Post-radiation Atypical Vascular Lesion/Angiosarcoma Arising in the Larynx

Abstract

Atypical vascular lesions (AVL) and angiosarcomas (AS) are lesions known to arise after radiation therapy. These lesions can show overlap in both their gross and histologic pictures, and distinction between the two can be extremely challenging at times. They are known most commonly to arise in the breast region after radiation therapy. We present the first unique case of post-radiation AVL/AS arising in the larynx of a 51 year old woman, occurring 8 years after she received radiation for tonsillar squamous cell carcinoma.

Introduction

Atypical vascular lesions (AVL) and angiosarcomas (AS) are lesions known to arise after radiation therapy [1–12]. They are most commonly described in the breast region status post radiation for breast carcinoma. A difficult challenge in pathology is to differentiate an AVL from a well-differentiated AS as they both have significant histologic overlaps. It is important to distinguish between these lesions as AVLs follow a benign course while ASs have the potential to metastasize. Post-radiation AS are rarely reported in the laryngeal region, and we did not encounter reports of AVL arising in the larynx. We present the first unique case of post-radiation AVL/AS arising in the larynx.

Case Report

The patient is a 51 year old female with a past medical history of right tonsillar squamous cell carcinoma in 2001 status post tonsillectomy and radical neck dissection. She received post-operative radiation therapy for 6 weeks at an outside hospital. Chart review did not detail the radiation dosage. The patient had a social history of being a 1 pack per day cigarette smoker for 10 years in her remote past.

In October 2009, she presented to an ENT physician at an outside hospital who noticed a lesion on her jawline that was biopsied and reported as ‘benign.’ In addition, he performed a direct laryngoscopy for unclear indications. The direct laryngoscopy revealed numerous raised vascular lesions over her hypopharynx and larynx (Fig. 1). Biopsies of the lesions were taken and sent for histopathologic examination. We reviewed the slides as the patient was transferred to our institution. The final diagnosis was “squamous mucosa with atypical vascular proliferation, differential diagnosis includes atypical vascular lesion versus angiosarcoma.” The clinical decision was to observe the patient and follow her with periodic laryngoscopies.

Fig. 1.

Laryngoscopy reveals raised vascular lesions over the patient’s larynx. Several prominent lesions are seen on the aryepiglottic folds.

During 2010, the patient underwent two laryngoscopic examinations as part of routine follow-up that revealed her lesions to be stable from her initial 2009 examination. No biopsies were performed during these examinations. In July of 2011, the patient underwent a repeat direct laryngoscopy. Again, raised vascular lesions were seen and noted to be stable from her initial 2009 examination. This time, the clinicians decided to take additional biopsies for pathological evaluation. The final diagnosis rendered was “squamous mucosa with underlying persistent atypical vascular proliferation.” The decision again was made to follow the patient clinically.

The initial biopsies taken in October 2009 revealed an unremarkable squamous epithelium with underlying interconnected anastomosing vascular spaces (Fig. 2). The vessels were seen to dissect the subepithelial tissue. The vascular spaces were predominantly lined by flattened endothelial cells with focal areas of cytologic atypia. Focal areas showed tufting and intraluminal proliferation of cells with cytologic atypia and intracytoplasmic lumina.

Fig. 2.

a Unremarkable squamous mucosa with underlying interconnected anastomosing vessels. b Slit-like vessels dissect the subepithelial tissue. c, d Some vessels demonstrate prominent endothelial cell hobnailing. e, f Focal areas showed tufting and intraluminal proliferation of cells with cytologic atypia and intracytoplasmic lumina.

The second set of biopsies taken in July 2011 showed a similar histology, but with more worrisome features (Fig. 3). Again, biopsy revealed an unremarkable squamous epithelium with underlying interconnected anastomosing vascular spaces. Compared to the prior set of biopsies, more vascular spaces were lined by hobnailed, hyperchromatic nuclei with cytologic atypia, and rare normal mitoses were present.

Fig. 3.

a Squamous mucosa with underlying vascular formation. b Many vessels demonstrate prominent endothelial hobnailing. c Focal areas demonstrate marked cytologic atypia

Lesional tissue was tested for C-myc amplification and found to be negative by FISH analysis. C-myc amplification has been reported in the majority of post-radiation AS arising in the breast [4, 6, 8]. Although it was negative in our case, several cases of post-radiation AS with negative C-myc amplification have been reported [1, 12].

Consultations were obtained for both sets of biopsies from two internationally recognized experts in soft tissue pathology. The expert diagnoses varied between AVL and AS.

