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Case study

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For citation purposes: Kyrgias G, Kostopoulou E, Zafiriou E, Zygogianni A, Skarlatos J, Roussaki-Schulze AV, Theodorou K. Hidradenocarcinoma of the temporal area successfully treated with concomitant electrochemotherapy and radiotherapy. Head Neck Oncol. 2013 Feb 06;5(2):14.

Hidradenocarcinoma of the temporal area successfully treated with concomitant electrochemotherapy and radiotherapy

G Kyrgias1*, E Kostopoulou2, E Zafiriou3, A Zygogianni1, J Skarlatos4, AV Roussaki-Schulze3, K Theodorou5

AbstractHidradenocarcinoma, the malignant counterpart of hidradenoma, is an extremely rare malignant tumour, which may exhibit an aggressive clinical course. The standard primary treat-ment is wide local excision with or without lymph node dissection. Radio-therapy has also been used in some cases but with controversial outcomes. At the University of Thessaly—Faculty of Medicine and the University Hospi-tal of Larissa, Greece, we successfully treated a hidradenocarcinoma of the skin of the temporo-parietal area using a combination of electrochemo-therapy and radiotherapy.

IntroductionHidradenocarcinoma (HADCA), the malignant counterpart of hidradenoma, is an extremely rare malignant tumour, which may exhibit an aggressive clinical course with metastasis and/or local recurrence1. A very limited num-ber of cases have been reported in the literature and the nomenclature has been inconsistent, making evaluation of clinical data more difficult. The standard primary treatment is wide

local excision with or without lymph node dissection. Radiotherapy (RT) has been used in some cases of HADCA with inconsistent results. Regardless of the surgical management technique, HADCAs may follow an aggressive course, demonstrating local recurrence rates of up to 50%, metastasis rates of 60% and a 5-year disease-free survival rate <30%. Faster growth and invasion of the surrounding tissues are characteristics of their biological behaviour after each local relapse2. They may also metastasise widely (at a rate of 60%), into regional nodes, bone, viscera and skin and cause death.

Case studyAn 86-year-old woman presented at our hospital complaining of a painless mass in the skin of the right temporo-parietal area that had progressively increased in size during the previous months. There was no history of trauma to the area and the patient denied suf-fering any pain or paraesthesia asso-ciated with the lesion, although she mentioned an episode of bleeding. On physical examination, the patient had a 48 × 45 × 18 mm sharply circum-scribed solitary lesion not fixed to the underlying tissues and with normal overlying skin. Gross examination of the bioptic specimen showed a cir-cumscribed solid mass measuring 27 × 20 × 11 mm and partly covered by skin. A multinodular growth pattern with a few small dispersed cystic areas was observed in the cut section.

Histopathological examination showed several tumour nodules varying in size and shape involving the dermis and exhibiting an infiltrative growth pattern in some areas. There was no connection with the epidermis. The nodules consisted of round-to-polygonal

epithelial cells with distinct cell borders, clear to eosinophilic cytoplasm and pleomorphic nuclei, with frequent mitotic figures (Figure 1). Several cen-tral areas of necrosis were observed. Evidence of ductal differentiation was detected focally in the form of small round ducts and intracytoplasmic vac-uoles (Figure 1). Hyalinized fibrous tissue and focal myxoid degeneration was widespread between tumour cell nests. Extensive sectioning did not reveal vascular or perineural invasion. The lesion extended close to the deep excisional margin.

Immunohistochemical staining showed positivity for AE1/AE3, p63 and focal positivity for carcinoembry-onic antigen (CEA) at the luminal border of ductal structures. Stains for Melan A, HMB45, TTF-1, ER and CD-10 were negative. In some areas, Ki-67 was positive in >90% of tumour cells. Periodic acid-Schiff staining demon-strated the presence of glycogen in several tumour cells.

