CASE REPORT
Fatal Case of Vulvar Pyoderma Gangrenosum with Pulmonary Involvement: Case Presentation and Literature Review Joshua M. Mercer, Paul Kuzel, M uhammad N. Mahmood, and Alain Brassard
In tro d u ctio n : W e re p o rt a case o f a 61 -ye a r-o ld w o m a n w ith lo c a lly d e s tru c tiv e v u lv a r p y o d e rm a g a n g re n o s u m (PG) w ith p u lm o n a ry in v o lv e m e n t w h o w a s re fra c to ry t o n u m e ro u s s y s te m ic th e ra p ie s an d d e ve lo p e d c o m p lic a tio n s re s u ltin g in her dem ise.
O bjective: To re p o rt a rare case o f tre a tm e n t-re s is ta n t v u lv a r PG w ith p u lm o n a ry in v o lv e m e n t th a t p ro v e d to be fa ta l. M ethods: PubM ed w a s used to search fo r o th e r re p o rts th a t discuss PG, o r m o re s p e c ific a lly p e rig e n ita l PG, w ith p u lm o n a ry in v o lv e m e n t.
Results and Conclusion: A th o ro u g h re v ie w o f th e lite ra tu re reve aled 33 cases o f PG w ith p u lm o n a ry in v o lv e m e n t, w ith o n ly 4 in v o lv in g th e p e rig e n ita l re g io n . W e re p o rt th e seco nd case o f a fe m a le w ith v u lv a r PG and p u lm o n a ry in v o lv e m e n t. In c o n tra s t to th e f ir s t case d e scrib e d , o u r p a tie n t d id n o t re sp o n d to s y s te m ic th e ra p y , and, u ltim a te ly , her disease w a s fa ta l. It is h o p e d th a t w ith c o n tin u e d d o c u m e n ta tio n o f th is rare an d p o te n tia lly le th a l p re s e n ta tio n o f PG, p h ysicia n s w ill d e te rm in e m o re e ffe c tiv e tre a tm e n ts .
In tro d u ctio n : Sera exp o se ici le cas d 'u n e fe m m e de 61 ans, a tte in te d 'u n e p y o d e rm ite ga ng re n e u se (PG) vu lv a ire , avec d e s tru c tio n lo ca le e t a tte in te p u lm o n a ire , q u i s 'e s t m o n tre e re fra cta ire a p lu s ie u rs tra ite m e n ts p a r v o ie ge n e ra le e t q u i a fin a le m e n t e n tra in e la m o r t de la p a tie n te p a r s u ite de c o m p lic a tio n s .
Object'd: L 'a rtic le v is a it a d e crire un cas rare de PG vu lv a ire , avec a tte in te p u lm o n a ire , q u i s 'e s t m o n tre e re fra c ta ire au tr a ite m e n t e t q u i s 'e s t so ld e e p a r la m o r t de la m alade.
M ethode: N o u s a v o n s e n tre p ris un e rech erch e da ns PubM ed afin de tro u v e r d 'a u tre s a rtic le s su r la PG, p lu s p re c is e m e n t su r la PG p e rig e n ita le , avec a tte in te p u lm o n a ire .
Resultats e t conclusion: U n e xa m en a p p ro fo n d i de la d o c u m e n ta tio n a reve le I'e xiste n ce de 33 cas de PG avec a tte in te p u lm o n a ire , m a is 4 s e u le m e n t fa is a ie n t e ta t d 'u n e a tte in te de la re g io n p e rig e n ita le . II s 'a g it ici du d e u xie m e cas de PG v u lv a ire , avec a tte in te p u lm o n a ire chez un e fe m m e . C o n tra ire m e n t au p re m ie r cas d e c rit, la p a tie n te en q u e s tio n n 'a pas rea gi au tra ite m e n t par v o ie ge n e ra le e t a f in i p a r su c c o m b e r a la m a la d ie . A ussi e sp e ro n s-n o u s que, p a r la d o c u m e n ta tio n c o n tin u e de cas de PG, m a la d ie rare e t p o te n tie lle m e n t m o rte lle , les m e d e cin s tro u v e ro n t des tra ite m e n ts p lu s effica ces qu e les tra ite m e n ts actuels.
61-YEAR-OLD WHITE WOMAN presented to the dermatology outpatient clinic with a 2-month history of progressively worsening ulcers involving the vulvar, perineal, and sacral regions. A review of systems was unremarkable, including no history of oral ulcers, skin eruptions, or constitutional symptoms. Her past medical history included hypertension, obesity, dyslipidemia, hypothyroidism, osteoarthritis, fatty liver, depression/ anxiety, and long-standing myasthenia gravis that was treated with azathioprine 100 mg orally (PO) twice daily. Examination revealed multiple deep ulcers with irregularly shaped, undermined, overhanging, violaceous borders and an eschar base located mainly on the vulva bilaterally, as well as the perineal and sacral regions (Figure 1). Multiple previous skin swabs of these ulcers were negative for
A From the Division o f Dermatology, Faculty o f Medicine & Dentistry, University o f A lberta, and D ivision o f A natom ical Pathology, Department o f Laboratory Medicine & Pathology, University o f Alberta Hospital, Edmonton, AB. Presented in part as a poster presentation at the 88th A nnual Canadian Dermatology Association Conference, Quebec City, QC, June 2013, and at the 22nd EAD V Congress in Istanbul, Turkey, October 2013. Address reprint requests to: Joshua M. Mercer, MD, Division o f Dermatology, Faculty o f Medicine & Dentistry, University o f Alberta, 2-125 Clinical Sciences Building, University o f Alberta Hospital, Edmonton, AB T6G 2G3; email: [email protected].
