease.
Dr Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY.
Disclosure: The authors report no relevant financial relationships.
References
1. Pereira EM, Millas I, Reis-Filho JS, Maeda SA, Franco M. Eosinophilic angiocentric fibrosis of the sinonasal tract: report on the clinicopathologic features of a case and review of the literature. Head Neck. 2002;24(3):307-311.
2. Holmes DK, Panje WR. Intranasal granuloma faciale. Am J Otolaryngol. 1983;4(3):184-186.
3. Roberts PF, McCann BG. Eosinophilic angiocentric fibrosis of the upper respiratory tract: a mucosal variant of granuloma faciale? A report of three cases. Histopathology. 1985;9(11):1217-1225.
4. Paun S, Lund VJ, Gallimore A. Nasal fibrosis: long-term follow up of four cases of eosinophilic angiocentric fibrosis. J Laryngol Otol. 2005;119(2):119-124.
5. LeBoit PE. Granuloma faciale: a diagnosis deserving of dignity. Am J Dermatopathol. 2002;24(5):440-443.
6. Burns BV, Roberts PF, De Carpentier J, Zarod AP. Eosinophilic angiocentric fibrosis affecting the nasal cavity. A mucosal variant of the skin lesion granuloma faciale. J Laryngol Otol. 2001;115(3):223-226.
7. Sheu SY, Wenzel RR, Kersting C, Merten R, Otterbach F, Schmid KW. Erdheim-Chester disease: case report with multisystemic manifestations including testes, thyroid, and lymph nodes, and a review of literature. J Clin Pathol. 2004;57(11):1225-1228.
8. McCarthy JM, White VA, Harris G, Simons KB, Kennerdell J, Rootman J. Idiopathic sclerosing inflammation of the orbit: immunohistologic analysis and comparison with retroperitoneal fibrosis. Mod Pathol. 1993;6(5):581-587.
9. Holodny AI, Kirsch CF, Hameed M, Sclar G. Tumefactive fibroinflammatory lesion of the neck with progressive invasion of the meninges, skull base, orbit, and brain. AJNR Am J Neuroradiol. 2001;22(5):876-879.
10. Deshpande V, Khosroshahi A, Nielsen GP, Hamilos DL, Stone JH. Eosinophilic angiocentric fibrosis is a form of IgG4-related systemic disease. Am J Surg Pathol. 2011;35(5):701-706.
11. Holsinger JM, Magro C, Allen C, Powell D, Agrawal A. Eosinophilic angiocentric fibrosis. J Otolaryngol Head Neck Surg. 2008;37(5):E155-E158.
12. Magro CM, Dyrsen M. Angiocentric lesions of the head and neck. Head Neck Pathol. 2008;2(2):116-130.
Clinical demographics of EAF highlight several important patterns. There does not appear to be an obvious gender bias, which of course is in contradistinction to the gender bias that one sees in granuloma faciale. Patients tend to be in overall good health, but there appears to be a higher incidence of allergic and atopic disorders in patients with EAF than in the general population. The reported age at diagnosis ranges from 25 to 79 years, with a median of 49 years and a mean of 47 years. Patients often have a history of chronic symptoms; however, in some cases, the symptoms may be significant including recurrent epistaxis and persistent nasal stuffiness. As with our patient, the patients may be diagnosed as having chronic sinusitis. Given the supervening allergic history in a significant percent of patients, the diagnosis of chronic sinusitis is not unreasonable. Nonspecific mucosal thickening and submucosal fullness may be seen on physical examination, while a soft-tissue, polypoid mass may be detected on imaging.4,6 However, in some instances, the vasculitis results in a saddle nose deformity reflective of insidious tissue ischemia. Conversely in cases where there is excessive fibroplasias, a convex hook nose deformity may eventuate.
The 2 defining morphologic features of EAF are vasculitis and fibrosis. Two separate histologic phases reflect the temporal evolution of these lesions. Early lesions show an active necrotizing vasculitis affecting capillaries and venules with a prominence of eosinophils in an angiocentric array. The more advanced lesions show a characteristic laminated scalloped pattern of fibrosis with accentuation around chronically injured vessels. The vessels typically show an onion bulb-like pattern of laminated fibrosis, which can become very striking. Unlike classic cutaneous granuloma faciale, in EAF the vasculitic changes may be very subtle while the fibrosis is extensive.4
Other causes of extensive upper airway and orbital tumefactive fibrosis would encompass 2 principle entities, namely Erdheim-Chester disease and idiopathic fibrosis. Erdheim-Chester disease is a rare non-Langerhans’ cell histiocytosis. About half of those affected have extraskeletal manifestations, with extensive fibrosis involving the hypothalamus-pituitary axis, lung, heart, retroperitoneum, skin, liver kidneys, spleen, and orbit.7 Idiopathic fibrosis typically involves the retroperitoneum and mediastinum.8 However, involvement of the orbit has been described.8,9 Cases showing dominant involvement of the nasopharynx have not been described. Furthermore, neither condition has inherent vasculitis.
