Report
Pyoderma gangrenosum associated with solid organ malignancies Varun Shahi1, BS, and David A. Wetter2, MD
1 Mayo Clinic College of Medicine, Mayo Clinic, and 2Department of Dermatology, Mayo Clinic, Rochester, MN, USA
Correspondence David A. Wetter, MD Department of Dermatology Mayo Clinic 200 First St SW Rochester MN 55905 USA E-mail: [email protected] Conflicts of interest: None.
Abstract Background Pyoderma gangrenosum (PG) can be associated with systemic diseases, including inflammatory bowel disease, inflammatory arthritis, and hematologic malignancy. Previous literature exploring the rare association between PG and solid organ malignancy is predominantly limited to single case reports. Methods We retrospectively reviewed the cases of five patients with PG and solid organ malignancies at our institution between 1996 and 2013. Results For the five patients identified, PG and solid organ malignancy occurred within three months of each other. Mean age at onset of PG was 55.6 years, and four patients were women. Three patients had breast carcinoma (one was recurrent), and two had gastrointestinal carcinoma. PG occurred before (n = 2), after (n = 2), or synchronously with (n = 1) the malignancy. In one patient with a history of PG and quiescent inflammatory bowel disease, recurrent PG developed synchronously with a new diagnosis of metastatic rectosigmoid carcinoma. Three patients had partial or complete response of PG with treatment of PG alone. Conclusions To our knowledge, our study is the first to report that the onset of PG can herald a recurrence of a solid organ malignancy and that recurrent PG can be associated with solid organ malignancy. A possible association of solid organ malignancy and PG should be considered in patients with PG of unknown etiology or with a history of malignancy.
Introduction Pyoderma gangrenosum (PG), originally described by Brunsting et al.,1 is an ulcerative disorder of the skin that may be associated with other conditions, including various arthritides, inflammatory bowel disease (IBD), and hematologic diseases.2 PG is frequently painful and commonly forms a scar during the healing process. Until recently, PG lacked specific diagnostic criteria and was primarily diagnosed by the exclusion of other conditions.3 Some studies have even shown a clinical association between PG and solid organ malignancies, but they are rare and have been mostly restricted to case reports or small case series.2,4–8 We sought to examine the clinical features, treatment, and outcomes of patients with PG and solid organ malignancies and to identify potential risk factors for the development of solid organ malignancies in patients with PG.
a diagnosis of both PG and solid organ malignancy at our institution between January 1, 1996, and June 1, 2013. Malignancies of the skin and hematopoietic system were excluded from the search. The initial search yielded 135 patients, and we reviewed the medical records of these patients to identify five patients with PG and solid organ malignancy who met the study inclusion criteria. All cases of solid organ malignancies were biopsy proven at Mayo Clinic and were diagnosed within one year before or after the development of PG. Only cases of PG that met the criteria described by Su et al.3 were included in this study. Cases of PG explained by more probable causes, including systemic diseases known to be associated with PG (IBD, rheumatoid or inflammatory arthritis, leukemia, or other hematologic malignancies) and IgA monoclonal gammopathy, were excluded from the study. Demographic and clinical data for the included patients were extracted from the electronic medical records.
Patients and Methods
Results
This study was approved by the Mayo Clinic Institutional
All of the five patients included in this study (four women, one man) gave written informed consent. The mean age at onset of PG was 55.6 years (range, 36–80 years) (Table 1).
Review Board. We used the institutional medical index and text retrieval system to retrospectively identify patients who received ª 2015 The International Society of Dermatology
International Journal of Dermatology 2015, 54, e351–e357
e351
International Journal of Dermatology 2015, 54, e351–e357
Ulcerative (classic)
Ulcerative (classic)
3/36/M
4/44/F
Upper extremity
Breast
Lower extremity
Lower extremity
Lower extremity
Anatomic location
After (3 months)
After (1 month)
Synchronous
Before (2 months)
Before (1 month)
Onset in relation to malignancy
None
None
Ulcerative colitisb
None
None
Other associated systemic diseases
No
No
Yesc
No
No
Recurrent?
Tacrolimus ointment; triamcinolone 0.1% cream; prednisone, 60 mg Prednisone, 80 mg; minocycline, 200 mg; methylprednisolone, 250 mg Prednisone, 80 mg; mycophenolate mofetil, 2000 mg; tetracycline, 500 mg Cyclosporine, unknown dose; prednisone, 40 mg; IVIG, 2 g/kg per cycle; triamcinolone 0.1% cream
Tacrolimus ointment 0.1%
Treatmenta
No response achieved
N/A
4
No response achieved
N/A
12
4
4
8
Time to resolution, weeks
4
Time to response, weeks
No response to treatment
Partial response with treatment of PG alone
Partial response with combined treatment of malignancy and PG
Complete response with treatment of PG alone Complete response with treatment of PG alone
Outcome
Recurrent
New
Ductal carcinoma of the breast
Breast cancer
New
Surgery, chemotherapy, irradiation
Surgery, chemotherapy
Surgery
Surgery
New
Invasive adenocarcinoma of the breast
Metastatic rectosigmoid carcinoma to lungs
Surgery
Treatment
New
New onset or recurrent
Adenocarcinoma of the ileum
Type
PG associated with malignancy
F, female; IVIG, intravenous immunoglobulin; M, male; N/A, not available; PG, pyoderma gangrenosum. a Maximum dose of systemic medication per day is stated, if known. b The ulcerative colitis was quiescent at the time of recurrent PG. c Recurrent PG was more extensive and sudden in onset than the previous PG lesion.
