Australasian Journal of Dermatology (2016) 57, e5–e7
doi: 10.1111/ajd.12251
CASE REPORT
Paraneoplastic subacute cutaneous lupus erythematosus associated with cholangiocarcinoma David Jenkins and Tess McPherson Dermatology Department, Churchill Hospital, Oxford University Hospitals NHS Trust, Headington, UK
ABSTRACT Subacute cutaneous lupus erythematosus (SCLE) is a dermatosis that occurs in genetically predisposed individuals. The exogenous stimulus that triggers this condition is usually unknown; however, medication is often implicated. Malignancy is a rare cause. We present a case of paraneoplastic SCLE to cholangiocarcinoma and briefly review the features of this interesting entity. Key words: cholangiocarcinoma, cutaneous lupus erythematosus, paraneoplastic, subacute cutaneous lupus erythematosus.
INTRODUCTION Cutaneous eruptions in association with, but not due to direct infiltration of, an underlying tumour have been well described. These are the paraneoplastic dermatoses. With manifestations as diverse as dermatomyositis, acanthosis nigricans and erythema gyratum repens, they cover a broad spectrum of skin pathologies. A lesser known member of this group is paraneoplastic subacute cutaneous lupus erythematosus (p-SCLE). We describe a case of SCLE appearing in a woman with a recent diagnosis of cholangiocarcinoma.
CASE REPORT A 38-year-old woman with no personal or family history of skin disease developed a widespread pruritic, scaly,
Correspondence: Dr David Jenkins, Unit 108, 244 Alison Road, Randwick, NSW 2031, Australia. Email: [email protected] Present address: Dermatology Department, Prince of Wales Hospital, Randwick, NSW 2031, Australia. David Jenkins, MBBS. Tess McPherson, MD. Conflict of interest: none Submitted 12 May 2014; accepted 3 August 2014. © 2014 The Australasian College of Dermatologists
Figure 1 Symmetrical erythrosquamous eruption on photoexposed areas. A widespread facial distribution with sparing of the periocular region, nasolabial folds, sub-nasal, sub-labial and submental regions is present.
erythematous eruption over a period of 3 months (Figs 1,2). It was in a photo-exposed distribution and on history there was a suggestion of photo-exacerbation. There was no mucous membrane involvement and her scalp and nails were normal. She denied using any medications at the onset of the rash. The patient presented with jaundice 1 month before any sign of her skin eruption and was diagnosed with cholangiocarcinoma based on the results of an endoscopic retrograde cholangiopancreatogram. Imaging revealed
Abbreviation: SCLE
subacute cutaneous lupus erythematosus
e6
D Jenkins and T McPherson
Figure 4 An interface reaction pattern showing vacuolar change and apoptotic bodies, some of which are suprabasal.
Figure 2 Left arm demonstrating the annular/polycyclic subtype of subacute cutaneous lupus erythematosus.
Given the morphology, distribution and photosensitivity of the rash, the suggestive histopathology and supportive immunological findings, she was considered to have SCLE. Due to the absence of a family history and associated drugs, the intimate timing of the rash with the development of malignancy and the manner in which it evolved, it was considered a paraneoplastic eruption. She was prescribed clobetasol 0.1% and clobetasone 0.05% ointments to the body and face, respectively. However, she found that these caused stinging, and so after the application of only a negligible amount, she changed to the use of an emollient only. Despite a lack of active treatment, the rash substantially abated over a period of 2–3 weeks, to the point where only mild activity remained. Therefore, the process of tumour debulking was the main process that triggered a regression in her rash. Palliative chemotherapy was decided against, and she was referred to the local community palliative care team.
DISCUSSION
Figure 3 Low-power view of interface reaction. The follicular infundibulum is significantly involved.
other intra-abdominal lesions and a tumour debulking was performed on a staging laparotomy. Systemic symptoms, including weight loss and fatigue, were attributed to the advancing, stage IV malignancy. A skin biopsy of her rash (Figs 3,4) revealed an interface dermatitis affecting the epidermis and follicular epithelium. Direct immunofluorescence was negative. Immunology showed a low-titre speckled anti-nuclear antibodies of 160, and positive anti-Ro60. Anti-La and the remainder of her extractable nuclear antigens was negative. Her baseline bloods showed a pancytopaenia with borderline microcytosis. © 2014 The Australasian College of Dermatologists
Paraneoplastic syndromes are said to occur in one of seven internal malignancies,1 with a significant proportion of these being skin related. The first paraneoplastic effect was noticed more than a century ago by Trousseau, but it was not until 1986 that the first case of p-SCLE was described.2 Since then, there have been fewer than 15 reports of p-SCLE in the literature and as an entity its characteristics are still being defined. In most cases of p-SCLE the rash precedes the tumour diagnoses. The underlying tumours have been lung, breast, gastric, hepatocellular, non-Hodgkin lymphoma, laryngeal, uterine and oesophageal adenocarcinoma in situ, but this is the first time SCLE has been linked to cholangiocarcinoma.3 Paraneoplastic SCLE has been described in relation to cancers of different stages. Sontheimer and colleagues described SCLE as a distinct subgroup of lupus in 1979.4 Diagnosis is made on the basis of a suggestive photosensitive rash, typical serology, supportive histopathology and the absence of systemic features.
