Copyright © 2012 John Wiley & Sons A/S
J Cutan Pathol 2012: 39: 741–746 doi: 10.1111/j.1600-0560.2012.01936.x John Wiley & Sons. Printed in Singapore
Journal of Cutaneous Pathology
Cutaneous collagenous vasculopathy: a rare cutaneous microangiopathy Cutaneous collagenous vasculopathy is a rare microangiopathy of superficial dermal blood vessels. Patients present with telangiectatic macules, predominantly on the extremities. A skin biopsy specimen is necessary to distinguish cutaneous collagenous vasculopathy from generalized essential telangiectasia. Microscopically, cutaneous collagenous vasculopathy resembles the superficial telangiectasias of generalized essential telangiectasia but additionally shows hyaline material in thickened vessel walls. The amorphous pink material is periodic acid-Schiff-positive and resistant to diastase. We describe a series of four patients with cutaneous collagenous vasculopathy and highlight its clinical and histopathologic features. Keywords: cutaneous vasculitis, cutaneous collagenous vasculopathy, generalized essential telangiectasia, microangiopathy, telangiectasia Burdick LM, Losher S, Somach SC, Billings SD. Cutaneous collagenous vasculopathy: a rare cutaneous microangiopathy. J Cutan Pathol 2012; 39: 741–746. © 2012 John Wiley & Sons A/S.
Cutaneous collagenous vasculopathy represents a rare microangiopathy of superficial dermal blood vessels. It is probably under-recognized and under-reported. Clinicians may mistake it for generalized essential telangiectasia and may not proceed to biopsy.1,2 Additionally, the diagnostic microscopic findings are quite subtle. Patients present with telangiectatic macules, predominantly on the extremities, reminiscent of generalized essential telangiectasia.1 – 5 Cutaneous collagenous vasculopathy has been documented more commonly in men, although it may affect a wider spectrum of patients, as the disorder has been described in women6 and in at least one pediatric patient.2 A skin biopsy is necessary to distinguish the two conditions.2 We describe a series of patients with cutaneous collagenous vasculopathy and highlight its clinical and histopathologic features. Case 1 A 68-year-old man with macular degeneration since childhood, hypertension, hyperlipidemia, gastroesophageal reflux disease and sleep apnea presented
Laura M. Burdick1 , Sara Losher2 , Stephen C. Somach3 and Steven D. Billings1 1 Cleveland
Clinic – Anatomic Pathology and Dermatology, Cleveland, OH, USA, 2 Cleveland Clinic – Dermatology, Cleveland, OH, USA, and 3 MetroHealth Medical Center, Case Western Reserve University – Dermatology, Cleveland, OH, USA Steven D. Billings, Cleveland Clinic, Department of Anatomic Pathology, 9500 Euclid Avenue L25, Cleveland, OH 44195, USA Tel: 216-444-2826 Fax: 216-445-6967 e-mail:
[email protected] Accepted for publication May 6, 2012
with a several-week history of asymptomatic, discrete, blanchable dark pink macules on his distal upper and lower extremities (Figs. 1 and 2). He had recently begun taking tramadol but had stopped this medication prior to his visit. Case 2 A 59-year-old man with diabetes mellitus, hypertension, hyperlipidemia, osteoarthritis and depression presented with a several-month history of a fine network of telangiectatic macules. They began on his distal legs and spread to involve his thighs and abdomen. Case 3 A 70-year-old man with hypertension, diabetes mellitus and hypercholesterolemia presented with a 10-year history of petechiae confined to the right leg. Case 4 A 41-year-old woman with a history of basal cell carcinoma and a remote history of resolved hepatitis
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Fig. 1. Discrete, blanchable dark pink macules symmetrically involve the distal upper extremities.
Fig. 3. Dilated, thick-walled vessels are present in the superficial dermis. There is no associated significant hemorrhage or inflammation (hematoxylin and eosin, ×40).