Ulcerative (classic)
Ulcerative (classic)
2/67/F
5/51/F
Ulcerative (classic)
Type
1/80/F
Patient/age at onset, years/sex
Malignancy-related characteristics
Report
PG-related characteristics
Table 1 Clinical characteristics of five patients with PG associated with solid organ malignancy
e352 Shahi and Wetter
ª 2015 The International Society of Dermatology
Shahi and Wetter
PG associated with malignancy
All five patients had the ulcerative (classic) form of PG (Fig. 1), and the anatomic location of PG included the lower extremity (n = 3), upper extremity (n = 1), and breast (n = 1). Cases of PG occurred either before (n = 2), after (n = 2), or synchronously with (n = 1) the solid organ malignancy, all occurring within 0–3 months of the PG. In all five patients, skin biopsy demonstrated findings compatible with PG. Four patients had newly diagnosed PG, and one had recurrent PG. The patient with recurrent PG had a history of ulcerative colitis that was quiescent during the onset of recurrent PG. In addition, the patient’s recurrent PG was more extensive and sudden in onset than the previous PG lesion and occurred synchronously with a new diagnosis of metastatic rectosigmoid carcinoma. The most common area of involvement of solid organ malignancy was the breast (n = 3), followed by the rectum (n = 1) and ileum (n = 1). Four patients had newonset malignancy, and one had recurrent malignancy (breast carcinoma). Treatment of solid organ malignancy included surgery in all patients, with chemotherapy used in two and radiotherapy in one. Partial or complete response to treatment was achieved in four patients (mean time to initial onset, four weeks), and systemic medications were used in four patients, one of whom showed no response. The most common systemic medication used for treatment of PG was prednisone (n = 4). Data regarding time to resolution of PG were available in two of four patients who showed response and occurred at a mean duration of 10 weeks. Two patients had complete response of PG with treatment of PG alone, one had partial response with treatment of PG and malignancy, one had partial response with treatment of PG alone, and one patient showed no response to treatment.
(a)
Report
Discussion Previous reports of PG in association with solid organ malignancy (excluding more probable causes of PG such as systemic diseases: IBD, rheumatoid arthritis, hematologic malignancy, and IgA monoclonal gammopathy) have been mainly limited to case reports or small case series.2,4–8 Important findings from previous reports are summarized in Table 2. Our results indicate several unique findings: (i) new-onset PG can herald a recurrence of a previously diagnosed solid organ malignancy, and (ii) recurrent PG can be associated with solid organ malignancy (when the previous PG was not associated with solid organ malignancy). To the best of our knowledge, neither of these findings has been reported previously. They suggest that in some patients with PG, it may be important to assess for solid organ malignancies, even if they were ruled out during the initial diagnosis of PG. In all five of our cases, the PG and solid organ malignancy occurred within three months of each other (with three of the five cases occurring within one month). The close timing of solid organ malignancy and PG onset supports a possible causal link of the solid organ malignancy in the development of PG in our five cases. In two (20%) of the previously reported 10 cases of PG in association with solid organ malignancy (probable association cases described in Table 2), response to PG was only achieved after the underlying malignancies were resected.10,14 In our study, three of five cases showed some response to treatment of PG alone; however, one of these cases received the PG diagnosis after that of the underlying solid organ malignancy. Since surgery had already occurred before the diagnosis of PG in this case, it is possible that the surgery was necessary to see the response of the PG.
(b)
Figure 1 Clinical images from patient
3. (a) Numerous ulcerations of the legs with violaceous and undermined borders consistent with pyoderma gangrenosum. (b) Six weeks later, partial response of ulcerations after combined treatment of pyoderma gangrenosum and malignancy
ª 2015 The International Society of Dermatology
International Journal of Dermatology 2015, 54, e351–e357
e353
International Journal of Dermatology 2015, 54, e351–e357
2
1
Powell et al., 19856,b
Hughes et al., 20002
1
Campbell et al., 201013
1
M/53
1
Bunte et al., 20087
RegnierRosencher et al., 201114
M/34
1
M/73
M/74
M/76
F/70
1
Sakai et al., 200611 Franca et al., 200612
F/67
Table 1
1
1
5
Sex/ Age,y
Gallo et al., 199510
Probable associationa Shahi and Wetter, 2013 (present study) Lee et al., 19769
No. of Pts
Peristomal
Classic
Classic
Classic
PG subtype
Peristoma
Right leg
Abdomen
Started on right foot and spread all over body, excluding palms, soles, and mucous membranes Right scapula
Peristoma
Legs
Both legs
PG location
Carcinoma of the bladder Metastatic prostatic carcinoma Bladder cancer
Renal adenocarcinoma
Carcinoid tumor of the ileum
Adenocarcinoma of the sigmoid colon
Gastric cancer
Rectal carcinoma
Carcinoid tumor of the ileum, hemangioma in the liver, and cortical adenoma in the left adrenal gland found during autopsy Gastric “signet ring” cell carcinoma
Solid organ cancer
11 months after
Synchronous
4 months before diagnosis of malignancy 7 d after hemicolectomy
40 d after ileostomy for rectal carcinoma Synchronous
Synchronous
1.5-year history of ulcers, then carcinoid tumor found at autopsy
Timing of PG in relation to malignancy
Dapsone, mycophenolate mofetil, prednisone, topical cromolyn sodium, clobetasol propionate
Urostomy
Nephrectomy
Hemicolectomy
Hemicolectomy and chemotherapy
Prednisolone and azathioprine Prednisolone, somatostatin, azathioprine Surgical excision and corticosteroid ointments
Chemotherapy
Gastrectomy
Treatment of cancer
Corticosteroids
Cyclosporine
Hexachlorophene; prednisone, 40 mg
Treatment of PG
Still active on follow-up
Complete healing after 8 months, only after renal adenocarcinoma was removed
Satisfactory recovery
Marked improvement of PG when treating malignancy with chemotherapy; patient died after 4 months of complications related to malignancy Complete response in 9 months
Skin lesions improved after gastrectomy and healed in 3 weeks
