Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Atypical Vascular Lesions

  • Lauren E. Rosen
  • Thomas KrauszEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_4741-1

Synonyms

Cutaneous atypical vascular lesions (AVLs) of the breast have been described using a variety of terms including post-mastectomy lymphangiomatosis, benign lymphangiomatous papules, benign lymphangioendothelioma, acquired lymphangiectasis, and lymphangioma circumscriptum (Baker and Schnitt 2017; Weaver and Billings 2009).

Definition

AVLs are benign vascular proliferations of the skin that occur following radiation therapy for breast cancer within the field of radiation. The term AVL was proposed by Fineberg and Rosen in 1994 to reflect the fact that these lesions were occasionally mistaken for angiosarcoma, and because their relationship to post-irradiation angiosarcomas (PIAS) is not fully understood (Fineberg and Rosen 1994).

Clinical Features

  • Incidence

    AVLs occur in the field of radiation after radiation therapy for breast cancer, with a latency period of 1 month to 20 years, occurring most frequently between 3 and 6 years post-treatment (Ginter et al. 2017).

  • Age

    AVLs are seen in a population ranging in age from 29 to 95 years, most occurring in the fifth and sixth decades (Ginter et al. 2017).

  • Sex

    All reported cases of AVLs of the breast have occurred in females, likely reflecting the higher incidence of breast cancer in this population (Weaver and Billings 2009).

  • Site

    AVLs occur most commonly in mammary or axillary skin, and can rarely involve the breast parenchyma. AVLs also occur in sites other than the breast following radiation therapy for various malignancies, such as gynecologic tumors and multiple myeloma (Brenn and Fletcher 2005).

  • Treatment

    AVLs are treated by excision with free margins and close clinical follow-up to monitor for development of new lesions (Baker and Schnitt 2017).

  • Outcome

    In approximately 10–20% of cases, AVLs can recur or new lesions can arise within the radiation field following complete excision (Baker and Schnitt 2017). Rare cases of progression to angiosarcoma have been reported, but it is unclear if these represent cases of angiosarcoma with AVL-like areas which were misdiagnosed on biopsy, or an angiosarcoma developing in the same area as an AVL (Brenn and Fletcher 2005). It has been suggested that vascular type AVLs have a higher risk of progression to angiosarcoma than the lymphatic type; however, this claim has not been well supported (Patton et al. 2008). While few reports raise the possibility that AVLs have the potential to progress to angiosarcoma in rare circumstances, overall the current evidence suggests that AVLs follow a benign course (Ginter et al. 2017).

Macroscopy

AVLs typically present as discrete flesh-toned to reddish or bluish papules arising in the field of radiation, and less frequently as vesicles, cystic lesions, or erythematous plaques (Brenn and Fletcher 2005; Koerner 2014). The lesions are generally less than 5 mm in size (range 1–20 mm), and can be single or multiple, with up to half of patients developing multiple lesions either at the time of initial diagnosis or subsequently (Baker and Schnitt 2017; Ginter et al. 2017; Flucke et al. 2013).

Microscopy

On low power, AVLs are frequently circumscribed lesions located within the superficial dermis. AVLs can be wedge-shaped with their base oriented toward the dermal-epidermal junction (Baker and Schnitt 2017). The lesions are generally flat, but may appear as exophytic papules that project from the skin surface. The overlying epidermis is usually normal or mildly acanthotic (Koerner 2014). When AVLs involve the breast parenchyma, they are usually encased within fibrous tissue without involvement of the mammary glandular tissue (Brenn and Fletcher 2005). AVLs are composed of ectatic, angulated, and variably anastomosing thin-walled vascular channels lined by a single layer of monomorphous endothelial cells (Baker and Schnitt 2017; Weaver and Billings 2009) (Fig. 1a: H&E). While in most cases the lesions are limited to the superficial dermis, in some cases the vessels extend into the deep dermis where they are often smaller, compressed, and infiltrative with focal dissection of collagen and infiltration of adnexal structures (Brenn and Fletcher 2005). More rarely, the lesions can extend into the subcutis. Two distinct morphologic subtypes of AVL have been described, lymphatic type and vascular type. Both patterns are often seen within the same lesion (Patton et al. 2008; Ginter et al. 2017).
Fig. 1

