DEDIFFERENTIATION IN LOW-GRADE MUCOEPIDERMOID CARCINOMA OF THE PAROTID GLAND

Transcription

1 DEDIFFERENTIATION IN LOW-GRADE MUCOEPIDERMOID CARCINOMA OF THE PAROTID GLAND TOSHITAKA NAGAO, MD, THOMAS A. GAFFEY, MD, PAUL A. KAY, MD, KRISHNAN K. UNNI, MD, ANTONIO G. NASCIMENTO, MD, THOMAS J. SEBO, MD, HIROMI SERIZAWA, MD, HIROSHI MINATO, MD, AND JEAN E. LEWIS, MD Mucoepidermoid carcinoma (MEC), a common malignant salivary gland neoplasm, is generally divided into low-, intermediate-, and high-grade types according to the histologic features. To our knowledge, the present report describes the first case of dedifferentiation occurring in a low-grade MEC. A 55-year-old man presented with a biphasic neoplasm of the right parotid gland composed of low-grade MEC and dedifferentiated high-grade anaplastic undifferentiated carcinoma. Immunohistochemically, carcinoembryonic antigen expression was restricted to the low-grade MEC portion. The Ki-67 labeling index was higher in the dedifferentiated component than in Mucoepidermoid carcinoma (MEC), one of the most common malignant salivary gland neoplasms, is divided into low-, intermediate-, and high-grade types according to the histologic features. 1,2 Low-grade MEC is a well-circumscribed mass with multicystic spaces consisting of mucinous and intermediate cells with bland nuclei. High-grade MEC has a more solid growth pattern and is composed of atypical epidermoid and intermediate cells and a small number of mucinous cells. Dedifferentiation is defined as the abrupt transformation from a low-grade, well-differentiated tumor into a tumor with high-grade histologic features and is a well-recognized phenomenon in bone and soft tissue tumor pathology. 3 This phenomenon has also been reported in some low-grade salivary gland tumors To our knowledge, however, no definitive description of dedifferentiation occurring in a low-grade MEC has been reported. In this paper, we present a case of dedifferentiation in a low-grade MEC arising in the parotid gland. Immunohistochemical and DNA image cytometric analyses were used to distinguish between the low-grade MEC component and the dedifferentiated component. CASE REPORT Clinical History A 55-year-old man presented with a 3-month history of a painless, right parotid mass. A computerized tomographic scan of the head and neck showed a cm enhancing mass within the superficial portion of the right parotid gland. A right subtotal parotidectomy with upper neck dissection was performed. Postoperatively, the patient received high-dose (70 Gy) radiotherapy. Local recurrences From the Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, and the Department of Surgical Pathology, Tokyo Medical University Hospital, Tokyo, Japan. Accepted for publication June 17, T.N. and H.M. are visiting clinicians at the Division of Anatomic Pathology of the Mayo Clinic. Address correspondence and reprint requests to Thomas A. Gaffey, MD, Division of Anatomic Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN Elsevier Inc. All rights reserved /03/ $30.00/0 doi: /s (03) the low-grade component. On image cytometric analysis, the lowgrade MEC was diploid, whereas the dedifferentiated carcinoma was aneuploid. Although the patient was alive 10 years after the initial diagnosis, the tumor has recurred twice, at 3 months and 7 months after the initial resection. It is important to recognize that dedifferentiation can occur in a low-grade MEC, similar to other low-grade salivary gland carcinomas. HUM PATHOL 34: Elsevier Inc. All rights reserved. Key words: case history, dedifferentiation, mucoepidermoid carcinoma, salivary gland. developed twice, at 3 months and 7 months after the initial resection. Both recurrent lesions were widely excised to achieve tumor-free margins. At the time of the second recurrence, intraoperative radiotherapy was delivered to the tumor bed, but no additional chemotherapy was given postoperatively. The patient was alive with no evidence of recurrent disease 9 years 5 months after the last recurrence. Pathology Findings The superficial right parotidectomy specimen contained a lobulated, generally well-circumscribed, cm tumor. Histologically, the tumor had 2 distinct carcinomatous components. One component had features consistent with a low-grade MEC, and the other component had features of a high-grade anaplastic carcinoma (Fig 1). The high-grade component occupied approximately 80% of the tumor mass. Although both the low-grade MEC and high-grade anaplastic carcinoma components were clearly separated from each other (Fig 1A), a mixture of the 2 cell types formed an intervening transitional zone (Fig 1B). The low-grade MEC component was characterized by multiple cystic structures with glandular formation and small solid cell nests (Fig 1A) consisting of intermediate and mucinous cells and a few epidermoid cells (Fig 1C). The nuclei of these cells were uniformly bland, and mitotic figures were extremely rare. Necrosis was absent in the low-grade component. Tumorassociated lymphoid proliferation surrounded the low-grade neoplasm. With mucicarmine and periodic acid-schiff stains, mucin was readily shown in the cytoplasm of mucinous cells and in glandular and cystic lumina in the low-grade MEC component. In comparison, the high-grade component consisted of solid and sheetlike growth patterns without any glandular or cystic structures (Fig 1A and D). Focally, sarcomatoid growth features were also observed (Fig 1E). Extensive central necrosis was seen in the high-grade component. The carcinoma cells had large pleomorphic nuclei with conspicuous nucleoli (Fig 1D) and a high mitotic rate ( 50 mitotic figures per 10 high-power fields). Also, bizarre tumor cells were seen occasionally. Although clear cells were identified focally, mucicarmine-positive mucus-producing cells were absent, and no keratinization or intercellular bridges were observed. Highgrade carcinoma cells invaded angiolymphatic spaces. Dissected neck lymph nodes were negative for tumor. The 1068