Symptom improvement in 3 weeks; patient died after 12 weeks
Outcome of PG
Report
Study, year
Table 2 Previously reported cases of PG associated with solid organ malignancies
e354 PG associated with malignancy Shahi and Wetter
ª 2015 The International Society of Dermatology
No. of Pts
ª 2015 The International Society of Dermatology Breast Breast Prostate Glioblastoma multiforme
Breast cancer
4
Left breast Glioblastoma
F/31
Rectal adenocarcinoma
Bladder cancer
Acinous cell cancer of the parotid gland Adenocarcinoma of the hypopharynx Breast cancer
Metastatic breast cancer
Cancer of the breast
Adenocarcinoma of the left breast Oral carcinoma
Solid organ cancer
1
1
Peristoma
Peristoma
2
Peristomal
Breast
1
F/64
Right shoulder
1
Peristomal
Arms
1
M/83
Buttock
1
Buttock and left leg
PG location
Breast
Ulcerative dermatitis
PG subtype
1
Sex/ Age,y
7 d after
22 years
20 years
19 months after
7 d after
204 months before
Timing of PG in relation to malignancy
Triamcinolone acetonide, topical clobetasol propionate Triamcinolone acetonide, topical clobetasol propionate Corticosteroids
Corticosteroids and clofazimine Clofazimine
Clofazimine
Treatment of PG
Healing
Resolved
Proctosigmoidectomy with colostomy
Tumor removal
Resolved
“Cured”
Complete response in 10 d
Outcome of PG
Urostomy
Parotidectomy and corticosteroids Hypopharyngectomy
Chemotherapy
Treatment of cancer
d, days; F, female; M, male; PG, pyoderma gangrenosum; Pts, patients. Adapted from Regnier-Rosencher et al.14 and used with permission. a Probable cases had occurrence of PG and solid organ malignancy within 1 year of each other and did not have another systemic disease that was active and was believed more likely to be associated with PG. b This study also reported two cases of colon adenocarcinoma, but both cases had longstanding and extensive ulcerative colitis. C Possible cases had more than 1 year (or unknown duration) between onset of PG and solid organ malignancy, or had a systemic disease that was believed more likely to be associated with PG, or not enough data were available from the article to make a definitive inclusion in the probable category. d Article in French, data gathered from Regnier-Rosencher et al.14
Descheemaeker et al., 20088,d von den Driesch, 199722 Al Ghazal et al., 201223
Baruch et al., 199017 Maigre et al., 199118 Basille et al., 199219 Bayle-Lebey et al., 199520 Labat et al., 200021 Hughes et al., 20002
Possible associationc Beurey 1 et al., 197715 Kuhn, 198516 1
Study, year
Table 2 (Continued)
Shahi and Wetter PG associated with malignancy Report
International Journal of Dermatology 2015, 54, e351–e357
e355
e356
Report
Shahi and Wetter
PG associated with malignancy
In contrast to previous reports in which gastrointestinal malignancies were most commonly associated with PG (six of 10 cases), we found breast carcinoma (three of five cases) to be the most commonly associated solid organ malignancy in our group. We also found that PG associated with solid organ malignancy was more common in women (four of five patients); previous studies with available data demonstrated a male predominance (five of seven patients). Our patients had a similar mean age (55.6 years) to that in previous studies (63.9 years). Although the exact mechanisms by which solid organ malignancies may trigger the development of PG are unknown, abnormal immune surveillance postulated to occur in other paraneoplastic conditions may have a role. For example, the increased production of proinflammatory cytokines by tumor cells has been hypothesized to result in the development of vasculitis in association with solid organ malignancy.24 Similarly, episodic expression of stimulatory tumor antigens has been posited to trigger the development of paraneoplastic subacute cutaneous lupus erythematosus.25 Our study is limited by its retrospective nature and small sample size. Therefore, it is difficult to draw definitive conclusions regarding the association of solid organ malignancy and PG. It is possible that the occurrence of PG and solid organ malignancy is unrelated in some of our patients and is only the result of increased prevalence of malignancy with increasing age.26 However, the close temporal profile and lack of more likely associated systemic conditions suggest that solid organ malignancy may have been associated with the development of PG in our patients, although the lack of long-term follow-up data in all patients precludes confirmation of a definite association between PG and solid organ malignancy. We were unable to determine the percentage of patients with PG in association with solid organ malignancy out of all patients with PG at our institution; our search strategy for ascertainment of cases did not include all patients who received a diagnosis of PG during the study timeframe but rather only included cases with diagnoses of both PG and solid organ malignancy. Although our sample size was small, most of the previous studies represent single case reports. To the best of our knowledge, our study is the largest single-center case series of PG occurring in association with solid organ malignancy and thus adds important information to the existing literature. In conclusion, we describe five cases of PG associated with an underlying solid organ malignancy that were diagnosed within three months of the development of the malignancy. To the best of our knowledge, our study is the first to report that the onset of PG can herald a recurrence of a previously diagnosed solid organ malignancy and that recurrent PG can be associated with solid organ International Journal of Dermatology 2015, 54, e351–e357
malignancy when the initial onset of PG was not associated with malignancy. Although the literature suggests that solid organ malignancy associated with PG is rare, our results suggest that solid organ malignancy should be considered as a possible cause of PG in several types of patients: (i) those without other more likely systemic diseases known to be associated with PG; (ii) those with a previous history of solid organ malignancy; and (iii) those with a recurrent episode of PG that is more sudden in onset, different in clinical presentation than previous episodes, and without an identifiable more likely systemic cause. Larger retrospective cases series and prospective studies are needed to clarify further the features of and relationship between PG and solid organ malignancy.