Angiocentric eosinophilic fibrosis is not typically associated with lethal midline granuloma-like lesions, although we have encountered cases showing extensive nasal fibrosis and obstruction as well as clinical features of lethal midline granuloma by virtue of the degree of destruction of the soft palate and uvula. The etiology of EAF remains elusive; however, there appears to be a higher incidence of allergic and atopic disorders consisting of asthma, drug allergy, environmental allergy, urticarial, or allergic rhinitis in patients with EAF than in the general population.10-12 A potential trigger (viral or drug) may evoke a type III hypersensitivity reaction; the tissue eosinophilia and extensive collagen synthesis suggests a Th2 dominant cytokine milieu.1
In addition, the patterned fibrosis is reminiscent of the laminated whorled fibroplasia seen in the setting of IgG4-positive sclerosing disease. This observation prompted the evaluation of these cases for the presence of IgG4-positive plasma cells in cases of EAF. Indeed there is at least a subset of cases of EAF that fulfill criteria to warrant categorization as a form of IgG4-related sclerosing disease, the latter encompassing a myriad of conditions characterized by the constellation of tumefactive fibroplasia with or without high serum IgG4 and increased numbers of IgG4-positive plasma cells on biopsy with an elevated IgG4-positive plasma cell to IgG4-positive plasma cell ratio in excess of 0.40. As with EAF, a significant percent of patients with IgG4 sclerosing disease have an allergic diathesis suggesting an interplay between what might be a Th2 dysregulatory state and a tendency for excessive production of polytypic IgG4-positive plasma cells. Recognizing the potential categorization of EAF as a form of IgG4-reactive sclerosing disease has critical therapeutic implications in regards to the administration of glucocorticoids and rituximab (Rituxan). One would expect a similar positive response as that noted in the setting of other forms of IgG4-reactive sclerosing disease.10
Mechanistically if one is to assume that EAF is part of IgG4-reactive sclerosing disease, then a Th2 dominant immune dysregulatory state could define a critical impetus to the disease process. The Th2 cytokines IL-4 and IL-10 are able to class switch plasma cells into producing IgG4, normally the least common of all immunoglobulins. In addition other Th2 cytokines, namely IL-13 and transforming growth factor-ß are potent fibrogenic cytokines. Hence, the fibrosis per se may not be specifically induced by the IgG4 but rather may be the sequelae of a dysregulated Th2 dominant microenvironment. If an abnormal Th2 immune response is a driving force behind this disorder, then IL-2-inducible kinase (ITK) becomes an important therapeutic target because its ablation would subvert Th2 immunity. Ibrutinib (Imbruvica) is a potent ITK inhibitor that could prove to be useful in the treatment of this disorder.
Treatment of EAF remains quite difficult. Oral corticosteroids, intralesional corticosteroids, as well as dapsone have been utilized for treatment with limited results. Local resection may result in progressive or persistent disease, as in our patient. There have been 2 reported cases where wide local excision in subglottic cases of EAF resulted in complete resolution of the disease.1,6 However, with the purported mechanisms involving T cells and IgG4-elaborating plasma cells, immunomodulatory drug therapy suppressing the Th2 response such as ibrutinab and potentially depleting B cells (ie, rituximab and glucocorticoids) defines a logical approach based on proposed pathogenetic mechanisms that underlie this condition. In our patient, the extent of Th2 T-cell infiltration along with the degree of IgG4-plasma cell infiltration would certainly suggest a combined biologic approach to prevent recurrence of this disease.
Dr Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY.
Disclosure: The authors report no relevant financial relationships.
References
1. Pereira EM, Millas I, Reis-Filho JS, Maeda SA, Franco M. Eosinophilic angiocentric fibrosis of the sinonasal tract: report on the clinicopathologic features of a case and review of the literature. Head Neck. 2002;24(3):307-311.
2. Holmes DK, Panje WR. Intranasal granuloma faciale. Am J Otolaryngol. 1983;4(3):184-186.
3. Roberts PF, McCann BG. Eosinophilic angiocentric fibrosis of the upper respiratory tract: a mucosal variant of granuloma faciale? A report of three cases. Histopathology. 1985;9(11):1217-1225.
4. Paun S, Lund VJ, Gallimore A. Nasal fibrosis: long-term follow up of four cases of eosinophilic angiocentric fibrosis. J Laryngol Otol. 2005;119(2):119-124.
5. LeBoit PE. Granuloma faciale: a diagnosis deserving of dignity. Am J Dermatopathol. 2002;24(5):440-443.
6. Burns BV, Roberts PF, De Carpentier J, Zarod AP. Eosinophilic angiocentric fibrosis affecting the nasal cavity. A mucosal variant of the skin lesion granuloma faciale. J Laryngol Otol. 2001;115(3):223-226.
7. Sheu SY, Wenzel RR, Kersting C, Merten R, Otterbach F, Schmid KW. Erdheim-Chester disease: case report with multisystemic manifestations including testes, thyroid, and lymph nodes, and a review of literature. J Clin Pathol. 2004;57(11):1225-1228.
8. McCarthy JM, White VA, Harris G, Simons KB, Kennerdell J, Rootman J. Idiopathic sclerosing inflammation of the orbit: immunohistologic analysis and comparison with retroperitoneal fibrosis. Mod Pathol. 1993;6(5):581-587.
9. Holodny AI, Kirsch CF, Hameed M, Sclar G. Tumefactive fibroinflammatory lesion of the neck with progressive invasion of the meninges, skull base, orbit, and brain. AJNR Am J Neuroradiol. 2001;22(5):876-879.
10. Deshpande V, Khosroshahi A, Nielsen GP, Hamilos DL, Stone JH. Eosinophilic angiocentric fibrosis is a form of IgG4-related systemic disease. Am J Surg Pathol. 2011;35(5):701-706.
11. Holsinger JM, Magro C, Allen C, Powell D, Agrawal A. Eosinophilic angiocentric fibrosis. J Otolaryngol Head Neck Surg. 2008;37(5):E155-E158.
12. Magro CM, Dyrsen M. Angiocentric lesions of the head and neck. Head Neck Pathol. 2008;2(2):116-130.
