Le Infezioni in Medicina, n. 4, 249-253, 2009 Casi clinici Squamous cell carcinoma arising from long-term Case reports (50-year) : is there a need for a close medical follow-up in such chronic diseases? Lupus vulgaris: evoluzione in carcinoma squamocellulare dopo 50 anni: e se fosse necessario un follow-up più stretto?

Pietro Leocata1, Giuliana Crisman1, Anna Rita Vitale1, Giovanni Siniscalchi2, Paolo Biondi2, Giuseppe Colella2 1Pathology Unit, Department of Health Sciences, University of L’Aquila, Italy; 2Second University of Naples, Department of Head and Neck Surgery, Naples, Italy

n INTRODUCTION lesion in the same region since she was 19-year- old, first diagnosed as an abscess and partially uberculosis is a systemic infectious disease resolved with antibiotics. The persistence of the caused by . lesion led the General Practitioner to suggest TAlthough this infection showed a remark- the diagnosis of angioma; thus the patient un- ably decline in past decades, the immigration phe- derwent electrodesiccation therapy. Ten years nomenon and the increasing number of patients later, the recurrence of the lesion led to a clini- affected by acquired immunodeficiency syn- cal diagnosis of LV and an anti-tuberculosis dromes could explain the well-established in- therapy was instituted with Etanicozid B6 (a crease in incidence observed in European coun- combination of -400 mg, - tries. Lupus vulgaris (LV) represents the most com- 125 mg, pyridoxine-50 mg) three capsules per mon cutaneous manifestation of tuberculosis. day and rifamycin (locally administered), with Even if it is a rare condition, squamous cell carci- a slight improvement. noma (SCC) is the most frequent malignancy aris- Since the patient’s clinical conditions worsened ing from LV, probably due to the chronic status of in 2006, she presented to the dermatologist for a inflammation [1-6]. slight extension of the eruption to the parotid A case of SCC on the left parotid region, arising region and to the pinna (Figure 1A). A skin from a pre-existing, misdiagnosed and under- biopsy at the periphery of the lesion was per- treated LV, is herein reported. formed, and all the specimens were fixed in a 10% solution of formaldehyde and embedded in paraffin. n CASE REPORT Five-micrometer thick sections were stained with haematoxylin-eosin and processed for A 67-year-old female farmer was referred to the histological examination and evaluation. Head and Neck Surgery Department of the Sec- Histopathological features showed a granulo- ond University of Naples for a nodular, ulcerat- matous dermatitis associated with a dense in- ed and bleeding lesion, involving the left ear flammatory infiltrate close to the granulomas, lobe and the parotid region. The patient report- involving both superficial and deep dermis. ed the onset of a small, nodular, erythematous Areas of hyperparakeratosis of the covering

249 2009 Figure 1 - Clinical presentation of the patient. epithelium and vacuolar changes of the basal A year later, the patient presented once again layer were also detected. Such histological with a nodular lesion in the same area. Dermo- findings suggested the diagnosis of a tubercu- scopic examination revealed a spoke-wheel pat- lotic lesion. A Skin Test was per- tern of vessels, which strongly suggested can- formed resulting in a strong positivity of 21 cer. A skin punch biopsy revealed a well-differ- mm (Figure 2). entiated (G1) squamous cell carcinoma (SCC) The patient was commenced on three capsules (Figure 3 A-B). per day of Miazide B6 (a combination of etham- When admitted to the surgical unit the patient butol-400 mg, isoniazid-125 mg, pyridoxine-50 showed a 3 x 3.5 cm, erythematous, nodular, ul- mg) for 6 months, with considerable improve- cerated and bleeding lesion, involving the ear- ment in the lesion (Figure 1B-C). lobe and the parotid region, of hard consistency and undefined borders, which seemed to reach the soft tissue (Figure 1D). A left facial nerve paralysis suggested nervous involvement by the lesion. Two enlarged lymph nodes of 30 mm and 25 mm in diameter were detected by ultrasound imaging, whereas computed to- mography revealed extensive ipsilateral parotid involvement. Full blood count, serum urea and electrolyte concentrations and liver function tests were normal. Chest X-ray showed no evidence of any active or metastatic disease. A radical excision of the lesion includ- ing the earlobe, the parotid gland with sacrifice of facial nerve and a functional neck dissection were performed. The final diagnosis was of a well differentiated (G1) squamous cell carcino- ma (SCC), pT4 pN1 M0. Post-operative radio- therapy (65 Gy) was administered and 18 months later the patient was healthy, with no recurrence.

n DISCUSSION

Skin manifestations by tuberculous infection are rare (less than 0.1% of dermatologic pa- tients), and they may be a consequence of a di- Figure 2 - Tuberculin Skin Test positivity. rect inoculation of tubercle bacilli in the skin