DOI 10.2310/7750.2014.13196 © 2014 Canadian Dermatology Association
DECKER^ Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 18, No 6 (November/December), 2014: pp 424-429
Vulvar Pyoderma Gangrenosum with Pulmonary Involvement
Figure 1. Multiple destructive, deep ulcers with irregular, under mined borders and a necrotic base located in the perigenital region.
pathogenic bacteria. O f note, her weight was approxi mately 100 kg. Subsequent investigations were conducted, including a punch biopsy of the skin, which revealed cutaneous ulceration with underlying presence of neutrophils extend ing deep into the dermis (Figure 2). Viral cytopathic changes were not seen, and special stains for microorgan isms (periodic acid-Schiff, Ziehl-Neelsen, Warthin-Starry) were negative. The histopathologic findings were consis tent with PG. Tissue cultures were negative for mycobac terial and fungal infections, and bacterial cultures only grew normal flora for intertriginous areas. A swab for viral cultures for herpes simplex virus (HSV)-l, HSV-2, and varicella-zoster virus was negative. Further investigations to
Figure 2. Skin biopsy showing the edge of cutaneous ulceration with underlying presence of neutrophils extending deep into the dermis (hematoxylin-eosin stain; original magnification X50).
rule out other underlying etiologies for the ulcers were conducted, including complete blood count with differen tial, liver and renal function tests, hepatitis B and C and human immunodeficiency virus (HIV) serology, Treponema palladum enzyme immunoassay, antineutrophil cytoplasmic antibody (ANCA) screen, rheumatoid factor (RF), antidouble-stranded DNA (anti-dsDNA), and immunoglobulin levels. All of these investigations were either normal or negative. The patient was diagnosed with vulvar PG and treated with oral prednisone 50 to 70 mg PO daily, along with local wound care (ie, morphine 2% gel, hydrogel [Intrasite gel] daily, and alginate dressings [SeaSorb Ag]). In addition, various other therapies were used with minimal improvement, including colchicine 0.6 mg PO twice daily, minocycline 100 mg PO twice daily (for antiinflammatory and antineutrophilic properties), topical fluticasone pro pionate (Flovent HF) 250 |ig inhaler sprayed to ulcer daily, and azathioprine, which was increased from 100 to 150 mg PO twice daily. Approximately 4 weeks later, the patient presented to the emergency department with worsening painful vulvar ulcers, which required opioids for analgesia. In addition, she reported a 1-week history of unexplained dyspnea, and a chest radiograph revealed bilateral pulmonary parenchymal masses, which were not present on a previous study from 2008. Subsequently, a computed tomographic (CT) scan of the chest showed multiple discrete, bilateral pulmonary nodules, one of which contained a crescentric cavitation or air crescent (Figure 3). There was no evidence of surrounding ground-glass halo to suggest a fungal infection. An extensive workup was conducted to determine the underlying etiology of these pulmonary nodules. Sputum cultures, ANCAs, oq-antitrypsin, complement levels, and an antibody panel including anti-dsDNA, RF, anti-glomerular basement membrane (anti-GBM), antiactin, anti-Smith, and antimitochondrial, were all either negative or normal. However, an antinuclear antibody (ANA) screen was positive and anti-SSA/Ro antibodies were elevated. A CT-guided core needle biopsy of a lung nodule revealed necrotic pulmonary parenchyma with associated mixed inflammation and organizing granulation tissue. Granuloma formation was not seen, and only focally, some small to medium-sized vessels showed vasculitis. The features were nonspecific, yet no evidence of malignancy was noted. Unfortunately, the specimen was not sent for tissue cultures; however, all special stains for microorganisms performed on the lung biopsy were negative. In addition to the pulmonary nodules noted on the CT scan, the patient had also developed pancytopenia. Serum
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Figure 3. Computed tomographic scan o f the chest revealing a pulmonary nodule in the right lung that crosses the oblique fissure and is associated with a crescentric cavitation or air crescent {arrow).
protein electrophoresis revealed panhypoproteinemia with no banding, and a subsequent bone marrow biopsy was negative for hematolymphoid or metastatic malignancy and revealed normal cytogenetics. The pancytopenia was felt to be secondary to a recent increase in azathioprine dosing; therefore, it was discontinued. Also, an endoscopic evaluation of the upper and lower gastrointestinal tracts was negative for any significant pathologic findings or malignancy. The patient’s condition further deteriorated, and she was transferred to the intensive care unit (ICU) with septic shock and enterococcal septicemia secondary to a urinary tract infection. There she was treated with vasopressors and broad-spectrum antibiotics. Her PG was treated with high-dose intravenous (IV) corticosteroids (ie, hydrocor tisone 50 mg IV every 6 hours) for 5 days, which transitioned to prednisolone 70 mg PO daily, cyclosporine 400 mg IV daily, and two doses of intravenous immu noglobulin 1 g/kg/day. She failed to respond to therapy and eventually died secondary to disseminated intravas cular coagulation (DIC) and fulminant liver failure 18 days from the date of her admission.