(a) AVL composed of irregular thin-walled dilated vascular spaces dissecting through collagen. The nuclei are widely spaced and lack cytologic atypia [H&E, 40X], (b) AVL with variable positivity for CD34 [20x], (c and d) AVL with strong diffuse positivity for D2-40 (c) and CD31 (d) [20x]

The lymphatic type is the most common subtype of AVL, and is comprised of variably-sized anastomosing vascular channels lined by a monolayer of attenuated to hobnail endothelial cells reminiscent of lymphangioma (Gengler et al. 2007; Koerner 2014). Endothelial-lined stromal projections can be seen within the vascular lumens, which are characteristically devoid of erythrocytes (Flucke et al. 2013; Patton et al. 2008). The vessels are typically tightly clustered within the superficial dermis; however, in a minority of cases, they extend into the deep dermis where they have a more infiltrative appearance. The lining endothelium is commonly hyperchromatic, but lacks significant nuclear atypia, prominent nucleoli, and mitoses (Patton et al. 2008; Requena et al. 2002).

Vascular type AVLs are composed of round to elongated capillary sized vessels that grow irregularly within the superficial or deep dermis, reminiscent of a capillary hemangioma (Patton et al. 2008). In contrast to lymphatic type AVLs, these lesions show intraluminal red cells and the vessels are surrounded by a layer of pericytes. Vascular type AVLs can show mild random nuclear atypia and rare mitotic figures; however, endothelial multilayering and necrosis are absent. The adjacent stroma may contain sparse to dense chronic inflammatory infiltrate composed of lymphocytic aggregates with occasional germinal centers, or there may be adjacent hemorrhage or hemosiderin (Ginter et al. 2017; Patton et al. 2008).

Immunophenotype

Lymphatic type AVLs are positive for CD31, D2-40, ERG, and positive or negative for CD34 (Fig. 1b: CD34 immunostaining; 1C: D2-40 immunostaining; 1D: CD31 immunostaining). Vascular type AVLs are positive for CD31, CD34, and ERG, but negative for D2-40 (Baker and Schnitt 2017). The pericytes surrounding the vessels in vascular type AVLs are positive for smooth muscle actin (Brenn and Fletcher 2005).

Molecular Features

Amplification of MYC has been implicated in the development of PIAS (Fernandez et al. 2012; Fraga-Guedes et al. 2015; Mentzel et al. 2012). The MYC oncogene is a transcription factor that has a role in cell proliferation, cellular differentiation, apoptosis, and angiogenesis. Dysregulated MYC expression due to gene amplification promotes cell proliferation through inappropriate progression to S-phase from G1 phase of the cell cycle. Amplification of MYC occurs in other sarcomas, such as high-grade chondrosarcomas, proximal type epithelioid sarcomas, and myxoid liposarcomas (Fraga-Guedes et al. 2015). Many studies have found high-level amplifications of MYC by fluorescence in situ hybridization (FISH) in the majority of post-radiation and lymphedema associated angiosarcomas, but not in primary cutaneous angiosarcomas or AVLs (Fernandez et al. 2012; Fraga-Guedes et al. 2015; Mentzel et al. 2012). Interestingly in one study, two patients had AVLs lacking MYC amplification adjacent to MYC amplified PIAS (Fraga-Guedes et al. 2015). Amplification of MYC by FISH has a strong correlation with MYC expression by immunohistochemistry (IHC). FLT4 is a gene that encodes for VEGFR3 and plays a role in lymphatic differentiation. FLT4 gene amplification is detected by FISH in 25% of PIAS, and is absent in AVLs, but the gene is co-amplified with MYC limiting its utility in this setting (Cornejo et al. 2015; Guo et al. 2011). One study demonstrated TP53 mutations in the majority of AVLs studied, and hypothesized that TP53 mutations may occur early in neoplastic development of AVL (Santi et al. 2011).

