Metastatic Basal Cell Carcinoma with Squamous Differentiation Report of a Case with Response of Cutaneous Metastases to Electrochemotherapy

OBSERVATION Metastatic Basal Cell Carcinoma With Squamous Differentiation Report of a Case With Response of Cutaneous Metastases to Electrochemotherapy

Fabrizio Fantini, MD; Giulio Gualdi, MD; Augusto Cimitan, MD; Alberto Giannetti, MD

Background: Metastatic basal cell carcinoma is a rare tiation at histopathologic examination. Despite 2 wide disease with poor prognosis. Palliative therapeutic ap- surgical resections involving lymphadenectomy with ax- proaches include surgery, radiotherapy, and/or chemo- illary vein substitution and systemic chemotherapy, a pro- therapy. These treatment modalities are invasive and risky gressive metastatic spreading, both cutaneous and vis- and associated with relevant adverse effects. Electroche- ceral, occurred in the following 2 years. Three successive motherapy is a recently described therapy that relies on sessions of electrochemotherapy with bleomycin sulfate the permeation of cancer cell membranes by electrical were then performed on isolated skin metastases. The pulses to enhance cytotoxic drug penetration. It has been treatment was well tolerated and led to a rapid clinical successfully used in the treatment of primary and meta- and histologic regression of the treated lesions. static skin cancers. We report a case of metastatic basal cell carcinoma in which electrochemotherapy was effec- Conclusion: Electrochemotherapy is an effective and well- tive in inducing local regression of skin metastases. tolerated adjunct to the therapeutic options in metastatic basal cell carcinoma, characterized by an advan- Observations: A 75-year-old man presented with a pig- tageous risk-benefit ratio and minimal downtime. mented, deeply infiltrating nodule in the right axilla mani- festing as basal cell carcinoma with squamous differen- Arch Dermatol. 2008;144(9):1186-1188

ASAL CELL CARCINOMA (BCC) cin has been successfully used in primary is the most common cutane- skin tumors, such as in Kaposi sarcoma ous malignant neoplasm, ac- and in selected cases of primary squa- counting for up to 80% of mous and BCC5-8 as well as in the pallia- nonmelanoma skin cancers, tive treatment of cutaneous metastases of with increasing incidence rates in recent melanoma9 and squamous cell carcino- B1 5,10 years. Basal cell carcinoma is character- ma. We report a case of metastatic BCC ized by a slow, local growth, with distant in which ECT has proven useful in the metastases being exceedingly rare (fre- treatment of cutaneous metastases. quency range estimated at 0.0028%- 2 0.55%). Metastatic spread most often in- REPORT OF A CASE volves local lymph nodes (70%), but lung, skin, and bone metastases are also de- A 75-year-old man was seen at our clinic for scribed.3 The prognosis of metastatic BCC a 3-year history of an enlarging skin lesion is poor, with a median survival time after in his right axilla. Medical history dis- diagnosis of 8 months.4 Currently avail- closed local radiotherapy for hidrosadeni- able treatment options for metastatic BCC tis and a progressive hypoesthesia of the include surgery, radiotherapy, and chemo- right arm in recent months. Physical ex- therapy, alone or in combination. amination revealed a pigmented nodule Electrochemotherapy (ECT) is a re- (1.5ϫ1.0 cm) fixed to the deep planes, in cent therapeutic technique that relies on an area of atrophic, scarred skin. A wide cu- pulsed, high-intensity electrical currents taneous excision, along with an axillary (electroporation) to reversibly increase cell lymphadenectomy, was performed. Intra- membrane permeability, thus enhancing operatively, a deeply infiltrating mass em- the penetration of cytotoxic drugs into tu- bedded in fibrous tissue, reaching the ad- mor cells.5 Although several chemothera- ventitia of the axillary vein, was apparent. peutic agents have been proposed, bleo- Findings from histopathologic examina- Author Affiliations: Clinica mycin sulfate, systemic or intralesional, has tion showed a BCC with squamous differ- Dermatologica, University of shown the greatest antitumor activity when entiation infiltrating the perivascular soft tis- Modena and Reggio Emilia, used in conjunction with electropora- sues. Lymph nodes were negative for tumor Modena, Italy. tion.6 Electrochemotherapy with bleomy- cells.

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C D

Figure. Clinical (A and B) and histologic (C and D) aspects of basal cell carcinoma (BCC) nodules in the right arm treated with electrochemotherapy. A, Pretreated metastatic nodules chosen for the first electrochemotherapy (ECT) test (circle); B, clinical aspect at 1 month after ECT. Note the shrinkage of the nodules (surrounded by the electrode marks) and ongoing inflammatory reaction. The 2 nodules to the right were not treated. C, Histologic aspect before ECT. Note the focal squamous differentiation within the infiltrating strands of basal cells (hematoxylin-eosin, original magnification ϫ100). D, Histologic findings 3 months after ECT show complete regression of the BCC metastases (hematoxylin-eosin, original magnification ϫ50).