Discussion PG is an uncommon, ulcerative disorder characterized clinically by chronic, recurrent, painful, disfiguring cutaneous ulcers that usually occur on the lower extremities, especially the pretibial area or trunk; it can also occur at any site, including the eyes, mucous membranes, scalp, and genitals.1,2 Only a few cases of PG involving the vulva have been published.3 Diagnosis of perigenital PG is clinical, and appropriate evaluations
w
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should be conducted to rule out other possible etiologies for perigenital ulcerations, including both infectious (ie, HSV, syphilis, HIV, chancroid, granuloma inguinale, lymphogranuloma venereum, and fungal and bacterial infections) and noninfectious (ie, trauma, malignancies, Behcet syndrome, and granulomatosis with polyangiitis) causes. Evaluation for presumed PG should include the following: a thorough history, including a medication review and physical examination; sterile deep skin punch biopsy for histopathologic evaluation and cultures (ie, bacterial, mycobacterial, fungal, and viral); and laboratory investigations (ie, complete blood count with differential, renal and liver functions testing, and urine analysis). More extensive evaluations to rule out infectious, neoplastic, or other systemic etiologies include a peripheral blood smear, serum protein electrophoresis, bone marrow biopsy (if indicated), ANA, antiphospholipid antibodies, ANCAs, T. palladum enzyme immunoassay, HIV and viral hepatitis serology, fecal occult blood, chest radiography, and sigmoidoscopy or colonoscopy.1,2 PG can be associated with a number of systemic diseases, such as inflammatory bowel disease and auto immune connective tissue and hematologic disorders (ie, monoclonal gammopathy, acute and chronic myelogenous leukemia, and myelodysplasia). Rarely, PG has associated pulmonary involvement.1 To date, only 33 cases of PG with pulmonary involvement have been reported in the literature.4"’ Radiologic findings included mainly unilateral or bilateral nodules with or without necrosis but also lung abscesses, pleural effusions, unilateral lung shadows, and interstitial pneumonitis.4 Also, of interest, a large number (ie, 13) of these patients with PG with pulmonary involvement had an associated underlying hematologic disorder (ie, myelodysplastic syndrome, IgA myeloma, or monoclonal IgA gammopathy).4 Of these previous cases of PG with pulmonary involvement, only 16 had lung biopsies performed.4-18 Histopathologic findings from the lung biopsies showed a spectrum of changes, including palisading granulomas around foci of necrosis, mixed inflammatory infiltration (ie, various combinations of lymphocytes, monocytes, histiocytes, and neutrophils), multifocal neutrophilic abscesses, intra-alveolar neutrophilic infiltrate, focal vas culitis, and fibrosis or necrosis of lung parenchyma.4-18 In the case described herein, the core needle biopsy of the lung nodule also revealed similar findings, which included parenchymal necrosis, mixed inflammation, and focal vasculitis. The extensive workup conducted by dermatology, various internal medicine specialties, and ICU physicians
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could not determine the underlying etiology of the pulmonary nodules that were noted on CT. Common causes for these CT findings, including malignancies and lymphoproliferative diseases, infections, vasculitis (eg, granulomatosis with polyangiitis), and granulomatous conditions (eg, pneumoconiosis or sarcoidosis), were excluded. 19 Foremost, the core needle lung biopsy, bone marrow biopsy, and CT of the abdomen/pelvis revealed no evidence of malignancy. Furthermore, although the lung biopsy was not sent for tissue cultures, all special stains for microorganisms performed were negative. In addition to the core needle biopsy not revealing any granulomatous inflammation, the patient denied any history of environ mental or occupational exposure to silica, asbestos, or beryllium, which would make the diagnosis of pneumo coniosis extremely unlikely. Finally, an extensive workup to exclude systemic vasculitis or an autoimmune condi tion, including ANCAs, anti-GBM, and RF, were all negative or normal except for a positive ANA screen with elevated anti-SSA/Ro antibodies.
Anti-SSA/Ro antibodies can be elevated in patients with Sjogren syndrome, systemic lupus erythematosus (SLE), and other autoimmune conditions. 20' 21 Flowever, our patient did not have any other clinical features, such as photosensitivity, oral ulcerations, or discoid or malar eruption often present in SLE or xerophthalmia, xerosto mia, keratoconjunctivitis sicca, or parotid gland swelling, which would be consistent with Sjogren syndrome. Furthermore, the elevated anti-SSA/Ro could possibly be related to her myasthenia gravis, as reported in another patient with myasthenia gravis.20 One possible explanation for our patient’s constella tion of symptoms (ie, vulvar ulcerations and pulmonary nodules) is that she had an undiagnosed occult neoplastic, infectious, or vasculopathic process account ing for the pulmonary nodules, and the perigential PG represented a secondary reactive process. However, it is also quite plausible that the pulmonary nodules were due to an aseptic inflammatory process in the lung (ie, extracutaneous PG), a theory that has been alluded to in
Table 1. Published Cases of Pyoderma Gangrenosum with Pulmonary and Perigenital Involvement Age Study
Skin
Area
(yr)
17
M
Y
Inguinal Multiple pulmonary region nodules, some with central cavitation
Kanoh et al10 54
M
Y
Scrotum Consolidation RLL; groundglass opacities in middle lung
Lebbe et al14
58
F
Y
Mlika et al16
67
M
Y
Bittencourt et al5
Biopsy Affected
C T Chest Findings
Sex
Vulva
Excavated lesion with irregular thick walls in RML
Scrotum Not described
Lung Biopsy Findings
Treatment Therapy
Response
Association
Improvement in None ulcers and pulmonary nodules disappeared within 2 wk Granulation tissue; High-dose Ulcers and AML inflammation CS pulmonary lesions with neutrophils, improved within lymphoplasma 2 wk; however, patient later cells; necrosis; no vasculitis or developed AML granuloma and died Intra-alveolar Prednisone Cutaneous and None neutrophilic 1 mg/kg/day ocular lesions infiltrate; improved suppurative completely by exudate with 1 mo; “dramatic interstitial clearing” of the pneumonitis and lung infiltrate mild fibrosis Neutrophils CS Radiologic “Lymphoid improvement; leukemia” however, patient eventually died N
CS
AML = acute myeloid leukemia; CS = corticosteroids; CT = computed tomography; mo = month; N = no; RLL := right lower lobe; RML = right middle lobe; wk = weeks; Y = yes.