Fig. 2. Similar macules are present on the bilateral distal lower extremities.
that was diagnosed during childhood presented with a several-year history of red macules on the bilateral forearms. These were reported to be more prominent from July to December, annually. Histopathology All cases showed similar microscopic features. Within the superficial dermis, there were dilated, thickwalled vessels without significant hemorrhage or inflammation (Fig. 3). The vessel walls contained amorphous, hyaline pink material (Fig. 4). This material was highlighted with a periodic acid-Schiff (PAS) stain and was resistant to diastase (Fig. 5). Discussion Cutaneous collagenous vasculopathy has almost exclusively been reported in middle-aged and elderly men,1,3 – 5,7 although more recent cases occurred in women6 and a 16-year-old child,2 suggesting that a broader patient population may be affected. Patients with cutaneous collagenous vasculopathy
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Fig. 4. The vessel wall contains amorphous pink hyaline material (hematoxylin and eosin, ×200).
present with blanchable, non-urticating macules that usually occur symmetrically.4 – 7 Typically, the macules begin on the lower extremities and progress, spreading to the trunk and upper extremities and sparing the mucosal surfaces and nail beds.2,4 – 7 The telangiectatic macules of the disorder tend to be asymptomatic7 but may rarely be associated with pruritus.6 Patients do not have photosensitivity or other symptoms suggestive of connective tissue disease, although occasional cases have been reported to worsen in the summer months.6 One of our cases (Case 3) also showed some seasonal variation, but it was not restricted to the summer months. The individual telangiectatic macules of cutaneous collagenous vasculopathy typically remain relatively stable, but they may darken with time,7 and patients may develop more of them over time. Table 1 lists a
Cutaneous collagenous vasculopathy
Fig. 5. The hyaline material within the vessel walls is periodic acid-Schiff (PAS)-positive and diastase resistant (PAS with diastase, ×400).
summary of the clinical and demographic features of this disease. There are currently no recommended laboratory studies to aid in the diagnosis of cutaneous collagenous vasculopathy. Reported laboratory studies have usually been unremarkable, including complete blood count, blood urea nitrogen, creatinine, fasting glucose and glucose tolerance test, antinuclear antibodies, extractable nuclear antigen, anti-centromere antibody, rheumatoid factor,5 C-reactive protein, erythrocyte sedimentation rate, creatinine kinase, tryptase,6 C3, C4, hepatitis B status, hepatitis C status, human immunodeficiency virus status4 and normal porphyrin status.2 The primary role for such studies would be to help exclude other entities in the clinical differential diagnosis. Histopathologically, cutaneous collagenous vasculopathy shows superficial dermal small blood vessels
that are dilated5 with flat endothelial cells7 and with thickened walls containing hyaline material. There is little inflammation, and no inflammatory cells are present within vessel walls.3,5 Little to no hemorrhage or hemosiderin is present.5 The hyaline material stains with PAS and is diastase resistant.3,6,7 It is also highlighted with Masson’s trichrome2,4,5 and by immunohistochemistry for laminin and type IV collagen3,6,7 but not with elastic stains. No amyloid is present in the vessel wall, as showed by negative staining for Congo red2,5 and crystal violet.7 These results indicate that the material is derived from basement membrane collagen, and there is evidence that it is the result of reduplication and splitting of the basement membrane zone surrounding small vessels as showed with immunostains to type IV collagen.3,5 Direct immunofluorescence is negative.5,7 Ultrastructurally, the first reported case of cutaneous collagenous vasculopathy had Luse bodies, representing collagen fibers with abnormally long spaces between electron-dense bands.5 These can be seen in many conditions and are not specific5 and may be absent in some cases of cutaneous collagenous vasculopathy.7 Vessel walls are composed of fibrils of interstitial collagen embedded in a granular material.7 Endothelial cells appear normal,5 but their basement membrane is embedded in the granular material.7 Pericytes are sparse and surrounded by thin external lamina resulting from splitting of basement membrane lamellae beneath endothelial cells.5 The basement membrane shows focal reduplication by immunohistochemistry and ultrastructural examination.5 The etiology of cutaneous collagenous vasculopathy is uncertain. In the first reported case, macules recurred in biopsy scars.5 In the second reported case, the macules of cutaneous collagenous vasculopathy