The findings were suggestive of a malignant adnexal skin tumour, more consistent with clear-cell HADCA. The staging procedure with skull base, neck and chest computed tomography (CT) scans was negative for evidence of metastatic disease, and the patient was referred to a multidisciplinary meeting to resolve the therapeutic challenge and deal with the therapeutic decision.

In our case, a major surgical proce-dure was contraindicated because of the patient’s old age and poor perfor-mance status. For the same reasons, a combined treatment with RT plus intravenous chemotherapy seemed impossible. Moreover, based on the literature, which offers limited and contradictory data, there was little to

* Corresponding authorEmails: gkyrgias@gmail.com; gkyrgias@med.uth.gr1 Department of Radiotherapy, University of

Thessaly, School of Health Sciences, Faculty of Medicine, Larissa, Greece

2 Department of Pathology, University of Thessaly, School of Health Sciences, Faculty of Medicine, Larissa, Greece

3 Department of Dermatology, University of Thessaly, School of Health Sciences, Faculty of Medicine, Larissa, Greece

4 Department of Radiotherapy, St Savvas” Anticancer Hospital of Athens, Greece

5 Department of Medical Physics, University of Thessaly, School of Health Sciences, Faculty of Medicine, Larissa, Greece

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Case study

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For citation purposes: Kyrgias G, Kostopoulou E, Zafiriou E, Zygogianni A, Skarlatos J, Roussaki-Schulze AV, Theodorou K. Hidradenocarcinoma of the temporal area successfully treated with concomitant electrochemotherapy and radiotherapy. Head Neck Oncol. 2013 Feb 06;5(2):14.

be expected from a full-course radio-therapeutic treatment.

After discussing the case at a multi-disciplinary meeting, it was decided that given the patient’s age and poor performance status, the only possible treatment would be combined

concurrent RT and electrochemother-apy (ECT) to maximize the likelihood of complete local control. Thus, the patient underwent a single session of ECT with intravenous bleomycin (15000 IU/m2 or 15 ml/m2 of body surface) and seven sessions of accel-erated hypofractionated RT. With a direct electron-beam field of 10 MeV energy and a dose/fraction of 6 Gy administered twice a week for a total of 7 fractions, the lesion received a total dose of 42 Gy over a total period of 22 days (equivalent radia-tion dose: 71 Gy).

ResultsA monthly clinical follow-up on an outpatient basis showed that the results of the combined therapy had been excellent. Strikingly, there was complete remission of the lesion, as can be seen from Figures 2 to 4. Quar-terly monitoring with head-and-neck and chest CT scans was negative for evidence of metastatic disease.

Seven months after completing the combined therapy, the patient died from a respiratory infection without signs of locoregional or metastatic relapse of malignant HADCA.

Discussion and conclusionHADCAs represent only a small group of adnexal neoplasms but may pose diagnostic problems, both clinically and pathologically. Lesions present most commonly on the face or extrem-ities, although they may appear any-where on the body surface, arising de novo or sometimes associated with a pre-existing hidradenoma3. They may be present as slowly expanding masses without any specific symp-toms or clinical presentation suspi-cious for malignancy, leading to delayed diagnosis.

The histopathological diagnosis of HADCAs may be problematic due to a combination of factors, including the rarity of the neoplasm, variable mor-phology and inconsistent nomencla-ture and classification. This is reflected in the variety of names which have been used to describe this type of

Figure 1: Sheets of clear or pale cells and areas of necrosis. Inset: Evidence of ductal differentiation was detected focally in the form of small round ducts and intracytoplasmic vacuoles. Stain: Haematoxylin and eosin. Original mag-nification: ×100 (inset: ×200).

Figure 2: Patient before treatment: one solitary sharply circumscribed lesion which consists of a small number of cystic translucent papules. Near to this lesion, on the forehead and cheek, there are multiple tiny rough lesions of actinic keratosis.

Figure 3: Patient at two months after combined treatment: the tumour lesion became smaller and hyperkeratotic. Numerous areas of actinic keratosis which are erythematous with tiny bleeding points, reflecting an inflam-matory response to 5FU (5%) therapy, are also observed.