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several other case reports of PG with pulm onary involvement.4,7,11,13 If the latter were true, then the diagnosis of extracutaneous PG, like that of cutaneous PG, would be one of exclusion. A thorough and complete review of the literature to determine possible therapies and treatment outcomes revealed only four cases of perigenital PG with pulmonary involvement,5,10'14’16 A brief summary of these cases is provided in Table 1. Of these previously described cases, one had PG involving the inguinal region, two involving the scrotum, and only one involving the vulva. Lebbe and colleagues reported a case of a 58-year-old woman who presented with vulvar ulcerations consistent with PG and subsequently developed pulmonary and ocular involvement.14 After 1 month of treatment with prednisone 1 mg/kg/day, this patient’s cutaneous and ocular ulcers completely cleared and there was significant improvement in her lung infiltrates.14 The prednisone was gradually tapered to 10 mg daily without any relapse after 2 years.14
Conclusion We report an extremely unique case of a 61-year-old woman with treatment-refractory and locally destructive vulvar PG who subsequently developed pulm onary nodules. An extensive review of the literature revealed only one other case of a female with vulvar PG and pulmonary involvement, and she responded to prednisone treatm ent. Unfortunately, our patient was not only refractory to systemic high-dose corticosteroids, she also failed m ultiple other systemic therapies, including azathioprine, minocycline, colchicine, cyclosporine, and IVIG. Furthermore, unlike the patient described in the first case, our patient developed numerous complications requiring ICU admission, including septic shock, DIC, and liver failure, which eventually resulted in her death. It is hoped that with continued documentation of this extremely rare presentation of PG, dermatologists and researchers will eventually determine or develop more effective treatment options.
Acknowledgments We would like to thank Dr. Evan Walters, resident of the Department of Radiology in the Faculty of Medicine & Dentistry at the University of Alberta, for his assistance in the selection of the CT image used in this article. Financial disclosure of authors and reviewers: None reported.
References 1. Ahronowitz I, Harp J, Shinkai K. Etiology and management of pyoderma gangrenosum. A comprehensive review. Am 1 Clin Dermatol 2012;13:191-211, doi:10.2165/l 1595240-00000000000000. 2. Powell FC, Su WPD, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol 1996;34: 396-409, dpi: 10.1016/S0190-9622(96)90428-4. 3. Sau M, Hill NCW. Pyoderma gangrenosum of the vulva. Br J Obstet Gynaecol 2001;108:1197-8. 4. Batalle A, Perez-Pedrosa A, Gracia-Doval I, et al. Lung involvement in pyoderma gangrenosum: a case report and review of the literature. Actas Dermosifiliogr 2011;102:373-7, doi:10.1016/j.ad. 2010,12.008. 5. Bittencourt MJS, Soares LFB, Lobato LS, et al. Multiple cavitary pulmonary nodules in association with pyoderma gangrenosum case report. An Bras Dermatol 2012;87:301-4, doi:10.1590/S036505962012000200018. 6. Bhat M, Dawson D. Wheezes, blisters, bumps and runs: multisystemic manifestations of a Crohn’s disease flare-up. CMAJ 2007; 177:715-8, doi:10.1503/cmai.070290. 7. Brown T, Marshall GS, Callen JP. Cavitating pulmonary infiltrate in an adolescent with pyoderma gangrenosum: a rarely recognized extracutaneous manifestation of neutrophilic derma tosis. J Am Acad Dermatol 2000;43:108-12, doi:10.1067/mjd. 2000.103627. 8. Chahine B, Chenivesse C, Tillie-Leblond I, et al. Pulmonary manifestations of pyoderma gangrenosum. Presse Med 2007;36: 1395-8, doi:10.1016/j.lpm.2007.03.031. 9. Field S, Powell C, Young V, Barnes L. Pyoderma gangrenosum manifesting as a cavitating lung lesion. Clin Exp Dermatol 2008;33: 418-21, doi:10.1111/j. 1365-2230.2008.02756.x. 10. Kanoh S, Kobayashi H, Sato K, et al. Tracheobronchial pulmonary disease associated with pyoderma gangrenosum. Mayo Clin Proc 2009;84:555-7, doi:10.4065/84.6,555. 11. Kasuga I, Yanagisawa N, Takeo C, et al. Multiple pulmonary nodules in association with pyoderma gangrenosum. Respir Med 1997;91:493-5, doi: 10.1016/S0954-6111(97)90115-3. 