References 1 Brunsting LA, Goeckerman WH, OLeary PA. Pyoderma (echthyma) gangrenosum: clinical and experimental observations in five cases occurring in adults. Arch Derm Syphilol 1930; 22: 655–680. 2 Hughes AP, Jackson JM, Callen JP. Clinical features and treatment of peristomal pyoderma gangrenosum. JAMA 2000; 284: 1546–1548. 3 Su WP, Davis MD, Weenig RH, et al. Pyoderma gangrenosum: clinicopathologic correlation and proposed diagnostic criteria. Int J Dermatol 2004; 43: 790–800. 4 Meissner PE, Jappe U, Niemeyer CM, et al. Pyoderma gangrenosum, a rare, but potentially fatal complication in paediatric oncology patients. Klin Padiatr 2007; 219: 296–299. 5 Kanno T, Ito M, Tsuji H, et al. A case of pyoderma gangrenosum involving the prostate gland after radiation therapy for prostate cancer. Hinyokika Kiyo 2002; 48: 565–568. (In Japanese.). 6 Powell FC, Schroeter AL, Su WP, et al. Pyoderma gangrenosum: a review of 86 patients. Q J Med 1985; 55: 173–186. 7 Bunte C, Popp-Habeler J, Mischer P, et al. Concomitant manifestation of pyoderma gangrenosum and colorectal carcinoma. Scand J Gastroenterol 2008; 43: 756–758. 8 Descheemaeker V, Aillet S, Morcel K, et al. Pyoderma gangrenosum and breast cancer: a case report. J Gynecol Obstet Biol Reprod (Paris) 2008; 37: 618–621. (In French.). 9 Lee SS, Biro L, Price E. Pyoderma gangrenosum with carcinoid tumor. Cutis 1976; 18: 791–794. 10 Gallo R, Parodi A, Rebora A. Pyoderma gangrenosum in a patient with gastric carcinoma. Int J Dermatol 1995; 34: 713–714. 11 Sakai H, Otsubo S, Iizuka H. Peristomal pyoderma gangrenosum associated with rectal adenocarcinoma. J Dermatol 2006; 33: 68–70. 12 Franca AE, Salvino LK, Leite SH, et al. Pyoderma gangrenosum as first clinical manifestation of gastric ª 2015 The International Society of Dermatology
Shahi and Wetter
13
14
15
16
17
18
19
adenocarcinoma. J Eur Acad Dermatol Venereol 2006; 20: 440–441. Campbell W, Baird E, Murtagh K, et al. Post-operative pyoderma gangrenosum in association with ileal carcinoid tumour. Ulster Med J 2010; 79: 102–103. Regnier-Rosencher E, Bizet N, Mery L. Pyoderma gangrenosum associated with renal carcinoma. J Am Acad Dermatol 2011; 64: 1208–1211. Beurey J, Weber M, Delrous JL, et al. Pyoderma gangrenosum: clofazimine therapy. Ann Dermatol Venereol 1977; 104: 631–634. (In French.). Kuhn A. Ulcerative dermatitis (pyoderma gangrenosum) with selective IgA deficiency and development of an oral carcinoma. Z Hautkr 1985; 60: 79–82. (In German.). Baruch J, Julien M, Touraine R, et al. Postoperative pyoderma gangrenosum and cancer of the breast. Apropos of a case. Ann Chir Plast Esthet 1990; 35: 73–75. (In French.). Maigre M, Bouachour G, Varache N, et al. Pseudosepticemic pyoderma gangrenosum and breast cancer. Apropos of a case caused by an intramuscular injection. Rev Med Interne 1991; 12: 452–454. (In French.). Basille W, Dompmartin A, Lorier E, et al. Pyoderma gangrenosum. Association to acinar cell carcinoma of the
ª 2015 The International Society of Dermatology
PG associated with malignancy
20
21
22
23
24
25
26
Report
parotid gland. Ann Dermatol Venereol 1992; 119: 381–383. (In French.). Bayle-Lebey P, Periole B, David JF, et al. Paraneoplastic pyoderma gangrenosum. Ann Med Interne (Paris) 1995; 146: 585–587. (In French.). Labat JP, Simon H, Metges JP, et al. Pyoderma gangrenosum and breast cancer: a new case. Ann Med Interne (Paris) 2000; 151: 314–315. (In French.). von den Driesch P. Pyoderma gangrenosum: a report of 44 cases with follow-up. Br J Dermatol 1997; 137: 1000–1005. Al Ghazal P, Korber A, Klode J, et al. Investigation of new co-factors in 49 patients with pyoderma gangrenosum. J Dtsch Dermatol Ges 2012; 10: 251–257 (In German.). Tatsis E, Reinhold-Keller E, Steindorf K, et al. Wegeners granulomatosis associated with renal cell carcinoma. Arthritis Rheum 1999; 42: 751–756. Chaudhry SI, Murphy LA, White IR. Subacute cutaneous lupus erythematosus: a paraneoplastic dermatosis? Clin Exp Dermatol 2005; 30: 655–658. Carsons S. The association of malignancy with rheumatic and connective tissue diseases. Semin Oncol 1997; 24: 360–372.