Table 1. Clinical demographics of reported cases of cutaneous collagenous vasculopathy Case 1 2 3 4 5 6 7 8 9 10 11 12 13
Author
Year
Age
Gender
Salama5 Davis3 Davis3 Davis3 Kanitakis7 Perez6 Perez6 Monteagudo4 Lloyd2 Current report Current report Current report Current report
2000 2008 2008 2008 2010 2010 2010 2010 2011 2011 2011 2011 2011
54 59 62 80 65 51 71 68 16 59 68 70 41
M M M M M F F M F M M M F
Distribution LE → trunk and UE UE, trunk LE LE, trunk LE → trunk and UE LE → trunk, UE, neck LE → UE, trunk, cheek LE, UE, and trunk LE, UE, and trunk LE → abdomen UE, LE Right LE UE
Comorbidities Depression DM, HTN, HPL Psoriasis, arthritis, HTN, DM Atrial fibrillation, GERD, venous insufficiency, elevated PSA HTN, MI, dyspnea, benign prostatic adenoma Psoriasis, hypothyroidism Benign pituitary tumor, osteoporosis HTN, HPL, hyperuricemia, BPH, alopecia universalis Mood disorder DM, HTN, HPL, OA, depression Macular degeneration, HTN, HPL, GERD, sleep apnea DM, HTN, HPL BCC, resolved hepatitis (unknown type)
M, male; F, female; LE, lower extremities; UE, upper extremities; →, spread to involve; DM, diabetes mellitus; HTN, hypertension; HPL, hyperlipidemia; GERD, gastro-esophageal reflux disease; BPH, benign prostatic hypertrophy; OA, osteoarthritis; BCC, basal cell carcinoma.
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Burdick et al. Table 2. Clinical differential diagnosis of cutaneous collagenous vasculopathy Arrangement Cutaneous collagenous vasculopathy Generalized essential telangiectasia Pigmented purpuric dermatosis (Schamberg’s disease) Unilateral nevoid telangiectasia Angioma serpiginosum Hereditary hemorrhagic telangiectasia Ataxia-telangiectasia Telangiectasia macularis eruptiva perstans Telangiectasias associated with connective tissue diseases
Symmetrical Symmetrical sheets Pinpoint macules with background yellow-brown patchesNon-blanching SegmentalUnilateral SerpiginousInitially unilateral RandomMat-like, papular on mucosa SymmetricLinear Random Random
Location
Age
Gender
Legs; may progress to arms, trunk Legs; may progress to arms, trunk Lower legs; may progress to thighs, buttocks, trunk, arms
Middle-aged
Men > women, one child
Adult (usually)
Women > men
Middle-aged
Men > women
Trigeminal/cervical dermatomes Extremities – but no palms/soles Mucosal – nasal, tongue,face, lips, hands Conjunctivaehead/neck Trunk and proximal extremities Varies with specific etiology; often sun-exposed areas and/or hands
Congenital or acquired
Either
First two decades
Girls, young women
Children > young adults (Cutaneous often in puberty) Young children Adults
Either
Adults and children
Either Either Either, often girls and young women
Table 3. Histopathologic differential diagnosis Dilated superficial vessels Amorphous hyaline material Cutaneous collagenous vasculopathy Telangiectasia Atrophie blanche Porphyrias and pseudoporphyria Secondary systemic amyloidosis
Yes Yes Yes Yes Yes
In vessel walls, PAS+ No In vessel walls, PAS+ In vessel walls, PAS+ In vessel walls, amyloid stains+
Lipoid proteinosis
Yes
In vessel walls
Thrombotic vasculopathy
Yes
In vessel lumens
TMEP Erythromelalgia
Yes Yes
No No
Other features Little hemorrhage or inflammation More hemorrhage and inflammation Subepidermal blister (often) May see the hyaline material in papillary dermis, fat and eccrine glands May see hyaline material around eccrine glandsAtrophy of eccrine glands More hemorrhage than in cutaneous collagenous vasculopathy Subtle increase in mast cells Endothelial swellingMild fibrosis, edema, inflammation
TMEP, telangiectasia macularis eruptiva perstans.
