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What would the diagnosis be and the treatment?
¿Cuál sería su diagnóstico y tratamiento?

Male patient, 59 years old, with arterial hypertension and Herpes zoster episode during the three previous months, attended the Oral and Maxillofacial surgery because of a submandibular tumor on the right side, which had developed fifteen years previously but which had, for the last two months, increased progressively in size and in induration. The patient reported no other signs nor symptoms.

On physical exploration a localized tumor was noted in the submandibular cell on the right side of 2,5 to 3 cm in diameter, clearly defined, mobile, with a hard consistency and not stuck to the skin nor to deep planes. No cervical homo nor contralateral cervical adenopathies were noted on palpitation.

A puncture with fine needle aspiration (FNA) was requested. In the smear corresponding to the first puncture, a hematic base was observed with necrotic looking material intermixed with groups of epithelial cells, having atypical cytology with anisonucleosis and prominent nucleolus. In the smears obtained after the second puncture (which was made on the anterior apex other side of the lesion) a primitive tumor of the salivary gland was observed, but no malignant looking cell was observed.

With these finding, a cervicofacial Nuclear Magnetic Resonance (MR) was requested which showed that the largest diameter of the polilobulated image was 2,8 cm, that it had well defined borders and that it was situated on the posterior half of the submandibular gland on the right side (Fig. 1). The signal was heterogeneous in the T2 weighted sequences and there was a high signal intensity in the T1 sequences. After gadolinium administration an irregular surface was also observed. No adenopathies in the cervical ganglion chain were seen. An invasion of the carotid space vessels was not observed either nor signal alterations in the mandibular body.

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Adenocarcinoma ex pleomorphic adenoma of the submaxilar gland
Adenocarcinoma ex adenoma pleomorfo de glándula submaxilar

R. González García¹, A. Capote Moreno¹, V. Escorial Hernández¹, S. Hyun Nam³, F.J. Rodríguez Campo²

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1 Médico Residente de Cirugía Oral y Maxilofacial.
2 Médico Adjunto de Cirugía Oral y Maxilofacial.
3 Médico Residente de Anatomía Patológica
Hospital Universitario de La Princesa. Madrid, España.

Correspondencia:
Raúl González García
C/ Los Yebenes 35, 8ºC
28047 Madrid, España.
Email: raugg@mixmail.com

The patient underwent surgical removal of the tumor, and a submaxillectomy of the right side was carried out. An intraoperative biopsy was carried out. A whitish nodule was macroscopically observed with a firm consistency, a 3,5 cm diameter, and some necrotic areas which do not reach the surgical border of the sample. A small group of cells was microscopically observed suggesting malignancy. Given the confined area of the cells, the existence of clear margins, and clinical and radiological absence of cervical adenopathies, it was decided that no further surgery was required.

In the definitive anatomopathological study, with microscopic examination, two well-defined areas of the nodule were observed. One of the areas was formed of epithelial cells which position themselves forming glands extending themselves on a fibromyxoid stroma. Myschondroid elements could be differentiated, suggesting a pleomorphic adenoma. Next to this area there was a small, noticeably atypical, epithelial colony, which showing pleomorphic and hyperchromatic nuclei, of a large size, with enlarged nuclei and abundant mitosis, which were positioned in a papillary pattern or as a solid mass, on a hyalinized stroma with necrotic areas and intense fibrosis. The malignant component was infiltrating the capsule of the pleomorphic adenoma, extending over it at some points, but without reaching the surgical border of the sample. The definitive diagnosis was poorly differentiated adenocarcinoma over a pleomorphic adenoma of the submaxillary gland (Fig. 2).

Following the definitive anatomopathologic report, local radiotherapy was decided upon so as to avoid recurrence at this level, as well as prophylactic radiotherapy at a homolateral cervical level.

Discussion

Pleomorphic adenoma is the most frequent type of tumor of the salivary glands and it represents 3% of cervicofacial tumors. It is a benign mixed tumor made up of epithelial and mesenchymal cells. Following diagnosis, clinical evolution can take months or years.¹ The benign mixed tumor is classed in three clinicopathological entities: 1. carcinoma ex pleomorphic adenoma; 2.true benign mixed tumor (carcinosarcoma); and 3. metastasizing mixed tumor. These last two cases are rare.² The carcinoma ex pleomorphic adenoma is an infrequent malignant neoplasm which is aggressive and poorly differentiated, representing most of the malignant mixed tumors; regional metastasis is common and mortality is high.³ The majority of pleomorphic adenomas are diagnosed between the 3^rd and 5^th decade of life, while carcinoma ex pleomorphic adenoma is extremely rare in patients under the age of 30.⁴

In 1991, the World Health Organization (WHO) proposed that the pleomorphic adenoma which shows obvious signs of malignancy, such as characteristics of histological and cytological of anaplasia, abnormal mitosis, progressive course and infiltrative growth pattern, should be called carcinoma ex pleomorphic adenoma. Revision of the literature shows that the development of a carcinoma in a pre-existing pleomorphic adenoma takes place in 3-4% of cases (1,5% during the first five years and 9,5% after 15 years of evolution)⁵ and which represents 5- 15% of malignant neoplasms of the salivary glands.⁶

The etiopathogenesis of this pathology is therefore controversial. Gerughty et al.⁷ claimed that these tumors are malignant from the onset, as 60% of patients in their series had no history of previous tumors and that these occurred principally in young people. On the other hand, Beahrs et al.⁸ claimed that a malignant transformation occurs in a benign mixed tumor, because the average time that a pleomorphic adenoma takes to appear is ten years less than that of a carcinoma ex pleomorphic adenoma, and that the majority of patients have a previous history of a mass of several years. Olsen & Lewis³ are of this same line of opinion.