12. Kitagawa KH, Grassi M. Primary pyoderma gangrenosum of the lungs. J Am Acad Dermatol 2008;59(5 Suppl:)S114-6, doi:10. 1016/j.jaad.2008.06.017. 13. Kruger S, Piroth W, Takyi AB, et al. Multiple aseptic pulmonary nodules with central necrosis in association with pyoderma gangrenosum. Chest 2001;119:977-8, doi:10.1378/chest.l 19.3. 977. 14. Lebbe C, Moulonguet-Michau I, Perrin P, et al. Steroid-responsive pyoderma gangrenosum with vulvar and pulmonary involvement. J Am Acad Dermatol 1992;27:623-5, doi:10.1016/S0190-9622 (08)80200-9. 15. Merke DP, Honig PJ, Potsic WP. Pyoderma gangrenosum of the skin and trachea in a 9-month-old boy. J Am Acad Dermatol 1996; 34:681-2, doi:10.1016/S0190-9622(96)80084-3. 16. Mlika RB, Riahi I, Fenniche S, et al. Pyoderma gangrenosum: a report of 21 cases. Int J Dermatol 2002;41:65-8, doi:10.1046/ j.l365-4362.2002.01329.x. 17. Vignon-Pennaman MD, Zelinsky-Gurung A, Jenssen F, et al. Pyoderma gangrenosum with pulmonary involvement. Arch
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Dermatol 1989;125:1239-42, doiilO.lOOl/archderm. 1989.0167021 0077011. 18. Wang JL, Wang JB, Zhu YJ. Pyoderma gangrenosum with lung injury. Thorax 1999;54:953-5, doi:10.1136/thx.54.10.953. 19. Leslie KO. My approach to interstitial lung disease using clinical, radiological and histopathological patterns. J Clin Pathol 2009;62: 387-401, doi: 10.1136/jcp.2008.059782.
20. Menedez A, Gomez J, Escanlar E, et al. Clinical associations of anti-SSA/Ro60 and anti-Ror2/TRIM21 antibodies: diagnostic utility of their separare detection. Autoimmunity 2013;46:32-9, doi:10.3109/08916934.2012.732131. 21. Nakamura MC, Imboden JB. Laboratory diagnosis. In: Imboden JB, Hellmann DB, Stone JH, editors. Current diagnosis & treatment: rheumatology. 3rd ed. New York: McGraw-Hill; 2013. p. 26.
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Fatal Case of Vulvar Pyoderma Gangrenosum with Pulmonary Involvement: Case Presentation and Literature Review Joshua M. Mercer, Paul Kuzel, M uhammad N. Mahmood, and Alain Brassard
In tro d u ctio n : W e re p o rt a case o f a 61 -ye a r-o ld w o m a n w ith lo c a lly d e s tru c tiv e v u lv a r p y o d e rm a g a n g re n o s u m (PG) w ith p u lm o n a ry in v o lv e m e n t w h o w a s re fra c to ry t o n u m e ro u s s y s te m ic th e ra p ie s an d d e ve lo p e d c o m p lic a tio n s re s u ltin g in her dem ise.
O bjective: To re p o rt a rare case o f tre a tm e n t-re s is ta n t v u lv a r PG w ith p u lm o n a ry in v o lv e m e n t th a t p ro v e d to be fa ta l. M ethods: PubM ed w a s used to search fo r o th e r re p o rts th a t discuss PG, o r m o re s p e c ific a lly p e rig e n ita l PG, w ith p u lm o n a ry in v o lv e m e n t.
Results and Conclusion: A th o ro u g h re v ie w o f th e lite ra tu re reve aled 33 cases o f PG w ith p u lm o n a ry in v o lv e m e n t, w ith o n ly 4 in v o lv in g th e p e rig e n ita l re g io n . W e re p o rt th e seco nd case o f a fe m a le w ith v u lv a r PG and p u lm o n a ry in v o lv e m e n t. In c o n tra s t to th e f ir s t case d e scrib e d , o u r p a tie n t d id n o t re sp o n d to s y s te m ic th e ra p y , and, u ltim a te ly , her disease w a s fa ta l. It is h o p e d th a t w ith c o n tin u e d d o c u m e n ta tio n o f th is rare an d p o te n tia lly le th a l p re s e n ta tio n o f PG, p h ysicia n s w ill d e te rm in e m o re e ffe c tiv e tre a tm e n ts .
In tro d u ctio n : Sera exp o se ici le cas d 'u n e fe m m e de 61 ans, a tte in te d 'u n e p y o d e rm ite ga ng re n e u se (PG) vu lv a ire , avec d e s tru c tio n lo ca le e t a tte in te p u lm o n a ire , q u i s 'e s t m o n tre e re fra cta ire a p lu s ie u rs tra ite m e n ts p a r v o ie ge n e ra le e t q u i a fin a le m e n t e n tra in e la m o r t de la p a tie n te p a r s u ite de c o m p lic a tio n s .
Object'd: L 'a rtic le v is a it a d e crire un cas rare de PG vu lv a ire , avec a tte in te p u lm o n a ire , q u i s 'e s t m o n tre e re fra c ta ire au tr a ite m e n t e t q u i s 'e s t so ld e e p a r la m o r t de la m alade.