Discussion

Atypical vascular lesions are defined as vascular proliferations developing in the radiation field that by definition follow a benign course [2, 5]. Most of the publications describing AVLs comes from breast literature and have been referred to by various different names such as benign lymphangiomatous papules, lymphangioma circumscriptum, acquired lymphangioma, and cutaneous lymphangiectasia [3, 9–11]. They have a typical post radiation median interval of 3 years and association with radiation dosages of 40–60 gray [2].

Atypical vascular lesions as described in the breast literature are usually < 5 mm multifocal papules with red to brown discoloration [3] that histologically are well-circumscribed lesions, located in the mid to superficial dermis, comprised of anastomosing vessels lined by a single layer of endothelial cells. Some have divided the histologic patterns seen in breast AVLs into two histologic subtypes [11]. The first is a superficial lymphangioma-like subtype that histologically resembles lymphangioma circumscriptum with large ectatic vessels. The second is a hobnail hemangioma-like/benign lymphangioendothelioma-like subtype that presents as well-formed, small, slit-like vessels lined by hobnailed nuclei.

In contrast to AVLs, breast post-radiation ASs tend to arise later with a median interval of 6 years versus the median 3 year interval of breast AVLs. Both lesions are associated with a similar median radiation dosage of 40–60 Gy [3].

Angiosarcomas as described in the breast literature are grossly larger erythematous to violaceous plaques that histologically are ill-defined diffusely infiltrating lesions invading into the subcutaneous tissue with anastomosing vessels lined by endothelial cells that display cytologic atypia with prominent nucleoli and endothelial multilayering. Mitoses are common. Blood lakes with areas of necrosis are present [3].

Differentiating between AVL and AS can be extremely challenging as there is significant overlap in their histologic features. Both lesions have anastomosing vessels that can be lined by hyperchromatic endothelial cells. While dissection of dermal collagen is more characteristic of AS, it can be seen in AVLs. Infiltration into the subcutis, papillary endothelial hyperplasia, significant cytologic atypia with prominent nucleoli, and mitotic figures are defining characteristics AS. Also, AS are not well-demarcated as compared to AVLs that tend to be well-circumscribed [3, 9].

Our case is challenging as it did not fit into an overt AS or an AVL that will follow a benign course. It demonstrated focal areas of prominent cytologic atypia in addition to focal papillary endothelial hyperplasia. However, solid areas were not present and no definite deeper tissue invasion could be appreciated. While focal rare mitoses were present, they were not widely seen.

Further complicating our case is its location in the larynx. Unlike a case of an AVL/AS arising in the breast, it is not easily amenable to surgical resection. If called an AS, our surgeons would likely perform a total laryngopharyngectomy. Not only does this surgery have serious morbidity associated with it, it would not guarantee clean surgical margins.

In order to help further differentiate the lesions, several interesting studies have emerged investigating C-myc amplification as a tool to distinguish the lesions that arise on the breast. In one study, all the cases of post radiation AS studied harbored c-myc amplifications while none of the AVLs or primary AS had c-myc amplification [6]. In another study, it was found that C-myc amplification was significantly upregulated in post radiation AS compared to primary AS [8]. In our case, C-myc amplification was negative and did not support a diagnosis of AS. Several cases of C-myc amplification negative post-radiation AS have been reported [1, 12], and thus its possibility could not be completely excluded. In addition, C-myc amplification has not been specifically investigated in the laryngeal region and may not play a role in post-radiation AS that arise in this region.

Reports of laryngeal angiosarcoma are rare in the literature. Loos et al. [7] describe five cases of laryngeal angiosarcoma. Of these five cases, the most common site was the epiglottis and four of the patients had received prior radiation therapy. No information was available for the 5th patient. Also, they did a review of the literature and found 8 additional cases. The male to female ratio was 2.3:1 and the mean age of presentation was 61.7 years.

Our case is the first case of AVL/AS in the larynx. Some propose that AVL and AS exist along a continuum rather than representing two distinct entities [3]. Our lesion seems to fall along this continuum and cannot be easily categorized as an AVL or an AS. AVL/AS in the larynx poses a challenging problem for both pathologists and clinicians. More cases are needed to determine proper patient management. Currently our patient is being followed clinically with laryngoscopic exams every 6 months. Her lesions are still stable. She declined the surgical option of a laryngopharyngectomy, but has opted for clinical followup as her lesions remain stable and asymptomatic.