occurred as bruising from a fall faded.3 One woman developed the disorder soon after the birth of her child.6 Several patients with cutaneous collagenous vasculopathy, including two of the patients in this series, had diabetes mellitus. Diabetes mellitus is sometimes associated with microangiopathy and could possibly contribute to the development of cutaneous collagenous vasculopathy.8 However, if diabetes mellitus plays a role, it is clearly not the only mechanism for the development of cutaneous collagenous vasculopathy, as many of patients are not diabetic. It is possible that the coexistence of diabetes mellitus may be a confounding factor given
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the high prevalence of this condition in the general population. While trauma could potentially play a role in selected, cases, there was no such history in our series, and it seems an unlikely explanation for this relatively anatomically widespread entity. It is also possible that cutaneous collagenous vasculopathy represents a reaction pattern to which there are multiple pathways. Ultimately, cutaneous collagenous vasculopathy is clearly related to damage to the superficial dermal vasculature. The absence of actin staining in vessel walls suggests that a decrease in contractile pericytes may be responsible for their dilation.5 Alternatively,
Cutaneous collagenous vasculopathy the abnormal collagen deposition may weaken the dermal support of the vascular structures.5 More study will be necessary to determine potential risk factors and the pathogenesis of cutaneous collagenous vasculopathy. It is our suspicion that cutaneous collagenous vasculopathy is under-recognized because it can be mistaken both clinically and histopathologically for other entities. Hereditary hemorrhagic telangiectasia syndrome and generalized essential telangiectasia perhaps have the most clinical overlap, but there are important differences. Unlike hereditary hemorrhagic telangiectasia, patients with cutaneous collagenous vasculopathy do not have lesions involving the mucosa, they lack a personal or family history of abnormal bleeding,2,4 – 7 and there is no autosomal dominant inheritance pattern.5 Similar to cutaneous collagenous vasculopathy, telangiectasias of generalized essential telangiectasia often begin on the lower extremities and progresses to the trunk and arms, and there is no abnormal bleeding. In contrast to cutaneous collagenous vasculopathy, generalized essential telangiectasia sometimes involves the oral and conjunctival mucosa, and it is more common in women.5 The dilated capillaries or postcapillary venules in the telangiectasias of hereditary hemorrhagic telangiectasia and generalized essential telangiectasia are thin-walled, without the perivascular hyalinization.9 – 11 Superficial dilated capillaries and post-capillary venules are also present in hereditary hemorrhagic telangiectasia, but deep dermal vessels may also be dilated, with irregular, thickened walls.12 In hereditary hemorrhagic telangiectasia, both superficial dermal venules and arterioles are dilated.13 Both hereditary hemorrhagic telangiectasia and generalized essential telangiectasia lack the hyaline deposits in the vessel walls that define cutaneous collagenous vasculopathy. In the absence of a good clinical history, there are other entities that could be considered in the histopathologic differential diagnosis. Amorphous,
PAS-positive hyaline material reminiscent of that in cutaneous collagenous vasculopathy may be observed in the porphyrias, pseudorphyria, lipoid proteinosis, atrophie blanche and amyloidosis. Similar to cutaneous collagenous vasculopathy, the hyaline deposits of the porphyrias, pseudoporphyria and lipoid proteinosis are also composed of basement membrane material, so recognition of other features aid in microscopic distinction. In the porphyrias and pseudoporphyria, subepidermal blisters or at least a history of blisters distinguishes these conditions from cutaneous collagenous vasculopathy.14 The hyaline deposits of lipoid proteinosis have a more varied distribution, involving not only the vessel walls but also eccrine sweat glands. In long-standing lipoid proteinosis, the deposits may have a concentric, ‘onion skin’ appearance around vessels and may lead to atrophy of eccrine glands.15 In atrophie blanche, the perivascular deposits are fibrin rather than basement membrane material, and there is vascular thrombosis with more inflammation and hemorrhage and often epidermal necrosis.16 In amyloidosis, eosinophilic hyaline material from amyloid may be found around blood vessels. However, these deposits may also be around sweat glands and can be highlighted with stains for amyloid.17 In contrast, the deposits of cutaneous collagenous vasculopathy are negative for amyloid stains. In entities, in which the deposits are not composed of basement membrane material, an immunostain for type IV collagen may help in the differential diagnosis. Entities in the clinical and histopathologic differential diagnosis of cutaneous collagenous vasculopathy are summarized in Tables 2 and 3. In summary, cutaneous collagenous vasculopathy is a rare microangiopathy of small cutaneous vessels that may be under-recognized. Increased awareness of this interesting condition will lead to improved recognition by both clinicians and pathologists and may over time lead to more insight into this unusual entity.
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