Figure 4: Patient at six months after combined treatment: the HADCA had disappeared and only a small yellow-brown crust remained on an atrophic base.

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Case study

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For citation purposes: Kyrgias G, Kostopoulou E, Zafiriou E, Zygogianni A, Skarlatos J, Roussaki-Schulze AV, Theodorou K. Hidradenocarcinoma of the temporal area successfully treated with concomitant electrochemotherapy and radiotherapy. Head Neck Oncol. 2013 Feb 06;5(2):14.

tumour4. The histopathological distinc-tion of such tumours from lesions char-acterized as atypical hidradenomas is based on an infiltrative growth pattern, deep extension, necrosis, nuclear pleo-morphism and an increased number of mitoses. Some HADCAs lack nuclear atypia and their diagnosis is based on architectural characteristics.

HADCAs may contain several types of cells, including clear cells with abundant glycogen, squamoid cells and transitional form with focal formation of tubular and ductal structures. When making the diagnosis, it is essential to exclude, in particular, other appenda-geal skin tumours with eccrine and apocrine differentiation, especially those presenting with clear cell cytology5, clear cell squamous cell carcinoma and balloon cell melanoma. In comparison to benign nodular hidradenomas, HADCAs are larger, asymmetrical in their configuration and show evidence of invasion into the surrounding tissue. HADCAs may also occasionally mimic metastatic adenocarcinomas.

Immunohistochemistry can be use-ful in these rare cases, since positivity for p63 has been reported to support a diagnosis of primary malignancy6. Clear cell carcinomas of thyroid or pulmonary origin may be excluded by TTF-1 staining. The absence of prom-inent vasculature and immunohisto-chemical stains may help in excluding metastatic clear-cell carcinoma of renal origin4.

RT has been used in several cases of HADCAs with conflicting results; in some reports RT appeared to be effec-tive7, while in others, radio-resistance was observed8. Regarding combined radiochemotherapy, some authors have concluded that adjuvant chemo-therapy and RT have no impact on local control or survival9.

ECT is a recent treatment for can-cer involving a combination of locore-gional or intravenous administration of very low doses of an antineoplastic drug (usually bleomycin or cisplatin) with electroporation of the cellular membranes. The cancer cells are

exposed to short/high electric field pulses (with a duration of micro- to milliseconds) delivered by an elec-troporator. This causes reversible permeabilization of cell membranes, thereby improving penetration of chemodrugs or deoxyribonucleic acid plasmids into the cytoplasm. The result is endogenous local ampli-fication of the effects of the antineo-plastic agent, with high levels of cytotoxicity in cancer cells, which usually demonstrate low or possibly even zero membrane permeability when such an agent is used. There are few side effects when this method is used, and normal function of neigh-bouring organs and surrounding healthy tissue is maintained. As a result, the patient tolerates the ther-apy well and recuperates rapidly. This is true even for areas of the body which have already been subjected to chemotherapy and/or RT. For all forms of solid tumours, ECT offers a non-thermal, safe, well-tolerated treatment method suitable mainly for cutaneous and subcutaneous areas.

The clinical use of ECT was pio-neered by Mir et al. (beginning in 1990 at the Institute Gustave Roussy, Paris, France—bleomycin using ECT)10 and by Sersa et al. (since 1994 at the Institute of Oncology, Ljubljana, Slovenia—cisplatin using ECT)11. Inter-national medical literature now includes more than 400 records of the clinical use of ECT. These contain details of the treatment of more than 1500 patients all over the world.

It is well known that the effects of RT on human tumours are boosted by traditional intravenous chemo-therapy. ECT also acts synergistically with RT on its own or when a combi-nation of ECT plus RT plus systemic chemotherapy is used, as reported by Kranijc et al. and Shil et al. in preclini-cal studies12,13. In animal models, very good results have also been obtained from radiosensitizing ECT with the use of bleomycin12, cisplatin11 or doxorubicin13. To the best of our knowledge, the Hellenic Group of

Electrochemotherapy14,15 was the first to report the use of external RT com-bined with ECT-bleomycin in humans.

