Case 5 -

Morphologic Changes Most Consistent with Ehlers-Danlos Syndrome Thomas V. Colby, Mayo Clinic Arizona, Scottsdale, AZ

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Clinical History A 28-year-old journalist who was a non-smoker and had never used illicit drugs presented with hemoptysis of 7 years duration. Since his initial presentation in 2003, he has had multiple recurrences of hemoptysis but it was never life threatening. This has been associated with transient infiltrates and alveolar opacities and at least two episodes of pneumothorax. At one point he had a cavitary lesion noted in the lung. Workup for alveolar hemorrhage syndromes was negative. His initial lung biopsy was taken in 2006 at the time of a left pneumothorax. Subsequently, in 2010, he presented with a second (right side) pneumothorax associated with hemoptysis and again lung biopsy was obtained and “apical bullae” were resected. Note: images 1-9 from 2006; images 10-17 from 2010 Case 5 - Figure 1 2006 Figure 1. Low power view shows a "hole" in the lung with a disruption of the alveolar architecture and a central nodule. Case 5 - Figure 2 2006 Figure 2. The nodule seen in the center of 2006 Figure 1 shows dense fibrous tissue that does not resemble any usual lung repair reaction. Case 5 - Figure 3 2006 Figure 3. The tissue surrounding the "hole" in 2006 Figure 1 shows hemosiderin-laden macrophages. Case 5 - Figure 5 2006 Figures 5 – 8. Detail of fibrous nodule showing dense fibrous connective tissue that is paucicellular and includes focal metaplastic bone formation Case 5 - Figure 6 2006 Figures 5 – 8. Detail of fibrous nodule showing dense fibrous connective tissue that is paucicellular and includes focal metaplastic bone formation Case 5 - Figure 7 2006 Figures 5 – 8. Detail of fibrous nodule showing dense fibrous connective tissue that is paucicellular and includes focal metaplastic bone formation Case 5 - Figure 8 2006 Figures 5 – 8. Detail of fibrous nodule showing dense fibrous connective tissue that is paucicellular and includes focal metaplastic bone formation Case 5 - Figure 9 Case 5 - Figure 10 Case 5 - Figure 11 2010 Figure 1. Low power view shows a region of hemorrhage and organization in the subpleural regions. Case 5 - Figure 12 2010 Figure 2. Higher power microscopy of 2010 Figure 1 shows fresh hemorrhage and organization within the lung tissue. Case 5 - Figure 13 2010 Figures 3 and 4. In another region of organization one can see early collagenization of the organizing intraluminal polyps. Case 5 - Figure 14 2010 Figures 3 and 4. In another region of organization one can see early collagenization of the organizing intraluminal polyps. Case 5 - Figure 15 2010 Figure 5. Low power view shows a region of organization with densely collagenized fibrous nodules developing (center). Case 5 - Figure 16 2010 Figure 6. Detail from 2010 Figure 5 shows a paucicellular dense collagenized nodule that does not resemble usual organization in the lung. Case 5 - Figure 17 2010 Figure 7. No abnormalities are noted on elastic tissue staining of a bronchovascular bundle and adjacent alveoli. Introduction: A 28-year-old journalist who was a non-smoker and had never used illicit drugs presented with hemoptysis of 7 years duration. Since his initial presentation in 2003, he has had multiple recurrences of hemoptysis but it was never life threatening. This has been associated with transient infiltrates and alveolar opacities and at least two episodes of pneumothorax. At one point he had a cavitary lesion noted in the lung. Workup for alveolar hemorrhage syndromes was negative. His initial lung biopsy was taken in 2006 at the time of a left pneumothorax. Subsequently, in 2010, he presented with a second (right side) pneumothorax associated with hemoptysis and again lung biopsy was obtained and "apical bullae" were resected. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The biopsy from 2006 shows portions of lung with disruption of parenchyma and "holes" in the lung tissue. The adjacent lung tissue shows fibrous nodules composed of rounded collagenized nodules with dense collagen and occasional fibrocytes. The surrounding lung tissue showed increase in hemosiderin-laden macrophages. Some of the fibrous nodules have osseous metaplasia with osteoid formation. The 2010 biopsy shows regions of organizing hemorrhage and in some regions the organization showed progression to collagenization of the organization with the formation of fibrotic nodules. Obvious abnormalities of elastic tissue staining, CD34 and smooth muscle actin staining were not observed. Differential Diagnoses: Most of the pathologic changes in this case are sufficiently nonspecific that no definitive etiology could be identified. Thus, the presence of a "hole" in the lung could be explained by emphysema/bulla formation, hemorrhage and organization represent common nonspecific findings, and hemosiderin-laden macrophages have a number of causes. The most distinctive feature in this case is the densely collagenized fibrous nodules which have also been termed fibrous pseudotumors. These do not resemble any usual repair reaction in the lung and their presence, sometimes with associated metaplastic ossification, is sufficient to raise the possibility of Ehlers-Danlos syndrome. Final Diagnosis: Morphologic changes most consistent with Ehlers- Danlos syndrome (probably type