P‐SCLE to cholangiocarcinoma
It is thought to be an autoimmune phenomenon triggered by environmental stimuli in a susceptible person. However, it may be more accurately described as an auto-adjuvant process to reflect the involvement of the innate immune system.5 Medications are known to be a trigger in some; however, the precipitant in most instances is usually unknown and malignancy only accounts for a tiny proportion of cases. Cholangiocarcinoma is an uncommon tumour that has only rarely been associated with skin eruptions. Isolated cases have been linked to acanthosis nigricans,6 Leser–Trélat syndrome,7 Sweets syndrome,8 erythema multiforme,9 necrolytic migratory erythema,10 yellow nail syndrome,11 adult-onset Stills disease,12 polyarteritis nodosa13 and Bazex syndrome.14 Different mechanisms for the development of a paraneoplastic phenomenon have been proposed but the exact mechanism remains unclear. One theory is that the tumour develops, uncovers or presents a neo-antigen to the immune system and creates a loss of immunotolerance with the skin. Given the high rate of anti-Ro positivity, Chaudhry and colleagues proposed that a tumour antigen with homology to the Ro ribonucleoprotein may be expressed.15 Cytoplasmic Ro is transferred to the keratinocyte cell membrane with UV exposure and this may explain why photosensitivity is a significant or necessary cofactor in the activity of the rash, even when it is driven by an underlying tumour. For a dermatoses to be considered paraneoplastic it should fulfil the criteria described by McLean a quarter of a century ago.16 Firstly, even though the rash may be diagnosed before the tumour, the onset of the tumour should precede the skin eruption, and in our patient this was clearly true. Usually there is a lag between onset of the tumour and appearance of the rash. It is thought that either a critical mass of tumour antigen is needed or a subpopulation within the tumour develops that instigates the process. McLean’s second criterion is that the rash and tumour should display a similar clinical course, such that regression of the dermatoses should occur with successful treatment of the tumour. Again, this is consistent with our case, given that surgical tumour debulking reduces the antigen load of the malignancy, and this is the most likely reason why the rash regressed. SCLE is only rarely associated with cancer and its routine appearance in a well patient should not prompt the search for an underlying neoplasm. The presence of systemic symptoms is more likely to be due to underlying systemic lupus than cancer. However, the possibility of p-SCLE should encourage dermatologists to be mindful of this association, and ensure relevant age and sex-appropriate cancer screening tests are up to date, in addition to those directed by clinical findings.