After 1 year, a local relapse occurred, consisting of peri- diameter (a) and the next longer diameter perpendicular lesional cutaneous and subcutaneous nodules in the lymph- to a (b), according to the formula V=ab2␲/6. The patient edematous arm and axilla. Echotomography of the axillary was prepared with local anesthesia (perilesional infiltration vault was consistent with deep soft tissue persistence. A wide of 1% mepivacaine hydrochloride) and general analgesia surgical excision of the axillary soft tissues with partial re- (ketorolac tromethamine, 30 mg intravenously) and vital section of the axillary vein (substituted with saphena) was parameters were monitored during the procedure. performed. After 1 additional year, clinical and instrumen- Bleomycin sulfate was injected in the 2 lesions accord- tal follow-up examination (echotomography, computed to- ing to the tumor volume (250 IUϫcm3 for tumor vol- mography,andpositron-emissiontomography)revealedme- umes Ͼ1.0 cm3; 500 IUϫcm3 for tumors 0.5-1.0 cm3; and diastinal, lung, and bone metastases. Progressive, massive 1000 IUϫcm3 for tumors Ͻ0.5 cm3), followed by electro- lymphedema of the upper right arm, with extensive cuta- poration (Cliniporator; IGEA, Carpi, Italy). Briefly, within neous and subcutaneous involvement by multiple nodular 2 minutes of bleomycin injection, a 7-needle (18-mm) hex- and plaque lesions, mostly ulcerated, led to severe functional agonal electrode (1.6-cm diameter) was inserted in the skin impairment,greatlyworseningthepatient’smobilityandqual- around each lesion and a run of 8 square-wave electrical ity of life. In particular, a large, ulcerated, neoplastic plaque pulses (730-V amplitude, 5000 Hz, 100 microseconds per developed in the right axilla, in the site of the original lesion. pulse) was delivered. Pulse deliverance was monitored to Systemic chemotherapy using cisplatin and fluorouracil was assure the effectiveness of the applied electrical field (1.5 started, with only partial and temporary results. A). Mild pain due to muscle contraction was experienced Because of the risks and morbidity of palliative surgery, by the patient during the pulse delivery, with no residual we decided to test the usefulness of ECT to control the cu- pain after treatment. In the following days a rapid re- taneous diffusion of the tumor and to reduce the patient’s sponse was observed, with ulcerative necrosis of the 2 le- disability. A few cutaneous metastatic nodules were cho- sions followed by progressive tumor shrinkage, resulting sen for initial testing because of their limited extension and in clinical healing in 1 to 3 months (Figure, B). Regres- superficial location. In the first therapy session, 2 nodular sion of the tumor nodules was histologically confirmed with lesions on the right arm (Figure, A) and 1 on the back were a skin biopsy performed after 2 months, which revealed selected for ECT with intralesional bleomycin according dermal fibrosis in the absence of tumor nodules (Figure, tothepreviouslypublishedstandardoperatingprocedures.11 C-D). A second ECT session with intralesional bleomycin Briefly, the tumor volume was calculated from the major was performed 1 month later on 3 different nodules, with

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 a similar response. A further ECT session with intrave- metastatic BCC. Electrochemotherapy allowed for the nous bleomycin sulfate (15 000 IU/m2, followed by elec- rapid treatment of multiple lesions, greatly reducing the troporation within 8-28 minutes) performed 2 months later risks, downtime, and adverse effects linked to surgery, on several other cutaneous lesions of the right arm and trunk radiotherapy, and systemic chemotherapy. again yielded a complete clinical regression of the lesions. In conclusion, ECT represents an effective, safe, and Three months later, sudden extensive deep venous well-tolerated adjunct to the therapeutic options in dif- thrombosis of the legs complicated by intestinal perfo- ficult-to-treat cutaneous tumors, and it is worthy to be ration and acute renal failure led to a rapid death. No au- considered in selected cases in which the extension of topsy was performed. Until the patient’s death, no sign the lesions or the patient’s conditions contraindicate tra- of tumor recurrence was detected in all the treated sites. ditional techniques.

COMMENT Accepted for Publication: December 19, 2007. Correspondence: Fabrizio Fantini, MD, Clinica Derma- A few clinical and histologic characteristics are consid- tologica, Azienda Policlinico di Modena, Via del Pozzo 71, ered predictive of metastatic risk in BCC. It is believed that 41100 Modena, Italy ([email protected]). long-standing lesions, large (Ͼ10 cm) solitary or multiple Author Contributions: All authors had full access to all primary tumors, head and neck localization, and a history the data in the study and take responsibility for the integ- of radiation therapy are risk factors for developing metas- rity of the data and the accuracy of the data analysis. Study tases.3 Aggressive histologic patterns, such as the baso- concept and design: Fantini, Gualdi, Cimitan, and Gian- squamous, morpheic, and adenocystic variants, as well as netti. Acquisition of data: Fantini, Gualdi, and Cimitan. perineurial invasion, have also increased metastatic poten- Analysis and interpretation of data: Fantini and Gualdi. Draft- tial.3 The characteristics of our case of metastatic BCC (long- ing of the manuscript: Fantini and Gualdi. Critical revision standing lesion developing on radiodermatitis, with a ba- of the manuscript for important intellectual content: Fantini, sosquamous histologic pattern) are consistent with the Gualdi, Cimitan, and Giannetti. Administrative, technical, literature reports. In our patient, tumor progression with and material support: Fantini and Gualdi. Study supervi- both regional and distant diffusion occurred in spite of wide sion: Fantini, Gualdi, Cimitan, and Giannetti. surgical excisions. Later, the response to systemic chemo- Financial Disclosure: None reported. therapy in controlling tumor spread was poor. 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