IV, "vascular" Ehlers- Danlos syndrome). Follow-up in this case was requested, but was not received. (Case courtesy Dr.M.C. Charpentier) Case Discussion: Ehlers-Danlos syndrome (EDS) is a heterogeneous group of disorders that share the common features of abnormalities in fibrillar collagen, or in the enzymes involved in their post-translational modifications. EDS occurs in 1 in 5,000 live births. In the past, subtypes have been numbered but more recently descriptive terms have been preferred and the following subtypes are recognized: Classical Hypermobility Vascular Kyphoscoliosis Arthrochalasis Dermatosporaxis Tenascin deficient Other rare subtypes Many of the subtype have specific mutational abnormalities in fibrillar collagens. Some types are autosomal dominant and some are autosomal recessive. Sporadic EDS is also recognized. The descriptive terms for the subtypes above denote the dominant clinical manifestation of the form of EDS identified. The diagnosis of EDS is based primarily on clinical findings, in conjunction with family history (in cases that are familial). The diagnosis can also be confirmed with identification of the specific mutations or with the identification of abnormal collagen production in skin fibroblast cultures. Depending on the subtype of EDS, the major clinical manifestations may be encountered in the skin (hyperelastability and abnormal scarring, either hypertrophic or atrophic), in the vascular system (rupture and aneurysms in major and minor blood vessels), the gut (rupture), or joints (arthritis). EDS is also encountered in animals, including dogs. The vascular form of EDS (formerly Type IV EDS) is said to carry the worst prognosis and the type that has been associated with pulmonary complications, which are relatively rare. No serious pulmonary complications were described in the large series of Pepin et. al. that included 220 patients with vascular EDS (vEDS). Initial presentation with vEDS may occur at any time from early childhood to late middle age. Pulmonary complications of vEDS can be related to spontaneous laceration of the lung (e.g. pneumothorax), disruption of vessels (with hemorrhage that can be fatal), alveolar wall weakness (with emphysema), and abnormal wound healing with fibrous pseudotumors. Organization of injury in vEDS may produce peculiar fibrous nodules that are distinct from normal inflammation and repair in the lung (e.g. organizing pneumonia, honeycomb fibrosis, etc.). The nodules are large, densely fibrotic and rounded in contour with fibrocytes, and are more reminiscent of a fibromatosis as seen in soft tissue than usual repair reactions in the lung. These nodules often become partially ossified. The fibrous nodules, with or without ossification, that represent the most distinctive histologic feature the pathologist may encounter, and upon which a suggestion of Ehlers-Danlos syndrome can be made. Other changes changes of vEDS, including pneumothorax, hemorrhage, and emphysema, are sufficiently common and nondescript that little specificity can be applied to them. While tears in elastic tissue have been described in the literature, it is difficult to appreciate these in routine practice and ascribe much clinical significance to them. Review of the Literature/Treatment Options (if applicable): The series of Kawabata et.al. included 9 cases of vEDS: 6 men and 3 women, with an age range of 16-43 years (mean of 23 years). Histologic findings in this series included: Pleural fibrosis/adhesions: 7/9 Hematoma formation: 7/9 Acute hemorrhage: 7/9 Fibrous nodules: 8/9 Ossification in the nodules: 6/9 Organizing pneumonia: 4/9 Hemosiderosis: 8/9 Vascular disruption (EVG): 5/9 Emphysema: 7/9 Kawabata et.al. also noted disruption in the pleura and lung that appeared to be related to the surgery, attesting to the fragility of these tissues which has implications for the surgeon. Conclusion(s): see discussion References: Byers PH, Schwarze U. Ehlers-Danlos Syndrome. Chapter 161 in Rimoin DL, et. al. EDS. Emory and Rimoin's Principles and Practice of Medical Genetics, 5th Edition. Churchill Livingston 2007; pp 3625-3645. Callewaert B, et. al. Ehlers-Danlos Syndromes and Marfan syndrome. Best Practice and Res, Clin Rheumatol. 2008; 22:165-189. Corrin B, Simpson CGB, Fisher C. Fibrous Pseudotumors and Cyst Formation in the Lungs and Ehlers-Danlos Syndrome. Histopathology 1990; 17:478-479. Dowton SB, Pincott S, Demmer L. Respiratory complications of Ehlers-Danlos syndrome type IV. Clin. Genet. 1996; 50; 510-514. Herman TE, McAlister WH. Cavitary pulmonary lesions in type IV Ehlers-Danlos syndrome. Pediatr. Radiol. 1995; 24; 263-265. Ishiguro T, Takayanagi N, Matsushima H et. al. Ehlers- Danlos syndrome with recurrent spontaneous pneumothoraces and cavitary lesion on chest x-ray as the initial complications. A case report. Intern. Med. 2009; 48; 717- 722. Kawabata Y, et. al. Pleuropulmonary pathology of vascular Ehlers-Danlos syndrome: spontaneous laceration, hematoma and fibrous nodules. Histopathology 2010; 56: 944-950. Murray RA, Poulton TB, Saltarelli MG et. al. Rare pulmonary manifestation of Ehlers-Danlos syndrome. J. Thorac. Imaging 1995; 10; 138-141 Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular? type. N. Engl. J. Med 2000; 342; 673-680. Yost BA, Vogelsang JP, Lie JT. Fatal hemoptysis in Ehlers- Danlos syndrome. Old malady with a new curse. Chest 1995; 107; 1465-1467.