KEY POINTS
e7
• Paraneoplastic SCLE is associated with a wide variety of malignancies and this report adds to that list. • Clinicians have the opportunity to detect an underlying neoplasm at an early stage, and hence influence the prognosis and mortality. Additionally, the rash can be a useful marker of tumour relapse. • Even in the setting of late stage cancer the dermatologist can play an important role in the reduction of morbidity and the effective palliation of skin symptoms.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Sokmen M, Demirsoy H, Ersoy O et al. Paraneoplastic porphyria cutanea tarda associated with cholangiocarcinoma: case report. Turk. J. Gastroenterol. 2007; 18: 201–5. Brenner S, Golan H, Gat A et al. Paraneoplastic subacute lupus erythematosus: report of a case associated with cancer of the lung. Dermatology 1997; 194: 172–4. Shaheen B, Milne G, Shaffrali F. Subacute cutaneous lupus erythematosus associated with breast cancer. Clin. Exp. Dermatol. 2009; 34: e480–1. Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus erythematosus: a cutaneous marker for a distinct lupus erythematosus subset. Arch. Dermatol. 1979; 115: 1409–15. Aringer M, Gunther C, Lee-Kirsch MA. Innate immune processes in lupus erythematosus. Clin. Immunol. 2013; 147: 216– 22. Pagnini F, Giomi B, Delfino C et al. Cutaneous paraneoplastic syndrome presenting with warty-like oral lesions. Cutis 2012; 89: 14–6. Scully C, Barratt WA, Gilkes J et al. Oral acanthosis nigricans, the sign of Leser–Trelat, and cholangiocarcinoma. Br. J. Dermatol. 2001; 145: 506–7. Shinojima Y, Toma Y, Terui T et al. Sweet syndrome associated with intrahepatic cholangiocarcinoma producing granulocyte colony stimulating factor. Br. J. Dermatol. 2006; 154: 1103–4. Tzovaras V, Liberopaulos EN, Zioga A et al. Persistent erythema multiforme in a patient with extrahepatic cholangiocarcinoma. Oncology 2007; 73: 127–9. Chiyomaru K, Takai T, Ohashi A et al. Necrolytic migratory erythema with cholangiocarcinoma: pseudoglucagonoma syndrome. Eur. J. Dermatol. 2010; 20: 238–9. Di Stefano F, Verna N, Balatsinou L et al. Genetic hemochromatosis with normal transferrin saturation in a man with cholangiocarcinoma and yellow nail syndrome. J. Gastroenterol. Hepatol. 2003; 18: 1221–2. Raza A, Houk L, Yousaf W et al. Unusual para-neoplastic manifestation of cholangiocarcinoma. J. Gastrointest. Canc. 2013; 44: 228–30. Hatzis GS, Papachristodoulou A, Delladetsima IK et al. Polyarteritis Nodosa associated with cholangiocarcinoma. Lupus 1988; 7: 301–6. Karabulut A, Sahin S, Sahin M et al. Paraneoplastic acrokeratosis of Bazex (Bazex syndrome): report of a female case associated with cholangiocarcinoma, and review of the published work. J. Dermatol. 2006; 33: 850–4. Chaudhry SI, Murphy LA, White IR. Subacute cutaneous lupus erythematosus: a paraneoplastic dermatosis? Clin. Exp. Dermatol. 2005; 30: 655–8. McLean DJ. Cutaneous paraneoplastic syndromes. Arch. Dermatol. 1986; 122: 765–7.
• Although p-SCLE is a rare entity it reminds us to be vigilant about the possible associations of cutaneous lupus, especially when the eruption is resistant to treatment. © 2014 The Australasian College of Dermatologists
doi: 10.1111/ajd.12251
CASE REPORT
Paraneoplastic subacute cutaneous lupus erythematosus associated with cholangiocarcinoma David Jenkins and Tess McPherson Dermatology Department, Churchill Hospital, Oxford University Hospitals NHS Trust, Headington, UK
ABSTRACT Subacute cutaneous lupus erythematosus (SCLE) is a dermatosis that occurs in genetically predisposed individuals. The exogenous stimulus that triggers this condition is usually unknown; however, medication is often implicated. Malignancy is a rare cause. We present a case of paraneoplastic SCLE to cholangiocarcinoma and briefly review the features of this interesting entity. Key words: cholangiocarcinoma, cutaneous lupus erythematosus, paraneoplastic, subacute cutaneous lupus erythematosus.
INTRODUCTION Cutaneous eruptions in association with, but not due to direct infiltration of, an underlying tumour have been well described. These are the paraneoplastic dermatoses. With manifestations as diverse as dermatomyositis, acanthosis nigricans and erythema gyratum repens, they cover a broad spectrum of skin pathologies. A lesser known member of this group is paraneoplastic subacute cutaneous lupus erythematosus (p-SCLE). We describe a case of SCLE appearing in a woman with a recent diagnosis of cholangiocarcinoma.
CASE REPORT A 38-year-old woman with no personal or family history of skin disease developed a widespread pruritic, scaly,
Correspondence: Dr David Jenkins, Unit 108, 244 Alison Road, Randwick, NSW 2031, Australia. Email: [email protected] Present address: Dermatology Department, Prince of Wales Hospital, Randwick, NSW 2031, Australia. David Jenkins, MBBS. Tess McPherson, MD. Conflict of interest: none Submitted 12 May 2014; accepted 3 August 2014. © 2014 The Australasian College of Dermatologists
Figure 1 Symmetrical erythrosquamous eruption on photoexposed areas. A widespread facial distribution with sparing of the periocular region, nasolabial folds, sub-nasal, sub-labial and submental regions is present.
erythematous eruption over a period of 3 months (Figs 1,2). It was in a photo-exposed distribution and on history there was a suggestion of photo-exacerbation. There was no mucous membrane involvement and her scalp and nails were normal. She denied using any medications at the onset of the rash. The patient presented with jaundice 1 month before any sign of her skin eruption and was diagnosed with cholangiocarcinoma based on the results of an endoscopic retrograde cholangiopancreatogram. Imaging revealed
Abbreviation: SCLE
subacute cutaneous lupus erythematosus
e6
D Jenkins and T McPherson
Figure 4 An interface reaction pattern showing vacuolar change and apoptotic bodies, some of which are suprabasal.