Differential Diagnosis

The main differential diagnosis for AVL is angiosarcoma (Angiosarcoma), particularly those that arise following radiation, termed PIAS. Both AVL and PIAS arise in the skin of the breast or chest wall following radiation, occur in middle aged to elderly women, and are characterized by anastomosing vascular channels. PIAS have a latency period of 5–6 years, which overlaps with the 3–6 year interval of AVLs (Weaver and Billings 2009). The majority of PIAS are high grade, but low and intermediate grade tumors have been described in which there is morphologic overlap with AVLs. AVLs may be multiple but are usually small pink papules (< 1 cm) while PIAS are often larger (>2 cm) and present as violaceous or erythematous plaques with ulceration (Weaver and Billings 2009; Brenn and Fletcher 2005). AVLs are relatively circumscribed and limited to the superficial dermis, however can invade into the deep reticular dermis and rarely into the subcutis; while PIAS often invade through the dermis and into the subcutis (Weaver and Billings 2009; Brenn and Fletcher 2005). The nuclei of AVLs are hyperchromatic and can show mild random atypia (Fig. 2a: H&E), while the nuclei in PIAS are uniformly enlarged with prominent nucleoli (Weaver and Billings 2009; Brenn and Fletcher 2005). Features that favor a diagnosis of AVL include circumscription, vessels lined by a single layer of endothelial cells, bloodless spaces, delicate projections of endothelial lined stroma into the vascular spaces, and associated chronic inflammation. Proliferation activity evaluated by Ki67 is low and cMYC is negative (Udager et al. 2016; Requena et al. 2002) (Fig. 2b and c: Ki67 immunostaining and cMYC immunostaining, respectively); (Table 1). Findings that favor PIAS include infiltration of the subcutis, prominent dissection of dermal collagen, hemorrhage and extravasated red blood cells, marked cytologic atypia, mitotic figures, necrosis, and multilayering of the endothelial cells (Fig. 2d: H&E). Proliferation activity evaluated by Ki67 is high and cMYC is overexpressed in nuclei (Udager et al. 2016; Requena et al. 2002) (Fig. 2e and f: Ki67 immunostaining and cMYC immunostaining, respectively). AVLs can very rarely show more worrisome features such as scattered variably enlarged nuclei with prominent nucleoli, an occasional mitosis, focal, limited multilayering (usually not more than a double layer of endothelium), poor circumscription, and extension into subcutis (Weaver and Billings 2009). In addition, AVLs and PIAS can coexist, and PIAS may exhibit AVL-like areas, which can be indistinguishable from a true AVL in a limited biopsy. For this reason, it is recommended that a diagnosis of AVL should not be made on a small biopsy, with preferred classification as an atypical vascular proliferation with the definitive diagnosis deferred to excision (Baker and Schnitt 2017).
Fig. 2

(a) AVL with irregularly shaped, dilated vascular channels and random cytologic atypia with variably enlarged and hyperchromatic nuclei [H&E, 40x]. (b and c) AVL with low Ki-67 proliferation index (b) and negativity for c-myc (c) [40x]. (d) Post-radiation angiosarcoma is composed of invasive (dissecting collagen), irregular vascular channels lined by focally multilayered neoplastic endothelium with marked diffuse nuclear atypia and extravasated red blood cells. (e and f) Post-radiation angiosarcoma with high Ki-67 proliferation index (e) and c-myc positivity (f) [40x]

Table 1

Histologic, immunohistochemical, and molecular features of AVL versus post-radiation angiosarcoma. (Adapted from Fineberg and Rosen (1994) and Flucke et al. (2013))

 

AVL

AS

Histology

Relative circumscription

+++

Anastomosing vessels

++

+++

Dissection of dermal collagen

+

+++

Infiltration into subcutis

−/+

+++

Stromal projections into lumen

+++

+

Multilayered endothelium

−/+

+++

Hyperchromatic endothelial nuclei

+++

++

Significant cytologic atypia

+++

Enlarged nuclei

−/+

+++

Prominent nucleoli

−/+

+++

Mitotic figures

−/+

+++

Extravasated red blood cells or blood lakes

++

Chronic inflammation

+++

+

Immunohistochemistry

CD34

++

+

CD31

+++

+++

ERG

+++

+++

D2-40

++

+

Molecular

MYC amplification/expression

+++

FLT-4 amplification/expression

+

AVL, atypical vascular lesion; AS, post radiation angiosarcoma; −, absent; −/+ rare focal finding; +, occasionally present; ++, present in most cases; +++, present in all cases