In conclusion, we believe that for all types of skin tumours in the head and neck area, combined therapy of concomitant ECT and RT can be of excellent therapeutic outcome, while cosmesis and function of the healthy surrounding tissues can be safely preserved.

References1. Gauerke S, Driscoll JJ. Hidradenocarci-nomas: a brief review and future directions. Arch Pathol Lab Med. 2010 May;134(5): 781–5. 2. Liapakis IE, Korkolis DP, Koutsoumbi A, Fida A, Kokkalis G, Vassilopoulos PP. Malignant hidradenoma: a report of two cases and review of the literature. Anticancer Res. 2006 May–Jun;26(3B): 2217–20.3. Kazakov DV, Ivan D, Kutzner H, Spagnolo DV, Grossmann P, Vanecek T, et al. Cutaneous hidradenocarcinoma: a clinico-pathological, immunohistochemical, and molecular biologic study of 14 cases, includ-ing Her2/neu gene expression/amplifica-tion, TP53 gene mutation analysis, and t(11;19) translocation. Am J Dermato-pathol. 2009 May;31(3):236–47.4. Obaidat NA, Alsaad KO, Ghazarian D. Skin adnexal neoplasms—part 2: an approach to tumours of cutaneous sweat glands. J Clin Pathol. 2007 Feb;60(2):145–59.5. Cohen M, Cassarino DS, Shih HB, Abemayour E, St John M. Apocrine hidrad-enocarcinoma of the scalp: a classification conundrum. Head Neck Pathol. 2009 Mar; 3(1):42–6.6. Mahalingam M, Nguyen LP, Richards JE, Muzikansky A, Hoang MP. The diag-nostic utility of immunohistochemistry in distinguishing primary skin adnexal carcinomas from metastatic adenocarci-noma to skin: an immunohistochemical reappraisal using cytokeratin 15, nestin, p63, D2-40, and calretinin. Mod Pathol. 2010 May;23(5):713–9.7. Long WP, Dupin C, Levine EA. Recurrent malignant acrospiroma. Treatment by chest wall excision. Dermatol Surg. 1998 Aug; 24(8):908–12.8. Verret DJ, Kabbani W, DeFatta RJ. Nodular hidradenocarcinoma over the

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the

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ocia

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for M

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ME)

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For citation purposes: Kyrgias G, Kostopoulou E, Zafiriou E, Zygogianni A, Skarlatos J, Roussaki-Schulze AV, Theodorou K. Hidradenocarcinoma of the temporal area successfully treated with concomitant electrochemotherapy and radiotherapy. Head Neck Oncol. 2013 Feb 06;5(2):14.

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using electroporation of tumors. Int J Radiat Oncol Biol Phys. 2000 Mar;46(4): 1037–41.12. Kranjc S, Tevz G, Kamensek U, Vidic S, Cemazar M, Sersa G. Radiosensitizing effect of electrochemotherapy in a fractionated regimen in radiosensitive murine sarcoma and radioresistant adenocarcinoma tumor model. Radiat Res. 2009 Dec;172(6): 677–85.13. Shil P, Kumar A, Vidyasagar PB, Mishra KP. Electroporation enhances radiation and doxorubicin-induced toxicity in solid

tumor in vivo. J Environ Pathol Toxicol Oncol. 2006;25(4):625–32.14. Kyrgias G, Mosa E, Filopoulos E, Kokalis G, Lepouras A, Zafiriou E, et al. Electrochem-otherapy (ECT) as a new anticancer thera-peutic modality: the Hellenic Group of ECT (HeGECT) experience. Melanoma Res. 2010;20:e42–3.15. Skarlatos I, Kyrgias G, Mosa E, Provatopoulou X, Spyrou M, Theodorou K, et al. Electrochemotherapy in cancer patients: first clinical trial in Greece. In Vivo. 2011 Mar–Apr;25(2):265–74.