Figure 2 Left arm demonstrating the annular/polycyclic subtype of subacute cutaneous lupus erythematosus.
Given the morphology, distribution and photosensitivity of the rash, the suggestive histopathology and supportive immunological findings, she was considered to have SCLE. Due to the absence of a family history and associated drugs, the intimate timing of the rash with the development of malignancy and the manner in which it evolved, it was considered a paraneoplastic eruption. She was prescribed clobetasol 0.1% and clobetasone 0.05% ointments to the body and face, respectively. However, she found that these caused stinging, and so after the application of only a negligible amount, she changed to the use of an emollient only. Despite a lack of active treatment, the rash substantially abated over a period of 2–3 weeks, to the point where only mild activity remained. Therefore, the process of tumour debulking was the main process that triggered a regression in her rash. Palliative chemotherapy was decided against, and she was referred to the local community palliative care team.
DISCUSSION
Figure 3 Low-power view of interface reaction. The follicular infundibulum is significantly involved.
other intra-abdominal lesions and a tumour debulking was performed on a staging laparotomy. Systemic symptoms, including weight loss and fatigue, were attributed to the advancing, stage IV malignancy. A skin biopsy of her rash (Figs 3,4) revealed an interface dermatitis affecting the epidermis and follicular epithelium. Direct immunofluorescence was negative. Immunology showed a low-titre speckled anti-nuclear antibodies of 160, and positive anti-Ro60. Anti-La and the remainder of her extractable nuclear antigens was negative. Her baseline bloods showed a pancytopaenia with borderline microcytosis. © 2014 The Australasian College of Dermatologists
Paraneoplastic syndromes are said to occur in one of seven internal malignancies,1 with a significant proportion of these being skin related. The first paraneoplastic effect was noticed more than a century ago by Trousseau, but it was not until 1986 that the first case of p-SCLE was described.2 Since then, there have been fewer than 15 reports of p-SCLE in the literature and as an entity its characteristics are still being defined. In most cases of p-SCLE the rash precedes the tumour diagnoses. The underlying tumours have been lung, breast, gastric, hepatocellular, non-Hodgkin lymphoma, laryngeal, uterine and oesophageal adenocarcinoma in situ, but this is the first time SCLE has been linked to cholangiocarcinoma.3 Paraneoplastic SCLE has been described in relation to cancers of different stages. Sontheimer and colleagues described SCLE as a distinct subgroup of lupus in 1979.4 Diagnosis is made on the basis of a suggestive photosensitive rash, typical serology, supportive histopathology and the absence of systemic features.
P‐SCLE to cholangiocarcinoma
It is thought to be an autoimmune phenomenon triggered by environmental stimuli in a susceptible person. However, it may be more accurately described as an auto-adjuvant process to reflect the involvement of the innate immune system.5 Medications are known to be a trigger in some; however, the precipitant in most instances is usually unknown and malignancy only accounts for a tiny proportion of cases. Cholangiocarcinoma is an uncommon tumour that has only rarely been associated with skin eruptions. Isolated cases have been linked to acanthosis nigricans,6 Leser–Trélat syndrome,7 Sweets syndrome,8 erythema multiforme,9 necrolytic migratory erythema,10 yellow nail syndrome,11 adult-onset Stills disease,12 polyarteritis nodosa13 and Bazex syndrome.14 Different mechanisms for the development of a paraneoplastic phenomenon have been proposed but the exact mechanism remains unclear. One theory is that the tumour develops, uncovers or presents a neo-antigen to the immune system and creates a loss of immunotolerance with the skin. Given the high rate of anti-Ro positivity, Chaudhry and colleagues proposed that a tumour antigen with homology to the Ro ribonucleoprotein may be expressed.15 Cytoplasmic Ro is transferred to the keratinocyte cell membrane with UV exposure and this may explain why photosensitivity is a significant or necessary cofactor in the activity of the rash, even when it is driven by an underlying tumour. For a dermatoses to be considered paraneoplastic it should fulfil the criteria described by McLean a quarter of a century ago.16 Firstly, even though the rash may be diagnosed before the tumour, the onset of the tumour should precede the skin eruption, and in our patient this was clearly true. Usually there is a lag between onset of the tumour and appearance of the rash. It is thought that either a critical mass of tumour antigen is needed or a subpopulation within the tumour develops that instigates the process. McLean’s second criterion is that the rash and tumour should display a similar clinical course, such that regression of the dermatoses should occur with successful treatment of the tumour. Again, this is consistent with our case, given that surgical tumour debulking reduces the antigen load of the malignancy, and this is the most likely reason why the rash regressed. SCLE is only rarely associated with cancer and its routine appearance in a well patient should not prompt the search for an underlying neoplasm. The presence of systemic symptoms is more likely to be due to underlying systemic lupus than cancer. However, the possibility of p-SCLE should encourage dermatologists to be mindful of this association, and ensure relevant age and sex-appropriate cancer screening tests are up to date, in addition to those directed by clinical findings.