M ethode: N o u s a v o n s e n tre p ris un e rech erch e da ns PubM ed afin de tro u v e r d 'a u tre s a rtic le s su r la PG, p lu s p re c is e m e n t su r la PG p e rig e n ita le , avec a tte in te p u lm o n a ire .
Resultats e t conclusion: U n e xa m en a p p ro fo n d i de la d o c u m e n ta tio n a reve le I'e xiste n ce de 33 cas de PG avec a tte in te p u lm o n a ire , m a is 4 s e u le m e n t fa is a ie n t e ta t d 'u n e a tte in te de la re g io n p e rig e n ita le . II s 'a g it ici du d e u xie m e cas de PG v u lv a ire , avec a tte in te p u lm o n a ire chez un e fe m m e . C o n tra ire m e n t au p re m ie r cas d e c rit, la p a tie n te en q u e s tio n n 'a pas rea gi au tra ite m e n t par v o ie ge n e ra le e t a f in i p a r su c c o m b e r a la m a la d ie . A ussi e sp e ro n s-n o u s que, p a r la d o c u m e n ta tio n c o n tin u e de cas de PG, m a la d ie rare e t p o te n tie lle m e n t m o rte lle , les m e d e cin s tro u v e ro n t des tra ite m e n ts p lu s effica ces qu e les tra ite m e n ts actuels.
61-YEAR-OLD WHITE WOMAN presented to the dermatology outpatient clinic with a 2-month history of progressively worsening ulcers involving the vulvar, perineal, and sacral regions. A review of systems was unremarkable, including no history of oral ulcers, skin eruptions, or constitutional symptoms. Her past medical history included hypertension, obesity, dyslipidemia, hypothyroidism, osteoarthritis, fatty liver, depression/ anxiety, and long-standing myasthenia gravis that was treated with azathioprine 100 mg orally (PO) twice daily. Examination revealed multiple deep ulcers with irregularly shaped, undermined, overhanging, violaceous borders and an eschar base located mainly on the vulva bilaterally, as well as the perineal and sacral regions (Figure 1). Multiple previous skin swabs of these ulcers were negative for
A From the Division o f Dermatology, Faculty o f Medicine & Dentistry, University o f A lberta, and D ivision o f A natom ical Pathology, Department o f Laboratory Medicine & Pathology, University o f Alberta Hospital, Edmonton, AB. Presented in part as a poster presentation at the 88th A nnual Canadian Dermatology Association Conference, Quebec City, QC, June 2013, and at the 22nd EAD V Congress in Istanbul, Turkey, October 2013. Address reprint requests to: Joshua M. Mercer, MD, Division o f Dermatology, Faculty o f Medicine & Dentistry, University o f Alberta, 2-125 Clinical Sciences Building, University o f Alberta Hospital, Edmonton, AB T6G 2G3; email: [email protected].
DOI 10.2310/7750.2014.13196 © 2014 Canadian Dermatology Association
DECKER^ Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 18, No 6 (November/December), 2014: pp 424-429
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Figure 1. Multiple destructive, deep ulcers with irregular, under mined borders and a necrotic base located in the perigenital region.
pathogenic bacteria. O f note, her weight was approxi mately 100 kg. Subsequent investigations were conducted, including a punch biopsy of the skin, which revealed cutaneous ulceration with underlying presence of neutrophils extend ing deep into the dermis (Figure 2). Viral cytopathic changes were not seen, and special stains for microorgan isms (periodic acid-Schiff, Ziehl-Neelsen, Warthin-Starry) were negative. The histopathologic findings were consis tent with PG. Tissue cultures were negative for mycobac terial and fungal infections, and bacterial cultures only grew normal flora for intertriginous areas. A swab for viral cultures for herpes simplex virus (HSV)-l, HSV-2, and varicella-zoster virus was negative. Further investigations to
Figure 2. Skin biopsy showing the edge of cutaneous ulceration with underlying presence of neutrophils extending deep into the dermis (hematoxylin-eosin stain; original magnification X50).
rule out other underlying etiologies for the ulcers were conducted, including complete blood count with differen tial, liver and renal function tests, hepatitis B and C and human immunodeficiency virus (HIV) serology, Treponema palladum enzyme immunoassay, antineutrophil cytoplasmic antibody (ANCA) screen, rheumatoid factor (RF), antidouble-stranded DNA (anti-dsDNA), and immunoglobulin levels. All of these investigations were either normal or negative. The patient was diagnosed with vulvar PG and treated with oral prednisone 50 to 70 mg PO daily, along with local wound care (ie, morphine 2% gel, hydrogel [Intrasite gel] daily, and alginate dressings [SeaSorb Ag]). In addition, various other therapies were used with minimal improvement, including colchicine 0.6 mg PO twice daily, minocycline 100 mg PO twice daily (for antiinflammatory and antineutrophilic properties), topical fluticasone pro pionate (Flovent HF) 250 |ig inhaler sprayed to ulcer daily, and azathioprine, which was increased from 100 to 150 mg PO twice daily. Approximately 4 weeks later, the patient presented to the emergency department with worsening painful vulvar ulcers, which required opioids for analgesia. In addition, she reported a 1-week history of unexplained dyspnea, and a chest radiograph revealed bilateral pulmonary parenchymal masses, which were not present on a previous study from 2008. Subsequently, a computed tomographic (CT) scan of the chest showed multiple discrete, bilateral pulmonary nodules, one of which contained a crescentric cavitation or air crescent (Figure 3). There was no evidence of surrounding ground-glass halo to suggest a fungal infection. An extensive workup was conducted to determine the underlying etiology of these pulmonary nodules. Sputum cultures, ANCAs, oq-antitrypsin, complement levels, and an antibody panel including anti-dsDNA, RF, anti-glomerular basement membrane (anti-GBM), antiactin, anti-Smith, and antimitochondrial, were all either negative or normal. However, an antinuclear antibody (ANA) screen was positive and anti-SSA/Ro antibodies were elevated. A CT-guided core needle biopsy of a lung nodule revealed necrotic pulmonary parenchyma with associated mixed inflammation and organizing granulation tissue. Granuloma formation was not seen, and only focally, some small to medium-sized vessels showed vasculitis. The features were nonspecific, yet no evidence of malignancy was noted. Unfortunately, the specimen was not sent for tissue cultures; however, all special stains for microorganisms performed on the lung biopsy were negative. In addition to the pulmonary nodules noted on the CT scan, the patient had also developed pancytopenia. Serum
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Figure 3. Computed tomographic scan o f the chest revealing a pulmonary nodule in the right lung that crosses the oblique fissure and is associated with a crescentric cavitation or air crescent {arrow).