250 2009 (tuberculosis verrucosa cutis) or secondary to tuberculotic infection [15, 16]. Ziehl-Neelsen systemic infection. The most common cuta- staining proved positive only in the South neous lesion is represented by Lupus vulgaris African patient, whereas Tuberculin Tine Test (LV), which is a typical expression of the pres- positivity was detected in both cases. More re- ence of the tubercle bacilli in the dermis of pa- cently, Zawirska et al. reported a case of a 65- tients with a previous tubercular infection, usu- year-old man presented in New Jersey with a ally at pulmonary level [1-6]. 40-year history of LV, misdiagnosed as psoria- LV is a chronic and progressive condition, sis and complicated by the development of a which usually occurs on the face, especially on cutaneous SCC. As in our case, the patient was the nose, as a solitary small, sharply marginat- a farmer: thus the authors suggested that ed, red-brown papule of gelatinous consisten- chronic sunlight exposure may have played a cy (“apple-jelly” nodules), with slow growing role in the aetiopathogenesis of malignancy into large plaques with central atrophy. Not from his long-standing LV [17]. uncommonly several bacilli persist at the pe- SCC is one of the most common non-melanoma riphery of the lesion, leading to a progression tumours of the skin, which recognizes several directly related to the status of the immune risk factors in its aetiology, such as X-ray irra- system. The mainstay therapy is represented diation, sunlight exposure and chronic inflam- by well-codified multi-drug anti-tubercular mation. In 1969 Forstrom et al. among 460 pa- chemotherapy [1-6]. tients affected by LV observed 8% of SCC aris- To the best of our knowledge, fewer than 30 ing on tuberculous skin lesions and suggested a similar cases have been reported, most pub- strict relation between SCC and long-standing lished before 1990 [7-17]. Two cases of SCC aris- chronic inflammation status [18]. ing on a chronic history of LV (about a 40-year Chronic inflammation (at least 10 years) causes history in both patients) have been reported in an increase in cytokine levels in loco. Cytokines the last two years: the country context (Turkey are proteins involved in fundamental mecha- and South Africa respectively) could suggest a nisms of tissue repair process, inducing cell

Figure 3 - Histological features of the well-differentiated squamous cell carcinoma: haematoxylin–eosin, ori- ginal magnification x4 (A) and x20 (B).

251 2009 proliferation. The continuous proliferative sta- above-mentioned risk factors: chronic (approx- tus leads to a shortened G2 phase, such that the imately 50-year) inflammation status and sun- DNA-repair process is impaired and several light exposure due to the rural environment. mutations are eventually accumulated, with a In conclusion, the reported case of SCC arising normal regeneration process easily slipping in- on a 50-year history of LV emphasizes how a to carcinogenesis [18-20]. chronic inflammation status could represent an X-ray irradiation and sunlight exposure are important risk factor for skin cancer. well-described risk factors for neoplastic A strict medical follow-up in such long-stand- processes due to their direct damage of DNA. ing lesions, especially when not responding to Deregulation of the cell cycle and genetic pre- any therapy, should be considered in order to disposition, after several years or decades, lead prevent malignant transformation or achieve a to cancer transformation [18-20]. correct diagnosis in earlier stages. In our patient, malignant transformation of the misdiagnosed and undertreated skin lesion Key words: Lupus vulgaris, Lupus Carcinoma, seems to be the result of at least two of the chronic inflammation

SUMMARY

Skin manifestations of tuberculous infection (My- condition, diagnosed in 10% of tuberculotic pa- cobacterium tuberculosis) are represented by miliary tients. tuberculosis of the skin, tuberculous chancre, scro- The authors report herein a case of squamous cell fuloderma, tuberculosis verrucosa cutis, periorifi- carci noma (SCC) arising from long-standing (50- cial tuberculosis, and Lupus vulgaris (LV). year) LV and underline the need of an extensive Among this group, LV is the most common skin follow-up of tuberculotic lesions.

RIASSUNTO

Le manifestazioni cutanee della tubercolosi rappresenta- anni, precedentemente diagnosticata come Lupus vul- no una condizione rara. Tra queste, il Lupus vulgaris garis. La paziente, pur presentando un Test Cutaneo al- è la forma più comune, coinvolgendo circa il 10% di tut- la Tubercolina fortemente positivo, non aveva tratto al- ti i pazienti tubercolotici. La regione più frequentemen- cun giovamento dalla terapie mediche e chirurgiche cui te interessata è il distretto testa-collo. Se non corretta- era stata sottoposta. Gli autori ipotizzano che lo stato di mente trattata, questa patologia presenta uno sviluppo infiammazione cronica protratta associato all’esposizio- cronico e progressivo che, a lungo termine, può portare ne alle radiazioni solari, dovute al contesto lavorativo allo sviluppo di gravi complicanze, come il carcinoma a della paziente, abbiano contribuito allo sviluppo del Lu- cellule squamose, che in questi casi viene anche definito pus Carcinoma con il quale è giunta all’osservazione. “Lupus Carcinoma”. Gli autori sottolineano l’importanza di un corretto ap- Gli autori riportano il caso di una donna di 67 anni con proccio diagnostico e terapeutico per lesioni infiamma- una lesione a livello della regione parotidea da circa 50 torie croniche di questo genere.