KEY POINTS
e7
• Paraneoplastic SCLE is associated with a wide variety of malignancies and this report adds to that list. • Clinicians have the opportunity to detect an underlying neoplasm at an early stage, and hence influence the prognosis and mortality. Additionally, the rash can be a useful marker of tumour relapse. • Even in the setting of late stage cancer the dermatologist can play an important role in the reduction of morbidity and the effective palliation of skin symptoms.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Sokmen M, Demirsoy H, Ersoy O et al. Paraneoplastic porphyria cutanea tarda associated with cholangiocarcinoma: case report. Turk. J. Gastroenterol. 2007; 18: 201–5. Brenner S, Golan H, Gat A et al. Paraneoplastic subacute lupus erythematosus: report of a case associated with cancer of the lung. Dermatology 1997; 194: 172–4. Shaheen B, Milne G, Shaffrali F. Subacute cutaneous lupus erythematosus associated with breast cancer. Clin. Exp. Dermatol. 2009; 34: e480–1. Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus erythematosus: a cutaneous marker for a distinct lupus erythematosus subset. Arch. Dermatol. 1979; 115: 1409–15. Aringer M, Gunther C, Lee-Kirsch MA. Innate immune processes in lupus erythematosus. Clin. Immunol. 2013; 147: 216– 22. Pagnini F, Giomi B, Delfino C et al. Cutaneous paraneoplastic syndrome presenting with warty-like oral lesions. Cutis 2012; 89: 14–6. Scully C, Barratt WA, Gilkes J et al. Oral acanthosis nigricans, the sign of Leser–Trelat, and cholangiocarcinoma. Br. J. Dermatol. 2001; 145: 506–7. Shinojima Y, Toma Y, Terui T et al. Sweet syndrome associated with intrahepatic cholangiocarcinoma producing granulocyte colony stimulating factor. Br. J. Dermatol. 2006; 154: 1103–4. Tzovaras V, Liberopaulos EN, Zioga A et al. Persistent erythema multiforme in a patient with extrahepatic cholangiocarcinoma. Oncology 2007; 73: 127–9. Chiyomaru K, Takai T, Ohashi A et al. Necrolytic migratory erythema with cholangiocarcinoma: pseudoglucagonoma syndrome. Eur. J. Dermatol. 2010; 20: 238–9. Di Stefano F, Verna N, Balatsinou L et al. Genetic hemochromatosis with normal transferrin saturation in a man with cholangiocarcinoma and yellow nail syndrome. J. Gastroenterol. Hepatol. 2003; 18: 1221–2. Raza A, Houk L, Yousaf W et al. Unusual para-neoplastic manifestation of cholangiocarcinoma. J. Gastrointest. Canc. 2013; 44: 228–30. Hatzis GS, Papachristodoulou A, Delladetsima IK et al. Polyarteritis Nodosa associated with cholangiocarcinoma. Lupus 1988; 7: 301–6. Karabulut A, Sahin S, Sahin M et al. Paraneoplastic acrokeratosis of Bazex (Bazex syndrome): report of a female case associated with cholangiocarcinoma, and review of the published work. J. Dermatol. 2006; 33: 850–4. Chaudhry SI, Murphy LA, White IR. Subacute cutaneous lupus erythematosus: a paraneoplastic dermatosis? Clin. Exp. Dermatol. 2005; 30: 655–8. McLean DJ. Cutaneous paraneoplastic syndromes. Arch. Dermatol. 1986; 122: 765–7.
• Although p-SCLE is a rare entity it reminds us to be vigilant about the possible associations of cutaneous lupus, especially when the eruption is resistant to treatment. © 2014 The Australasian College of Dermatologists