Immunohistochemistry can be useful in distinguishing AVL from PIAS. The endothelial markers CD31, CD34, and ERG are generally positive in both AVLs and angiosarcoma. While positive in most AVLs, D2-40 is less frequently positive in angiosarcomas (Flucke et al. 2013). Ki-67 may be useful in distinguishing between the two, as it is high (>20%) in PIAS, and low or absent in most AVLs (Requena et al. 2002). Prospero homeobox 1 (Prox-1) is a lymphatic endothelial marker that is strongly expressed in angiosarcomas but only focally positive in AVLs (Flucke et al. 2013). The majority of PIAS show MYC protein expression by IHC or amplification by FISH, while AVLs do not. However, AVLs can very rarely show rare MYC positive endothelial cells by IHC (Udager et al. 2016).

Benign lesions that can mimic AVLs include hemangioma (Hemangioma), acquired progressive lymphangioma, reactive angioendotheliomatosis, and diffuse dermal angiomatosis. Clinicopathologic correlation is mandatory to distinguish these entities from AVLs, and history of radiotherapy to the region is very important in solving the differential diagnostic dilemma. Hemangiomas are small and often incidental superficial lesions composed of dilated vascular channels lined by bland endothelial cells (Ginter et al. 2017). Microvenular hemangiomas typically occur on the trunk, but can involve the breast and are characterized by a well-circumscribed proliferation of thin-walled vessels with attenuated endothelial cells, which dissect through the dermal collagen, mimicking vascular type AVLs (Baker and Schnitt 2017). Hobnail hemangiomas preferentially involve the trunk and thighs, and are characterized by dilated vessels lined by hobnail endothelial cells within the superficial dermis with stromal papillary projections and thin narrow vascular channels in the deep dermis, mimicking lymphatic type AVLs. However, hobnail hemangiomas contain extravasated red blood cells, hemorrhage, and hemosiderin deposition, which distinguish the lesion from lymphatic type AVLs (Flucke et al. 2013). In addition, atypical hemangiomas can show increased vascular anastomoses, infiltration, and nuclear hyperchromasia, similar to AVLs (Ginter et al. 2017).

Acquired progressive lymphangioma, also known as benign lymphangioendothelioma presents as slowly enlarging erythematous papules with a mean size of 1.5 cm that predominately involve the limbs and rarely also the breast. It is comprised of dilated, irregular, and anastomosing vascular spaces containing red blood cells involving the superficial dermis. The dermis is often hyalinized with a band of acellular collagen separating the lesion from the overlying epidermis. Similar to AVLs, benign lymphangioendotheliomas show endothelial lined papillary stromal projections, hobnailing of bland endothelial cells, and lack intraluminal red blood cells. With extension into the deep dermis, lymphangioendotheliomas have a pseudomalignant appearance with prominent dissection of collagen and wrapping of vascular channels around collagen bundles and dermal adnexae (Flucke et al. 2013).

Reactive angioendotheliomatosis is a rare vascular disorder that occurs in the setting of co-existent systemic disease, such as renal and cardiac disease. It presents as multifocal erythematous macules, papules, plaques, or ecchymoses typically involving the limbs; however, rare cases with breast involvement have been reported. Reactive angioendotheliomatosis is characterized histologically by a proliferation of closely packed capillaries predominately involving the dermis with occasional extension into the subcutis. The capillaries lack endothelial atypia and multilayering, and are often accompanied by stromal hemosiderin, a mild chronic inflammatory infiltrate, microthrombi, and extravasated red blood cells (Weaver and Billings 2009).

Diffuse dermal angiomatosis is a rare vascular lesion of the breast which presents as nonhealing painful plaques or ulcers on the breast skin surrounded by prominent vessels and occurs most frequently in obese women with macromastia. Histologically, diffuse dermal angiomatosis is characterized by an extravascular endothelial cell proliferation involving the dermal stroma. In a small biopsy, diffuse dermal angiomatosis may be difficult to distinguish from an atypical vascular lesion, or even a low-grade angiosarcoma (Requena et al. 2002; Baker and Schnitt 2017).

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PathologyUniversity of ChicagoChicagoUSA