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Malignant Transformation of Non-healing Ulcer - Basal Cell Carcinoma

Michael Nicoara, D.O, Kevin Bain, D.O., Ronak Patel, D.O., Omkaar Jaikaran, D.O.,
Anil Hingorani, M.D., Enrico Asher, M.D

PII: S0890-5096(20)30156-4
DOI: https://doi.org/10.1016/j.avsg.2020.01.100
Reference: AVSG 4902

To appear in: Annals of Vascular Surgery

Received Date: 25 November 2019

Revised Date: 9 January 2020
Accepted Date: 26 January 2020

Please cite this article as: Nicoara M, Bain K, Patel R, Jaikaran O, Hingorani A, Asher E, Malignant
Transformation of Non-healing Ulcer - Basal Cell Carcinoma, Annals of Vascular Surgery (2020), doi:
https://doi.org/10.1016/j.avsg.2020.01.100.

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1 Title:

2 • Malignant Transformation of Non-healing Ulcer - Basal Cell Carcinoma

3 Authors Affiliations:

4 • Michael Nicoara, D.O.; NYU Langone Hospital – Brooklyn, Department of Vascular Surgery

5 • Kevin Bain D.O.; NYU Langone Hospital – Brooklyn, Department of Vascular Surgery

6 • Ronak Patel D.O.; NYU Langone Hospital – Brooklyn, Department of Vascular Surgery

7 • Omkaar Jaikaran D.O.; NYU Langone Hospital – Brooklyn, Department of Vascular Surgery

8 • Anil Hingorani M.D.; NYU Langone Hospital – Brooklyn, Department of Vascular Surgery

9 • Enrico Asher M.D.; NYU Langone Hospital – Brooklyn, Department of Vascular Surgery

10 Corresponding Author:

11 • Michael Nicoara D.O.; Michael.Nicoara@nyumc.org; (718)-630-7351

12 NYU Langone Hospital- Brooklyn 150 55th Street Brooklyn NY 11220

13 Author Contribution

14 • Conception and design: Michael Nicoara D.O

15 • Administrative support: Anil Hingorani M.D.; Enrico Ascher M.D.

16 • Provision of study material or patients: Omkaar Jaikaran D.O.

17 • Collection and assembly of data: Ronak Patel D.O.; Omkaar Jaikaran D.O.

18 • Data analysis and interpretation: All authors

19 • Manuscript writing: All authors

20 • Final approval of manuscript: All authors

21 Disclosure of Conflict of interest:

22
23 • The authors have no conflicts of interest to declare
24

25

26
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27 Abstract:

28 We discuss the rare case of a 72 year old female with a history of a non-healing lower extremity ulcer that

29 was biopsied revealing malignant transformation to basal cell carcinoma (BCC). Although basal cell car-

30 cinoma is the most common malignancy worldwide, malignant transformation of non-healing wounds are

31 more often associated with squamous cell carcinoma. Current literature estimates the rate of BCC arising

32 from venous stasis ulcer to occur between 1.5-15%. When diagnosed early, BCC can have cure rates of

33 up to 95%. However, metastatic BCC has a median survival of roughly 8 months. We believe it is im-

34 portant to raise awareness of this rare, but often curable clinical diagnosis in order to improve long term

35 outcomes.

36 Introduction:

37 Basal cell carcinoma (BCC) is the most common malignancy affecting mankind. Its incidence is increas-

38 ing and estimated to afflict over 1 million new patients each year nationwide. The common identified risk

39 factors for developing BCC include ultra violet (UV) radiation, and behavioral factors associated with

40 increased UV radiation, such as occupational sun exposure and multiple sunburns at a young age. [1,2] In

41 the following report, we describe the case of BCC arising atypically in a chronic venous stasis ulcer.

42 Case Report:

43 Patient is a 72 year old female with a history of anti-thrombin 3 deficiency, prior femoral popliteal deep

44 venous thrombosis (DVT), bilateral greater saphenous vein (GSV) ablation, on Coumadin. Patient pre-

45 sented with history of a left calf non-healing venous stasis ulcer for over 20 years. Ulcer size and symp-

46 toms of pruritus and burning did not regress despite conservative management using compression stock-

47 ings, Unna boots, silver alginate, topical ointments and multiple debridements. On exam, the patient had

48 +3 pitting edema, skin thinning, brown discoloration and lipdermatosclerosis surrounding a 5.0 x 5.0 x

49 0.2 cm non infected ulcer (figure 1). Due to the chronicity of the ulcer, she was taken to the operating

50 room for debridement and biopsy. In the operating room multiple biopsies were taken from the wound
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51 edge at the junction of the ulcer and the skin. Pathology results were consistent with nodular type basal

52 cell carcinoma (figure 2). She was referred to an outside hospital where she was treated successfully with

53 radiation therapy alone as surgical excision of the whole wound was felt to place the patient at significant

54 risk for wound complications and possible limb loss. She is continuing to receive local wound care with

55 several excisional debridements and wound biopsies which show no further evidence of malignancy.