International Journal of Dermatology 2015, 54, e351–e357
e357
Pyoderma gangrenosum associated with solid organ malignancies Varun Shahi1, BS, and David A. Wetter2, MD
1 Mayo Clinic College of Medicine, Mayo Clinic, and 2Department of Dermatology, Mayo Clinic, Rochester, MN, USA
Correspondence David A. Wetter, MD Department of Dermatology Mayo Clinic 200 First St SW Rochester MN 55905 USA E-mail: [email protected] Conflicts of interest: None.
Abstract Background Pyoderma gangrenosum (PG) can be associated with systemic diseases, including inflammatory bowel disease, inflammatory arthritis, and hematologic malignancy. Previous literature exploring the rare association between PG and solid organ malignancy is predominantly limited to single case reports. Methods We retrospectively reviewed the cases of five patients with PG and solid organ malignancies at our institution between 1996 and 2013. Results For the five patients identified, PG and solid organ malignancy occurred within three months of each other. Mean age at onset of PG was 55.6 years, and four patients were women. Three patients had breast carcinoma (one was recurrent), and two had gastrointestinal carcinoma. PG occurred before (n = 2), after (n = 2), or synchronously with (n = 1) the malignancy. In one patient with a history of PG and quiescent inflammatory bowel disease, recurrent PG developed synchronously with a new diagnosis of metastatic rectosigmoid carcinoma. Three patients had partial or complete response of PG with treatment of PG alone. Conclusions To our knowledge, our study is the first to report that the onset of PG can herald a recurrence of a solid organ malignancy and that recurrent PG can be associated with solid organ malignancy. A possible association of solid organ malignancy and PG should be considered in patients with PG of unknown etiology or with a history of malignancy.
Introduction Pyoderma gangrenosum (PG), originally described by Brunsting et al.,1 is an ulcerative disorder of the skin that may be associated with other conditions, including various arthritides, inflammatory bowel disease (IBD), and hematologic diseases.2 PG is frequently painful and commonly forms a scar during the healing process. Until recently, PG lacked specific diagnostic criteria and was primarily diagnosed by the exclusion of other conditions.3 Some studies have even shown a clinical association between PG and solid organ malignancies, but they are rare and have been mostly restricted to case reports or small case series.2,4–8 We sought to examine the clinical features, treatment, and outcomes of patients with PG and solid organ malignancies and to identify potential risk factors for the development of solid organ malignancies in patients with PG.
a diagnosis of both PG and solid organ malignancy at our institution between January 1, 1996, and June 1, 2013. Malignancies of the skin and hematopoietic system were excluded from the search. The initial search yielded 135 patients, and we reviewed the medical records of these patients to identify five patients with PG and solid organ malignancy who met the study inclusion criteria. All cases of solid organ malignancies were biopsy proven at Mayo Clinic and were diagnosed within one year before or after the development of PG. Only cases of PG that met the criteria described by Su et al.3 were included in this study. Cases of PG explained by more probable causes, including systemic diseases known to be associated with PG (IBD, rheumatoid or inflammatory arthritis, leukemia, or other hematologic malignancies) and IgA monoclonal gammopathy, were excluded from the study. Demographic and clinical data for the included patients were extracted from the electronic medical records.
Patients and Methods
Results
This study was approved by the Mayo Clinic Institutional
All of the five patients included in this study (four women, one man) gave written informed consent. The mean age at onset of PG was 55.6 years (range, 36–80 years) (Table 1).
Review Board. We used the institutional medical index and text retrieval system to retrospectively identify patients who received ª 2015 The International Society of Dermatology
International Journal of Dermatology 2015, 54, e351–e357
e351
International Journal of Dermatology 2015, 54, e351–e357
Ulcerative (classic)
Ulcerative (classic)
3/36/M
4/44/F
Upper extremity
Breast
Lower extremity
Lower extremity
Lower extremity
Anatomic location
After (3 months)
After (1 month)
Synchronous
Before (2 months)
Before (1 month)
Onset in relation to malignancy
None
None
Ulcerative colitisb
None
None
Other associated systemic diseases
No
No
Yesc
No
No
Recurrent?
Tacrolimus ointment; triamcinolone 0.1% cream; prednisone, 60 mg Prednisone, 80 mg; minocycline, 200 mg; methylprednisolone, 250 mg Prednisone, 80 mg; mycophenolate mofetil, 2000 mg; tetracycline, 500 mg Cyclosporine, unknown dose; prednisone, 40 mg; IVIG, 2 g/kg per cycle; triamcinolone 0.1% cream
Tacrolimus ointment 0.1%
Treatmenta
No response achieved
N/A
4
No response achieved
N/A
12
4
4
8
Time to resolution, weeks
4
Time to response, weeks
No response to treatment
Partial response with treatment of PG alone
Partial response with combined treatment of malignancy and PG
Complete response with treatment of PG alone Complete response with treatment of PG alone
Outcome
Recurrent
New
Ductal carcinoma of the breast
Breast cancer
New
Surgery, chemotherapy, irradiation
Surgery, chemotherapy
Surgery
Surgery
New
Invasive adenocarcinoma of the breast
Metastatic rectosigmoid carcinoma to lungs
Surgery
Treatment
New
New onset or recurrent
Adenocarcinoma of the ileum
Type
PG associated with malignancy
F, female; IVIG, intravenous immunoglobulin; M, male; N/A, not available; PG, pyoderma gangrenosum. a Maximum dose of systemic medication per day is stated, if known. b The ulcerative colitis was quiescent at the time of recurrent PG. c Recurrent PG was more extensive and sudden in onset than the previous PG lesion.