n REFERENCES bacteriologic study. J. Am. Acad. Dermatol. 33 (3): 433- 440, 1995. [1] Dye C., Scheele S., Dolin P., Pathania V., Rav- [3] Kumar B., Muralidhar S. Cutaneous tuberculosis: iglione M.C. Consensus statement. Global burden a twenty-year prospective study. Int. J. Tuberc. Lung of tuberculosis: estimated incidence, prevalence, Dis. 3 (6): 494-500, 1999. and mortality by country. WHO Global Surveil- [4] MacGregor R.R. Cutaneous tuberculosis. Clin. lance and Monitoring Project. JAMA. 282 (7): 677- Dermatol. May-Jun 13 (3): 245-255, 1995. 686, 1999. [5] Sehgal V.N., Srivastava G., Khurana V.K., Sharma [2] Farina M.C., Gegundez M.I., Pique E., et al. Cuta- V.K., Bhalla P., Beohar P.C. An appraisal of epide- neous tuberculosis: a clinical, histopathologic, and miologic, clinical, bacteriologic, histopathologic, and

252 2009 immunologic parameters in cutaneous tuberculosis. al presentations over the face. J. Eur. Acad. Dermatol. Int. J. Dermatol. 26 (8): 521-526, 1987. Venereol. 17 (6): 706-710, 2003. [6] Chong L.Y., Lo K.K. Cutaneous tuberculosis in [14] Yerushalmi J., Grunwald M.H., Halevy D.H., Hong Kong: a 10-year retrospective study. Int. J. Der- Avionach I., Halevy S. Lupus vulgaris complicated matol. 34 (1): 26-29, 1995. by metastatic squamous cell carcinoma. Int. J. Derma- [7] Haim S., Friedman-Birnbaum R. Cutaneous tu- tol. 37 (12): 934-935, 1998. berculosis and malignancy. Cutis 21: 643-647, 1978. [15] Ekmekci TR, Koslu A, Sakiz D, Ozcivan M. Squa- [8] Betti R., Tolomio E., Vergani R., Crosti C. Squa- mous cell carcinoma arising from lupus vulgaris. J. mous epithelial carcinoma as a complication of lupus Eur. Acad. Dermatol. Venereol. 19 (4): 511-513, 2005. vulgaris. Hautarzt. 53 (2): 118-120, 2002. [16] Motswaledi MH, Doman C. Lu pus vulgaris with [9] Kimmritz J., Hermes B., Schewe C., Haas N. Squa- squamous cell carcinoma. J. Cutan. Pathol. 34 (12): mous cell carcinoma in lupus vulgaris. J. Dtsch. Der- 939-941, 2007. matol. Ges. 2 (2): 116-119, 2004 [17] Zawirska A, Adamski Z, Stawicka E, Schwartz [10] Motta A., Feliciani C., Toto P., De Benedetto A., RA. Cutaneous squamous cell carcinoma developing Morelli F., Tulli A. Lupus vulgaris developing at the in lupus vulgaris exfoliativus persistent for 40 years. site of misdiagnosed scrofuloderma. J. Eur. Acad. Int. J. Dermatol. 48 (2): 125-127, 2009. Dermatol. Venereol. 17 (3): 313-315, 2003. [18] Ziegler A., Jonason A.S., Leffell D.J., Simon J.A., [11] Thomas S., Suhas S., Pai K.M., Raghu A.R. Lu- Sharma H.W., Kimmelman J., et al. Sunburn and p53 pus vulgaris - report of a case with facial involve- in the onset of skin cancer. Nature 372: 773-776, 1994. ment. Br. Dent. J. 198 (3): 135-137, 2005. [19] Kripke M.L. Ultraviolet radiation and immunol- [12] Ceylan C, Gerceker B., Ozdemir F, Kazandi A. ogy: Something new under the sun - Presidential ad- Delayed diagnosis in a case of lupus vulgaris with dress. Cancer Res. 54: 6102-6105, 1994. unusual localization. J. Dermatol. 31 (1): 56-59, 2004 [20] Forstrom L. Carcinomatous changes in lupus [13] Khandpur S., Reddy B.S. Lupus vulgaris: unusu- vulgaris. Ann. Clin. Res. 1 (3): 213-219, 1969.

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