56 Discussion:

57 Chronic wounds and their association with malignancy have been well documented in literature. The first

58 author to report on this finding was Marjolin, in 1827, where he observed borders of a chronic wound un-

59 dergoing malignant changes. From this finding, we have come to refer to chronic wounds that develop

60 into malignancy as Marjolin ulcers. [3]

61 There are several proposed mechanisms through which this association may occur. Two common descrip-

62 tions include primary malignancies that present as chronic wounds, and even rarer, chronic wounds that

63 degenerate into cancer. [3-5] Signs of malignant transformation include hyperkeratotic granulation, al-

64 tered margins, unusual pain, bleeding, and prolonged course despite treatment. [4]

65 Although the exact mechanism is not clearly understood, wound degeneration into malignancy likely aris-

66 es through chronic antigenic or nonspecific stimulation. [3,5] It is estimated that 1.7% of chronic wounds

67 undergo this type of transformation. [3] Most often this degeneration is seen in the presence of a draining

68 sinus tract from chronic osteomyelitis. Other scenarios where malignant degeneration may occur include

69 chronic wounds secondary to burns, trauma, radiation exposure, diabetes, and venous insufficiency. [3]

70 Looking closer at chronic venous stasis ulcers, it is documented that 2.4% undergo malignant degenera-

71 tion. [4,5] It is important to remember this association, as venous stasis ulcers have become a prevalent

72 disease affecting 3-5% of the population over 65 years of age. [4] Most commonly, these malignant trans-

73 formations lead to well-differentiated squamous cell carcinoma (SCC). [4,6-8] Conversely, venous stasis
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74 ulcer degeneration into basal cell carcinoma (BCC) is a more rare occurrence. [4,8-10] Current literature

75 suggests that BCC can arise from venous stasis ulcers 1.5-15% of the time. [4,5,11]

76 Making the diagnosis of BCC in an expeditious manner is extremely important, as these patients have a

77 10-fold risk of developing BCC at another site. [4,12] Metastatic BCC has a median survival of 8 months.

78 [5] Tissue biopsy remains the gold standard for diagnosis.

79

80 Although some controversy remains surrounding the timing, it is recommended that tissue biopsy be per-

81 formed if a chronic wound fails to respond to treatment after 3-4 months. [3,12] Threshold for biopsy

82 should be patient specific. Clinical features such as irregular boarders, or new spontaneous bleeding

83 should increase suspicion for possible malignant degeneration. Social history may play an important role

84 as well. For example, patient noncompliance can raise concern for missed follow up appointments. In

85 these instances healthcare providers must be extra vigilant and perform wound biopsy at more frequent

86 intervals.

87 Performing a biopsy to rule out underlying malignancy in non-healing wounds can be performed using

88 several different methods dependent on size and site of lesion, as well as physician preference and com-

89 fortability. Some of these methods include punch biopsy, wedge biopsy, excisional biopsy, and shave bi-

90 opsy. All have their own particular advantages and disadvantages. [13] Despite the different biopsy op-

91 tions it is ideal to perform several biopsies both from the wound edge and the wound bed. Our preferred

92 biopsy technique tends to be a wedge resection as it provides a much deeper tissue sample, which include

93 the subcutaneous tissue.

94 Although specific treatment of SCC arising from chronic wounds has not been widely accepted or proto-

95 coled, therapy often mirrors traditional SCC therapy. Once biopsy results of SCC are confirmed patient,

96 evaluation for metastatic disease should be considered as risk of metastasis has been reported as high as

97 30%. [14] If there is no concern for metastatic disease, wide local excision with at least 2 cm margins is
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98 the preferred treatment option. [15] The role of lymph node dissection in the treatment of SCC continues

99 to evolve but in general palpable lymph nodes in susceptible node basins should be biopsied or removed.

100 Chemoradiation is typically reserved for poor surgical candidates, or patients with large, high risk tumors.

101 Other experimental treatment have been described and include intralesional interferon, photodynamic

102 therapy and carbon dioxide laser. [16]

103

104 Treatment guidelines for Basal Cell carcinoma arising from non healing wounds are even more sparse and

105 again much of the therapy is extrapolated from trials and data examining nonmelanoma skin cancers.