Ulcerative (classic)
Ulcerative (classic)
2/67/F
5/51/F
Ulcerative (classic)
Type
1/80/F
Patient/age at onset, years/sex
Malignancy-related characteristics
Report
PG-related characteristics
Table 1 Clinical characteristics of five patients with PG associated with solid organ malignancy
e352 Shahi and Wetter
ª 2015 The International Society of Dermatology
Shahi and Wetter
PG associated with malignancy
All five patients had the ulcerative (classic) form of PG (Fig. 1), and the anatomic location of PG included the lower extremity (n = 3), upper extremity (n = 1), and breast (n = 1). Cases of PG occurred either before (n = 2), after (n = 2), or synchronously with (n = 1) the solid organ malignancy, all occurring within 0–3 months of the PG. In all five patients, skin biopsy demonstrated findings compatible with PG. Four patients had newly diagnosed PG, and one had recurrent PG. The patient with recurrent PG had a history of ulcerative colitis that was quiescent during the onset of recurrent PG. In addition, the patient’s recurrent PG was more extensive and sudden in onset than the previous PG lesion and occurred synchronously with a new diagnosis of metastatic rectosigmoid carcinoma. The most common area of involvement of solid organ malignancy was the breast (n = 3), followed by the rectum (n = 1) and ileum (n = 1). Four patients had newonset malignancy, and one had recurrent malignancy (breast carcinoma). Treatment of solid organ malignancy included surgery in all patients, with chemotherapy used in two and radiotherapy in one. Partial or complete response to treatment was achieved in four patients (mean time to initial onset, four weeks), and systemic medications were used in four patients, one of whom showed no response. The most common systemic medication used for treatment of PG was prednisone (n = 4). Data regarding time to resolution of PG were available in two of four patients who showed response and occurred at a mean duration of 10 weeks. Two patients had complete response of PG with treatment of PG alone, one had partial response with treatment of PG and malignancy, one had partial response with treatment of PG alone, and one patient showed no response to treatment.
(a)
Report
Discussion Previous reports of PG in association with solid organ malignancy (excluding more probable causes of PG such as systemic diseases: IBD, rheumatoid arthritis, hematologic malignancy, and IgA monoclonal gammopathy) have been mainly limited to case reports or small case series.2,4–8 Important findings from previous reports are summarized in Table 2. Our results indicate several unique findings: (i) new-onset PG can herald a recurrence of a previously diagnosed solid organ malignancy, and (ii) recurrent PG can be associated with solid organ malignancy (when the previous PG was not associated with solid organ malignancy). To the best of our knowledge, neither of these findings has been reported previously. They suggest that in some patients with PG, it may be important to assess for solid organ malignancies, even if they were ruled out during the initial diagnosis of PG. In all five of our cases, the PG and solid organ malignancy occurred within three months of each other (with three of the five cases occurring within one month). The close timing of solid organ malignancy and PG onset supports a possible causal link of the solid organ malignancy in the development of PG in our five cases. In two (20%) of the previously reported 10 cases of PG in association with solid organ malignancy (probable association cases described in Table 2), response to PG was only achieved after the underlying malignancies were resected.10,14 In our study, three of five cases showed some response to treatment of PG alone; however, one of these cases received the PG diagnosis after that of the underlying solid organ malignancy. Since surgery had already occurred before the diagnosis of PG in this case, it is possible that the surgery was necessary to see the response of the PG.
(b)
Figure 1 Clinical images from patient
3. (a) Numerous ulcerations of the legs with violaceous and undermined borders consistent with pyoderma gangrenosum. (b) Six weeks later, partial response of ulcerations after combined treatment of pyoderma gangrenosum and malignancy
ª 2015 The International Society of Dermatology
International Journal of Dermatology 2015, 54, e351–e357
e353
International Journal of Dermatology 2015, 54, e351–e357
2
1
Powell et al., 19856,b
Hughes et al., 20002
1
Campbell et al., 201013
1
M/53
1
Bunte et al., 20087
RegnierRosencher et al., 201114
M/34
1
M/73
M/74
M/76
F/70
1
Sakai et al., 200611 Franca et al., 200612
F/67
Table 1
1
1
5
Sex/ Age,y
Gallo et al., 199510
Probable associationa Shahi and Wetter, 2013 (present study) Lee et al., 19769
No. of Pts
Peristomal
Classic
Classic
Classic
PG subtype
Peristoma
Right leg
Abdomen
Started on right foot and spread all over body, excluding palms, soles, and mucous membranes Right scapula
Peristoma
Legs
Both legs
PG location
Carcinoma of the bladder Metastatic prostatic carcinoma Bladder cancer
Renal adenocarcinoma
Carcinoid tumor of the ileum
Adenocarcinoma of the sigmoid colon
Gastric cancer
Rectal carcinoma
Carcinoid tumor of the ileum, hemangioma in the liver, and cortical adenoma in the left adrenal gland found during autopsy Gastric “signet ring” cell carcinoma
Solid organ cancer
11 months after
Synchronous
4 months before diagnosis of malignancy 7 d after hemicolectomy
40 d after ileostomy for rectal carcinoma Synchronous
Synchronous
1.5-year history of ulcers, then carcinoid tumor found at autopsy
Timing of PG in relation to malignancy
Dapsone, mycophenolate mofetil, prednisone, topical cromolyn sodium, clobetasol propionate
Urostomy
Nephrectomy
Hemicolectomy
Hemicolectomy and chemotherapy
Prednisolone and azathioprine Prednisolone, somatostatin, azathioprine Surgical excision and corticosteroid ointments
Chemotherapy
Gastrectomy
Treatment of cancer
Corticosteroids
Cyclosporine
Hexachlorophene; prednisone, 40 mg
Treatment of PG
Still active on follow-up
Complete healing after 8 months, only after renal adenocarcinoma was removed
Satisfactory recovery
Marked improvement of PG when treating malignancy with chemotherapy; patient died after 4 months of complications related to malignancy Complete response in 9 months
Skin lesions improved after gastrectomy and healed in 3 weeks