On physical exploration the presence of a painless, firm, mobile tumor is observed.1 The clinical characteristics of a carcinoma ex pleomorphic adenoma which have been described are: 1. long history of a pleomorphic adenoma; 2. elderly age; 3. localization in a major salivary gland; and 4. history of rapid growth with occasional pain, neural invasion or ulceration.^5,9

The anatomopathologic diagnosis of carcinoma ex pleomorphic adenoma requires the presence of a recognizable mixed tumor in association with a carcinoma. ^2,6 Histologically the malignant areas are moderately to poorly differentiated, or undifferentiated carcinomas. When there are necrotic or hemorrhagic areas in a pleomorphic adenoma, the possibility of malignant transformation should be considered.⁶ Auclair and Ellis⁴ consider that hyalinization and moderate mitotic activity are the only histological factors of atypical mixed tumors which can be significantly associated with an increased risk of malignant transformation. For Spiro et al.¹⁰ the presence of atypical hyperchromatic cells within the middle of a hyaline stroma constitutes immediate microscopic evidence of malignant transformation. Eneroth and Zetterberg¹¹ suggest that, as the mixed tumors grow, the cells can experiment a transformation which leads to the carcinomatosis component. This is based on finding colonies of diploid cells in pleomorphic adenomas with an evolution of at least one year, and tetraploid in those with an evolution of more than five years, similar to the discovery related to carcinoma ex pleomorphic adenoma.¹²

With regard to survival rates, tumor grading and staging, proliferation rate, carcinoma proportion, and extent of the invasion, these are prognostic factors.⁶ The most important isolated prognosis is the extension of the tumor outside the capsule.² It has been suggested that if the carcinomatous component is contained within the capsule of the pleomorphic adenoma, the prognosis is favorable. It has been observed that fixation of the tumor has reduced the survival rate from 53% to 14% and that in 25% of cases cervical lymphatic, regional metastasis is produced.^3,2 Several authors^5,7,9,10 present global survival rates between 30 to 65% at five years., with a recurrence rate of 40 to 50%. In a series of seven carcinomas ex pleomorphic adenomas in our Service, the results shown in table 1 were achieved.

With respect to treatment, this should be individual, taking into account localization, histological subtype and tumor grade. The treatment of choice is the extirpation of the submaxillary gland with total resection of the tumor with clear margins.¹ Some authors recommend elective cervical dissection for high-grade tumors. According to several studies, radiotherapeutic treatment can be used as an alternative to surgery in the management of a primary tumor. Likewise, postoperative adjuvant radiotherapy (to which we subscribe in this case) has shown a greater efficiency than surgery on its own5 and a reduction of locoregional recurrence.³ Lastly, in patients with recurring metastasis in other organs, chemotherapy should be considered.

To conclude we would indicate that all benign mixed tumors of salivary glands have the capacity of becoming malignant, particularly those is the submaxillary gland; that the morphological differences between pleomorphic adenomas that reach malignant transformation and those that do not are minimal; and finally, that the best prevention of the carcinoma ex pleomorphic adenoma consists in the prompt resection of the benign glandular neoplasm.

References

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6. Lewis JE, Olsen KD, Sebo TJ. Carcinoma ex pleomorphic adenoma. Pathologic análisis of 73 cases. Hum Pathol 2001;32:596-604.         [ Links ]

7. Gerughty RM, Scofield HH, Brown FM, Hennigar GR. Malignant mixed tumors of salivary gland origin. Cancer 1969;24:471-86.         [ Links ]

8. Beahrs OH, Woolner LB, Kirklin JW, Devine KD. Carcinomatous transformation of mixed tumors of the parotid gland. AMA Arch Surg 1957;75:605-14.         [ Links ]

9. Yamamoto Y, Kishimoto Y, Virmani AK, Smith A, Vuitch F, Albores-Saavedra J, Gazdar AF. Mutations associated with carcinomas arising from pleomorphic adenomas of the salivary glands. Hum Pathol 1996;27:782-6.         [ Links ]

10. Spiro RH, Huvos AG, Strong EW. Malignant mixed tumor of salivary origin: a clinicopathologic study of 146 cases. Cancer 1977;39:388-96.         [ Links ]

11. Eneroth CM, Zetterberg A. Malignancy in pleomorphic adenoma. A clinical and microspectophotometric study. Acta Otolaryngol 1974;77:426-432.         [ Links ]

12. McGrath MH. Malignant transformation in concurrent benign mixed tumors of the parotid and submaxillary glands. Plast Reconstr Surg 1980;65:676-678.         [ Links ]