Case 3 -

Radiation Associated Atypical Vascular Lesion (AVL) Thomas Brenn Western General Hospital and The University of Edinburgh Edinburgh

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Clinical History A 79 year old female presents with three recently developed skin lesions in the right axilla (two biopsies are shown below). The patient has a past medical history of invasive breast carcinoma treated with mastectomy, axillary lymph node clearance and adjuvant radiation in 2004. Case 3 - Figure 1 This dermal based and relatively circumscribed tumor shows vasoformative elements with a complex and dissecting growth within pre-existing dermal collagen bundles. Vascular channels are lined by a single layer of endothelial cells lacking significant cytological atypia. Case 3 - Figure 2 This dermal based and relatively circumscribed tumor shows vasoformative elements with a complex and dissecting growth within pre-existing dermal collagen bundles. Vascular channels are lined by a single layer of endothelial cells lacking significant cytological atypia. Case 3 - Figure 3 This dermal based and relatively circumscribed tumor shows vasoformative elements with a complex and dissecting growth within pre-existing dermal collagen bundles. Vascular channels are lined by a single layer of endothelial cells lacking significant cytological atypia. Case 3 - Figure 4 Immunohistochemistry for CD31 stains lesional endothelial cells. It also emphasizes lesional circumscription and lack of subcutaneous involvement. Case 3 - Figure 5 Biopsy of a second lesion shows a circumscribed and nodular tumor with dilated vascular channels based within mid to deep dermis and abutting subcutaneous tissue. Case 3 - Figure 6 Higher magnification highlights the complex architecture. Also note the absence of endothelial cell layering and cytological atypia. Case 3 - Figure 7 Immunohistochemistry for CD31 demonstrates lesional circumscription as well as absence of endothelial cell multilayering. Case 3 - Figure 8 Immunohistochemistry for CD31 demonstrates lesional circumscription as well as absence of endothelial cell multilayering. Introduction: The presence of multiple newly developed cutaneous lesions at the site of prior surgery and adjuvant radiation therapy for carcinoma of the breast raises significant clinical concern. Important considerations include recurrent breast carcinoma as well as radiation associated disease. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The main histological features in this case are: 1. Well-circumscribed, dermal based vasoformative tumors without subcutaneous involvement. 2. Complex growth pattern composed of anastomosing vascular channels focally showing dissection among pre-existing dermal collagen bundles. 3. Lack of significant endothelial cell atypia or pleomorphism and absence of endothelial multilayering. 4. Immunohistochemistry for CD31 confirms that vascular channels are lined by a single cell layer of endothelial cells. It also highlights lesional circumscription despite the complex growth pattern. Differential Diagnoses: The main differential diagnosis includes vascular proliferations arising in the field of previous radiation treatment such as: - Radiation-associated atypical vascular lesion (AVL) - Radiation-associated angiosarcoma Final Diagnosis: Radiation associated atypical vascular lesion (AVL) Case Discussion: The present case illustrates the important clinical and histological features of AVL and emphasizes the diagnostic difficulties concerning radiation-associated vascular lesions. Vascular lesions arising at the site of prior radiation show a wide morphologic spectrum and their clinical behavior ranges from presumably benign to outright malignant with high associated mortality. They have been documented in the past, mainly in isolated case reports, but the etiological link with radiation has been established more firmly only recently with the increasing use of radiation therapy particularly in the setting of breast conserving treatment for mammary carcinoma. The term 'atypical vascular lesion' (AVL) was first used by Fineberg and Rosen in 1994 for vascular lesions with 'atypical' histological features but reportedly benign behavior in order to separate them from frank angiosarcoma arising in the area of previous radiation treatment for carcinoma of the breast [1]. Subsequent, more comprehensive reports have provided further insights into the clinical presentation of AVL and have expanded its histological spectrum. As yet, however, the true biologic potential and the relationship to radiation-associated angiosarcoma is not fully understood [2, 3, 4, 5, 6, 7]. Clinically, AVL present as solitary or multiple papules and only rarely as larger plaques confined to the field of prior radiation. They are skin colored to brown/erythematous, typically measuring a few millimeters up to 10 mm (median: 5 mm) in diameter [3, 7]. Larger variants are exceptional. Although AVL have been reported following radiation for various causes and affecting a wide range of anatomical locations, the vast majority occur on the breast and chest wall following radiation in the setting of either breast conserving therapy or as an adjuvant to mastectomy for breast carcinoma [3, 5, 6, 7]. The post radiation latency period is relatively short with a reported median of around 3 years. Females in the 5th to 6th decade of life are predominantly affected. Morphologically, AVL may show concerning features and there is at least some overlap with cutaneous well-differentiated angiosarcoma. Both entities share a complex