Symptom improvement in 3 weeks; patient died after 12 weeks
Outcome of PG
Report
Study, year
Table 2 Previously reported cases of PG associated with solid organ malignancies
e354 PG associated with malignancy Shahi and Wetter
ª 2015 The International Society of Dermatology
No. of Pts
ª 2015 The International Society of Dermatology Breast Breast Prostate Glioblastoma multiforme
Breast cancer
4
Left breast Glioblastoma
F/31
Rectal adenocarcinoma
Bladder cancer
Acinous cell cancer of the parotid gland Adenocarcinoma of the hypopharynx Breast cancer
Metastatic breast cancer
Cancer of the breast
Adenocarcinoma of the left breast Oral carcinoma
Solid organ cancer
1
1
Peristoma
Peristoma
2
Peristomal
Breast
1
F/64
Right shoulder
1
Peristomal
Arms
1
M/83
Buttock
1
Buttock and left leg
PG location
Breast
Ulcerative dermatitis
PG subtype
1
Sex/ Age,y
7 d after
22 years
20 years
19 months after
7 d after
204 months before
Timing of PG in relation to malignancy
Triamcinolone acetonide, topical clobetasol propionate Triamcinolone acetonide, topical clobetasol propionate Corticosteroids
Corticosteroids and clofazimine Clofazimine
Clofazimine
Treatment of PG
Healing
Resolved
Proctosigmoidectomy with colostomy
Tumor removal
Resolved
“Cured”
Complete response in 10 d
Outcome of PG
Urostomy
Parotidectomy and corticosteroids Hypopharyngectomy
Chemotherapy
Treatment of cancer
d, days; F, female; M, male; PG, pyoderma gangrenosum; Pts, patients. Adapted from Regnier-Rosencher et al.14 and used with permission. a Probable cases had occurrence of PG and solid organ malignancy within 1 year of each other and did not have another systemic disease that was active and was believed more likely to be associated with PG. b This study also reported two cases of colon adenocarcinoma, but both cases had longstanding and extensive ulcerative colitis. C Possible cases had more than 1 year (or unknown duration) between onset of PG and solid organ malignancy, or had a systemic disease that was believed more likely to be associated with PG, or not enough data were available from the article to make a definitive inclusion in the probable category. d Article in French, data gathered from Regnier-Rosencher et al.14
Descheemaeker et al., 20088,d von den Driesch, 199722 Al Ghazal et al., 201223
Baruch et al., 199017 Maigre et al., 199118 Basille et al., 199219 Bayle-Lebey et al., 199520 Labat et al., 200021 Hughes et al., 20002
Possible associationc Beurey 1 et al., 197715 Kuhn, 198516 1
Study, year
Table 2 (Continued)
Shahi and Wetter PG associated with malignancy Report
International Journal of Dermatology 2015, 54, e351–e357
e355
e356
Report
Shahi and Wetter
PG associated with malignancy
In contrast to previous reports in which gastrointestinal malignancies were most commonly associated with PG (six of 10 cases), we found breast carcinoma (three of five cases) to be the most commonly associated solid organ malignancy in our group. We also found that PG associated with solid organ malignancy was more common in women (four of five patients); previous studies with available data demonstrated a male predominance (five of seven patients). Our patients had a similar mean age (55.6 years) to that in previous studies (63.9 years). Although the exact mechanisms by which solid organ malignancies may trigger the development of PG are unknown, abnormal immune surveillance postulated to occur in other paraneoplastic conditions may have a role. For example, the increased production of proinflammatory cytokines by tumor cells has been hypothesized to result in the development of vasculitis in association with solid organ malignancy.24 Similarly, episodic expression of stimulatory tumor antigens has been posited to trigger the development of paraneoplastic subacute cutaneous lupus erythematosus.25 Our study is limited by its retrospective nature and small sample size. Therefore, it is difficult to draw definitive conclusions regarding the association of solid organ malignancy and PG. It is possible that the occurrence of PG and solid organ malignancy is unrelated in some of our patients and is only the result of increased prevalence of malignancy with increasing age.26 However, the close temporal profile and lack of more likely associated systemic conditions suggest that solid organ malignancy may have been associated with the development of PG in our patients, although the lack of long-term follow-up data in all patients precludes confirmation of a definite association between PG and solid organ malignancy. We were unable to determine the percentage of patients with PG in association with solid organ malignancy out of all patients with PG at our institution; our search strategy for ascertainment of cases did not include all patients who received a diagnosis of PG during the study timeframe but rather only included cases with diagnoses of both PG and solid organ malignancy. Although our sample size was small, most of the previous studies represent single case reports. To the best of our knowledge, our study is the largest single-center case series of PG occurring in association with solid organ malignancy and thus adds important information to the existing literature. In conclusion, we describe five cases of PG associated with an underlying solid organ malignancy that were diagnosed within three months of the development of the malignancy. To the best of our knowledge, our study is the first to report that the onset of PG can herald a recurrence of a previously diagnosed solid organ malignancy and that recurrent PG can be associated with solid organ International Journal of Dermatology 2015, 54, e351–e357
malignancy when the initial onset of PG was not associated with malignancy. Although the literature suggests that solid organ malignancy associated with PG is rare, our results suggest that solid organ malignancy should be considered as a possible cause of PG in several types of patients: (i) those without other more likely systemic diseases known to be associated with PG; (ii) those with a previous history of solid organ malignancy; and (iii) those with a recurrent episode of PG that is more sudden in onset, different in clinical presentation than previous episodes, and without an identifiable more likely systemic cause. Larger retrospective cases series and prospective studies are needed to clarify further the features of and relationship between PG and solid organ malignancy.