protein electrophoresis revealed panhypoproteinemia with no banding, and a subsequent bone marrow biopsy was negative for hematolymphoid or metastatic malignancy and revealed normal cytogenetics. The pancytopenia was felt to be secondary to a recent increase in azathioprine dosing; therefore, it was discontinued. Also, an endoscopic evaluation of the upper and lower gastrointestinal tracts was negative for any significant pathologic findings or malignancy. The patient’s condition further deteriorated, and she was transferred to the intensive care unit (ICU) with septic shock and enterococcal septicemia secondary to a urinary tract infection. There she was treated with vasopressors and broad-spectrum antibiotics. Her PG was treated with high-dose intravenous (IV) corticosteroids (ie, hydrocor tisone 50 mg IV every 6 hours) for 5 days, which transitioned to prednisolone 70 mg PO daily, cyclosporine 400 mg IV daily, and two doses of intravenous immu noglobulin 1 g/kg/day. She failed to respond to therapy and eventually died secondary to disseminated intravas cular coagulation (DIC) and fulminant liver failure 18 days from the date of her admission.
Discussion PG is an uncommon, ulcerative disorder characterized clinically by chronic, recurrent, painful, disfiguring cutaneous ulcers that usually occur on the lower extremities, especially the pretibial area or trunk; it can also occur at any site, including the eyes, mucous membranes, scalp, and genitals.1,2 Only a few cases of PG involving the vulva have been published.3 Diagnosis of perigenital PG is clinical, and appropriate evaluations
w
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should be conducted to rule out other possible etiologies for perigenital ulcerations, including both infectious (ie, HSV, syphilis, HIV, chancroid, granuloma inguinale, lymphogranuloma venereum, and fungal and bacterial infections) and noninfectious (ie, trauma, malignancies, Behcet syndrome, and granulomatosis with polyangiitis) causes. Evaluation for presumed PG should include the following: a thorough history, including a medication review and physical examination; sterile deep skin punch biopsy for histopathologic evaluation and cultures (ie, bacterial, mycobacterial, fungal, and viral); and laboratory investigations (ie, complete blood count with differential, renal and liver functions testing, and urine analysis). More extensive evaluations to rule out infectious, neoplastic, or other systemic etiologies include a peripheral blood smear, serum protein electrophoresis, bone marrow biopsy (if indicated), ANA, antiphospholipid antibodies, ANCAs, T. palladum enzyme immunoassay, HIV and viral hepatitis serology, fecal occult blood, chest radiography, and sigmoidoscopy or colonoscopy.1,2 PG can be associated with a number of systemic diseases, such as inflammatory bowel disease and auto immune connective tissue and hematologic disorders (ie, monoclonal gammopathy, acute and chronic myelogenous leukemia, and myelodysplasia). Rarely, PG has associated pulmonary involvement.1 To date, only 33 cases of PG with pulmonary involvement have been reported in the literature.4"’ Radiologic findings included mainly unilateral or bilateral nodules with or without necrosis but also lung abscesses, pleural effusions, unilateral lung shadows, and interstitial pneumonitis.4 Also, of interest, a large number (ie, 13) of these patients with PG with pulmonary involvement had an associated underlying hematologic disorder (ie, myelodysplastic syndrome, IgA myeloma, or monoclonal IgA gammopathy).4 Of these previous cases of PG with pulmonary involvement, only 16 had lung biopsies performed.4-18 Histopathologic findings from the lung biopsies showed a spectrum of changes, including palisading granulomas around foci of necrosis, mixed inflammatory infiltration (ie, various combinations of lymphocytes, monocytes, histiocytes, and neutrophils), multifocal neutrophilic abscesses, intra-alveolar neutrophilic infiltrate, focal vas culitis, and fibrosis or necrosis of lung parenchyma.4-18 In the case described herein, the core needle biopsy of the lung nodule also revealed similar findings, which included parenchymal necrosis, mixed inflammation, and focal vasculitis. The extensive workup conducted by dermatology, various internal medicine specialties, and ICU physicians
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could not determine the underlying etiology of the pulmonary nodules that were noted on CT. Common causes for these CT findings, including malignancies and lymphoproliferative diseases, infections, vasculitis (eg, granulomatosis with polyangiitis), and granulomatous conditions (eg, pneumoconiosis or sarcoidosis), were excluded. 19 Foremost, the core needle lung biopsy, bone marrow biopsy, and CT of the abdomen/pelvis revealed no evidence of malignancy. Furthermore, although the lung biopsy was not sent for tissue cultures, all special stains for microorganisms performed were negative. In addition to the core needle biopsy not revealing any granulomatous inflammation, the patient denied any history of environ mental or occupational exposure to silica, asbestos, or beryllium, which would make the diagnosis of pneumo coniosis extremely unlikely. Finally, an extensive workup to exclude systemic vasculitis or an autoimmune condi tion, including ANCAs, anti-GBM, and RF, were all negative or normal except for a positive ANA screen with elevated anti-SSA/Ro antibodies.