106 However unlike SCC, BCC rarely metastasizes or has nodal involvement. [17] Surgical excision with 2-3

107 mm margins is advised and has been shown to provide adequate clearance of disease in 95% of lesions.

108 [18] Given the rarity of nodal metastasis, lymph node biopsy or resection is rarely indicated. Radiation

109 therapy is useful as adjunct therapy in locally advanced disease or where extensive surgical resection may

110 cause significant morbidity. It has even been described as an alternative to surgical excision for the very

111 frail and elderly patients, with reported cure rates of roughly 90% when used alone. [19] Other treatment

112 modalities that have been described include, cryotherapy, systemic chemotherapy using platinum based

113 agents and topical imiquimod or 5-flouorouracil.

114 Conclusion:

115 Biopsies of non-healing venous stasis wounds are warranted and should be repeated every 3-6 months if

116 healing continues to be stagnant. Several tissue samples from the wound base and edges should be ob-

117 tained. Most common malignant transformation is SCC but other pathologies like melanoma, sarcoma

118 and basal cell carcinoma have been reported.

119 References:
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120 1. DeVita, Vincent T., et al. Cancer: Principles & Practice of Oncology. Wolters Kluwer Health,

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122 2. Crouch, H Elizabeth. “History of Basal Cell Carcinoma and Its Treatment.” Journal of the Royal

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125 Care, vol. 16, no. 1, 2003, pp. 31–34., doi:10.1097/00129334-200301000-00014.

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127 Review of the Literature” Wounds. 2014;26(4):E30-35.

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129 Stasis Ulcer to Basal Cell Carcinoma in a Diabetic Patient: Case Study and Review of the Patho-

130 physiology.” The Journal of Foot and Ankle Surgery, vol. 49, no. 1, 2010, pp. 75–79.,

131 doi:10.1053/j.jfas.2009.07.015

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135 7. Harris, Brian, et al. “Basal Cell Carcinoma Arising in Venous Ulcers and Mimicking Granulation

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137 doi:10.1111/j.1524-4725.1993.tb03445.x.

138 8. Blank, Armin A., and U.w. Schnyder. “Squamous Cell Carcinoma and Basal Cell Carcinoma

139 within the Clinical Picture of a Chronic Venous Insufficiency in the Third Stage.” Dermatology,

140 vol. 181, no. 3, 1990, pp. 248–250., doi:10.1159/000247946.

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143 doi:10.1016/0190-9622(91)70172-x

144 10. Patel, Nma P., et al. “Venous Ulceration and Basal Cell Carcinoma: Coincident or Synergistic?”

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146 11. Schwabegger, A., et al. “A Rare Case of Recurrent Morphea-like Basal Cell Carcinoma (BCC)

147 Arising from Chronic Venous Stasis Ulcer in the Lower Leg.” European Journal of Plastic Sur-

148 gery, vol. 20, no. 2, 1997, pp. 110–111., doi:10.1007/bf01419149.

149 12. Tchanque-Fossuo, Catherine N., et al. “Ulcerated Basal Cell Carcinomas Masquerading as Ve-

150 nous Leg Ulcers.” Advances in Skin & Wound Care, vol. 31, no. 3, 2018, pp. 130–134.,

151 doi:10.1097/01.asw.0000530068.44631.dc.

152 13. Nischal U., Nischal KC, Khopkar U., Techniques of Skin Biopsy and Practical Considerations. J

153 Cutan Aesthet Surg. 2008;1(2): 107-111

154 14. Baskara A., Sikka L., Khan F., Sapanara N. Development of a Marjolin's ulcer within 9 months in

155 a plantar pressure ulcer. Eur J Dermatol. 2010;20(2):225

156 15. Asuguo M., Ugare G., Ebughe G. Marjolin's ulcer: the importance of surgical management of

157 chronic cutaneous ulcers. Int J Dermatol. 2007;46(Suppl 2):29–32.

158 16. Enoch S., Miller D., Price P. Early diagnosis is vital in the management of squamous cell carci-

159 nomas associated with chronic non healing ulcers: a case series and review of the literature. Int

160 Wound J. 2004;1(3):165–175

161 17. Netscher DT, Leong M, Orengo I et al.: Cutaneous malignancies: melanoma and nonmelanoma

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164 344

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167 Figure Legends:

168 • Figure 1. Left Lower Extremity Nonhealing Venous Stasis Ulcer

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169 • Figure 2A. Pathology from wound biopsy depicting atypical basaxoid cells consistent with basal

170 cell carcinoma ((hematoxylin and eosin stainin x 40)

171 • Figure 2B. Same histological slide depicting the atypical basaxoid cells (hematoxylin and eosin

172 stainin x 100)