References 1 Brunsting LA, Goeckerman WH, OLeary PA. Pyoderma (echthyma) gangrenosum: clinical and experimental observations in five cases occurring in adults. Arch Derm Syphilol 1930; 22: 655–680. 2 Hughes AP, Jackson JM, Callen JP. Clinical features and treatment of peristomal pyoderma gangrenosum. JAMA 2000; 284: 1546–1548. 3 Su WP, Davis MD, Weenig RH, et al. Pyoderma gangrenosum: clinicopathologic correlation and proposed diagnostic criteria. Int J Dermatol 2004; 43: 790–800. 4 Meissner PE, Jappe U, Niemeyer CM, et al. Pyoderma gangrenosum, a rare, but potentially fatal complication in paediatric oncology patients. Klin Padiatr 2007; 219: 296–299. 5 Kanno T, Ito M, Tsuji H, et al. A case of pyoderma gangrenosum involving the prostate gland after radiation therapy for prostate cancer. Hinyokika Kiyo 2002; 48: 565–568. (In Japanese.). 6 Powell FC, Schroeter AL, Su WP, et al. Pyoderma gangrenosum: a review of 86 patients. Q J Med 1985; 55: 173–186. 7 Bunte C, Popp-Habeler J, Mischer P, et al. Concomitant manifestation of pyoderma gangrenosum and colorectal carcinoma. Scand J Gastroenterol 2008; 43: 756–758. 8 Descheemaeker V, Aillet S, Morcel K, et al. Pyoderma gangrenosum and breast cancer: a case report. J Gynecol Obstet Biol Reprod (Paris) 2008; 37: 618–621. (In French.). 9 Lee SS, Biro L, Price E. Pyoderma gangrenosum with carcinoid tumor. Cutis 1976; 18: 791–794. 10 Gallo R, Parodi A, Rebora A. Pyoderma gangrenosum in a patient with gastric carcinoma. Int J Dermatol 1995; 34: 713–714. 11 Sakai H, Otsubo S, Iizuka H. Peristomal pyoderma gangrenosum associated with rectal adenocarcinoma. J Dermatol 2006; 33: 68–70. 12 Franca AE, Salvino LK, Leite SH, et al. Pyoderma gangrenosum as first clinical manifestation of gastric ª 2015 The International Society of Dermatology
Shahi and Wetter
13
14
15
16
17
18
19
adenocarcinoma. J Eur Acad Dermatol Venereol 2006; 20: 440–441. Campbell W, Baird E, Murtagh K, et al. Post-operative pyoderma gangrenosum in association with ileal carcinoid tumour. Ulster Med J 2010; 79: 102–103. Regnier-Rosencher E, Bizet N, Mery L. Pyoderma gangrenosum associated with renal carcinoma. J Am Acad Dermatol 2011; 64: 1208–1211. Beurey J, Weber M, Delrous JL, et al. Pyoderma gangrenosum: clofazimine therapy. Ann Dermatol Venereol 1977; 104: 631–634. (In French.). Kuhn A. Ulcerative dermatitis (pyoderma gangrenosum) with selective IgA deficiency and development of an oral carcinoma. Z Hautkr 1985; 60: 79–82. (In German.). Baruch J, Julien M, Touraine R, et al. Postoperative pyoderma gangrenosum and cancer of the breast. Apropos of a case. Ann Chir Plast Esthet 1990; 35: 73–75. (In French.). Maigre M, Bouachour G, Varache N, et al. Pseudosepticemic pyoderma gangrenosum and breast cancer. Apropos of a case caused by an intramuscular injection. Rev Med Interne 1991; 12: 452–454. (In French.). Basille W, Dompmartin A, Lorier E, et al. Pyoderma gangrenosum. Association to acinar cell carcinoma of the
ª 2015 The International Society of Dermatology
PG associated with malignancy
20
21
22
23
24
25
26
Report
parotid gland. Ann Dermatol Venereol 1992; 119: 381–383. (In French.). Bayle-Lebey P, Periole B, David JF, et al. Paraneoplastic pyoderma gangrenosum. Ann Med Interne (Paris) 1995; 146: 585–587. (In French.). Labat JP, Simon H, Metges JP, et al. Pyoderma gangrenosum and breast cancer: a new case. Ann Med Interne (Paris) 2000; 151: 314–315. (In French.). von den Driesch P. Pyoderma gangrenosum: a report of 44 cases with follow-up. Br J Dermatol 1997; 137: 1000–1005. Al Ghazal P, Korber A, Klode J, et al. Investigation of new co-factors in 49 patients with pyoderma gangrenosum. J Dtsch Dermatol Ges 2012; 10: 251–257 (In German.). Tatsis E, Reinhold-Keller E, Steindorf K, et al. Wegeners granulomatosis associated with renal cell carcinoma. Arthritis Rheum 1999; 42: 751–756. Chaudhry SI, Murphy LA, White IR. Subacute cutaneous lupus erythematosus: a paraneoplastic dermatosis? Clin Exp Dermatol 2005; 30: 655–658. Carsons S. The association of malignancy with rheumatic and connective tissue diseases. Semin Oncol 1997; 24: 360–372.
International Journal of Dermatology 2015, 54, e351–e357
e357