Anti-SSA/Ro antibodies can be elevated in patients with Sjogren syndrome, systemic lupus erythematosus (SLE), and other autoimmune conditions. 20' 21 Flowever, our patient did not have any other clinical features, such as photosensitivity, oral ulcerations, or discoid or malar eruption often present in SLE or xerophthalmia, xerosto mia, keratoconjunctivitis sicca, or parotid gland swelling, which would be consistent with Sjogren syndrome. Furthermore, the elevated anti-SSA/Ro could possibly be related to her myasthenia gravis, as reported in another patient with myasthenia gravis.20 One possible explanation for our patient’s constella tion of symptoms (ie, vulvar ulcerations and pulmonary nodules) is that she had an undiagnosed occult neoplastic, infectious, or vasculopathic process account ing for the pulmonary nodules, and the perigential PG represented a secondary reactive process. However, it is also quite plausible that the pulmonary nodules were due to an aseptic inflammatory process in the lung (ie, extracutaneous PG), a theory that has been alluded to in
Table 1. Published Cases of Pyoderma Gangrenosum with Pulmonary and Perigenital Involvement Age Study
Skin
Area
(yr)
17
M
Y
Inguinal Multiple pulmonary region nodules, some with central cavitation
Kanoh et al10 54
M
Y
Scrotum Consolidation RLL; groundglass opacities in middle lung
Lebbe et al14
58
F
Y
Mlika et al16
67
M
Y
Bittencourt et al5
Biopsy Affected
C T Chest Findings
Sex
Vulva
Excavated lesion with irregular thick walls in RML
Scrotum Not described
Lung Biopsy Findings
Treatment Therapy
Response
Association
Improvement in None ulcers and pulmonary nodules disappeared within 2 wk Granulation tissue; High-dose Ulcers and AML inflammation CS pulmonary lesions with neutrophils, improved within lymphoplasma 2 wk; however, patient later cells; necrosis; no vasculitis or developed AML granuloma and died Intra-alveolar Prednisone Cutaneous and None neutrophilic 1 mg/kg/day ocular lesions infiltrate; improved suppurative completely by exudate with 1 mo; “dramatic interstitial clearing” of the pneumonitis and lung infiltrate mild fibrosis Neutrophils CS Radiologic “Lymphoid improvement; leukemia” however, patient eventually died N
CS
AML = acute myeloid leukemia; CS = corticosteroids; CT = computed tomography; mo = month; N = no; RLL := right lower lobe; RML = right middle lobe; wk = weeks; Y = yes.
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several other case reports of PG with pulm onary involvement.4,7,11,13 If the latter were true, then the diagnosis of extracutaneous PG, like that of cutaneous PG, would be one of exclusion. A thorough and complete review of the literature to determine possible therapies and treatment outcomes revealed only four cases of perigenital PG with pulmonary involvement,5,10'14’16 A brief summary of these cases is provided in Table 1. Of these previously described cases, one had PG involving the inguinal region, two involving the scrotum, and only one involving the vulva. Lebbe and colleagues reported a case of a 58-year-old woman who presented with vulvar ulcerations consistent with PG and subsequently developed pulmonary and ocular involvement.14 After 1 month of treatment with prednisone 1 mg/kg/day, this patient’s cutaneous and ocular ulcers completely cleared and there was significant improvement in her lung infiltrates.14 The prednisone was gradually tapered to 10 mg daily without any relapse after 2 years.14
Conclusion We report an extremely unique case of a 61-year-old woman with treatment-refractory and locally destructive vulvar PG who subsequently developed pulm onary nodules. An extensive review of the literature revealed only one other case of a female with vulvar PG and pulmonary involvement, and she responded to prednisone treatm ent. Unfortunately, our patient was not only refractory to systemic high-dose corticosteroids, she also failed m ultiple other systemic therapies, including azathioprine, minocycline, colchicine, cyclosporine, and IVIG. Furthermore, unlike the patient described in the first case, our patient developed numerous complications requiring ICU admission, including septic shock, DIC, and liver failure, which eventually resulted in her death. It is hoped that with continued documentation of this extremely rare presentation of PG, dermatologists and researchers will eventually determine or develop more effective treatment options.
Acknowledgments We would like to thank Dr. Evan Walters, resident of the Department of Radiology in the Faculty of Medicine & Dentistry at the University of Alberta, for his assistance in the selection of the CT image used in this article. Financial disclosure of authors and reviewers: None reported.
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