growth of anastomosing vascular channels within dermis with at least focal dissection of pre-existing collagen bundles [1, 3, 5, 6]. In contrast to angiosarcoma, AVL appear well-circumscribed and somewhat symmetrical. The tumors are centered within dermis and show a wedge-shaped or nodular architecture. Dilated vascular channels are often found in the superficial aspects while a more complex, dissecting growth pattern of compressed vascular channels is seen in the deeper reaches. There is no infiltrative growth or significant invasion into subcutaneous tissues. While endothelial cells may appear prominent, showing hobnail features, true cytological atypia, pleomorphism or endothelial multilayering are not seen. AVL show at least some morphologic heterogeneity and, more recently, AVL have been subgrouped into lymphatic and vascular types [7]. Immunohistochemically, endothelial cells stain positively for CD31 and variably for CD34 [3, 7]. D2-40 expression was observed in the lymphatic but not the vascular type, whereas SMA-positive pericytes are said to be present only in the latter [7]. The behavior of AVL, its true biological potential and its relationship to cutaneous angiosarcoma remain topics of ongoing debate [1, 2, 3, 5, 6, 7]. Patients frequently present with multiple AVL and they are at risk for the development of further AVL in the radiation field [4]. Clinical behavior in the vast majority of patients, however, appears to be benign [5]. Local recurrence is rare after complete removal and true progression to frank angiosarcoma is a documented but exceptional complication [3, 7]. Sampling error and underdiagnosis of angiosarcoma as AVL is a particular problem on small, partial diagnostic biopsies [6]. Current treatment recommendations therefore advise complete excision with careful histological re-assessment. Furthermore, careful clinical follow-up is indicated with repeat biopsy of any newly developing or recurrent vascular lesions in the radiation field. The main differential diagnosis of AVL is with well-differentiated radiation-associated angiosarcoma which affects the same patient population. As there is significant overlap, reliable separation may be difficult or even impossible in rare cases. Clinically, angiosarcoma is large, measuring multiple centimeters and presenting as violaceous to erythematous or ecchymotic plaques and nodules, often affecting large areas of the radiation field [3, 4, 8]. Like AVL the disease often presents multifocally. The post-radiation latency interval is longer (median: 6 years) than that of AVL but tumors may occur as early as one year after radiation [3, 4, 8]. Histologically, cutaneous angiosarcoma shows poorly demarcated and diffuse growth within dermis and invasion of deeper underlying structures is a characteristic feature. Vascular channels are lined by atypical and often pleomorphic endothelial cells, and endothelial multilayering is a diagnostic hallmark even in well-differentiated tumors. Immunohistochemistry is of little differentiating value in this setting as both AVL and angiosarcoma express endothelial markers CD31 and CD34 as well as D2-40 [3]. Recently, myc amplification has been identified in radiation-associated angiosarcoma of the breast but not AVL, a finding that may prove diagnostically useful in the future [9]. Conclusion(s): Post-radiation vascular lesions are a rare but important complication of radiation therapy, especially as their frequency appears to be increasing. They arise predominantly in the setting of radiation treatment for breast carcinoma. Post-radiation AVL and angiosarcoma may represent a morphological and possibly biological continuum with AVL representing the benign and angiosarcoma the malignant end of the spectrum. Awareness of and familiarity with vascular lesions in the radiation field are important to pathologists and clinicians alike to guide appropriate patient management. References: Fineberg S, Rosen PP. Cutaneous angiosarcoma and atypical vascular lesions of the skin and breast after radiation therapy for breast carcinoma. Am J Clin Pathol. 1994; 102(6): 757. Requena L, Kutzner H, Mentzel T, Duran R, Rodriguez-Peralto JL. Benign vascular proliferations in irradiated skin. Am J Surg Pathol. 2002; 26(3): 328. Brenn T, Fletcher CD. Radiation-associated cutaneous atypical vascular lesions and angiosarcoma: clinicopathologic analysis of 42 cases. Am J Surg Pathol. 2005; 29(8): 983. Brenn T, Fletcher CD. Postradiation vascular proliferations: an increasing problem. Histopathology. 2006; 48(1): 106. Gengler C, Coindre JM, Leroux A, et al. Vascular proliferations of the skin after radiation therapy for breast cancer: clinicopathologic analysis of a series in favor of a benign process: a study from the French Sarcoma Group. Cancer. 2007; 109(8): 1584. Mattoch IW, Robbins JB, Kempson RL, Kohler S. Post-radiotherapy vascular proliferations in mammary skin: a clinicopathologic study of 11 cases. J Am Acad Dermatol. 2007; 57(1): 126. Patton KT, Deyrup AT, Weiss SW. Atypical vascular lesions after surgery and radiation of the breast: a clinicopathologic study of 32 cases analyzing histologic heterogeneity and association with angiosarcoma. Am J Surg Pathol. 2008; 32(6): 943. Billings SD, McKenney JK, Folpe AL, Hardacre MC, Weiss SW. Cutaneous angiosarcoma following breast-conserving surgery and radiation: an analysis of 27 cases. Am J Surg Pathol. 2004; 28(6): 781. Guo T, Zhang L, Chang NE, Singer S, Maki RG, Antonescu CR. Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions. Genes Chromosomes Cancer. 2011; 50(1): 25.