2 CASE STUDIES FIGURE 1. (A) Low-power view showing a low-grade mucoepidermoid carcinoma (MEC) component composed mainly of cystic structures (on the right) and a high-grade anaplastic carcinoma component with a solid and sheetlike growth pattern (on the left). Note that the 2 components are sharply separated from each other. (B) The low-grade MEC component consisting of cystic and glandular formations (right lower portion) and the solid growth of the high-grade anaplastic carcinoma component (left upper portion) are intimately connected. (C) Low-grade MEC component showing a mixture of intermediate, mucous goblet, and epidermoid cells. Note the bland appearance of the tumor cell nuclei. (D) High-grade carcinoma component showing solid growth of markedly pleomorphic tumor cells with prominent nucleoli. (E) Sarcomatoid feature of the high-grade carcinoma component. twice-recurrent lesions consisted of only the high-grade component. Immunohistochemical studies were performed on formalin-fixed and paraffin-embedded material, using a labeled streptavidin-biotin detection method. Table 1 lists the primary antibodies used and summarizes the immunohistochemical results. Immunohistochemically, both the low- and high-grade components diffusely expressed cytokeratins (AE1/AE3) and epithelial membrane antigen, but immunoreactivity was not detected for -smooth muscle actin, S-100 protein, or glial fibrillary acidic protein. The low-grade MEC component was diffusely positive for carcinoembryonic antigen, but the high-grade carcinoma component was negative (Fig 2A). No overexpression of HER-2/neu or p53 was observed. The Ki-67 labeling index, which was determined by the percentage of Ki-67 positive cells in 1000 tumor cells, was 1069

3 TABLE 1. Antibodies Used and Results of Immunohistochemistry Antigen (antibody) Source Clonality Dilution Results Low-grade MEC DC Cytokeratin (AE1/AE3) Zymed, San Francisco, CA M 1:200 EMA DAKO, Carpinteria, CA M 1:20 -Smooth muscle actin DAKO M 1:150 S-100 protein DAKO P 1:800 GFAP DAKO P 1:300 CEA DAKO M 1:50 BRST-2 (GCDFP-15) Signet Laboratories, Dedham, MA M 1:200 HER-2/neu Novocastra Laboratories, Newcastle, UK M 1:50 p53 (DO7) DAKO M 1:200 Focal Focal Ki-67 (MIB-1) DAKO M 1: % 61.6% Abbreviations: CEA, carcinoembryonic antigen; DC, dedifferentiated carcinoma component; EMA, epithelial membrane antigen; GCDFP- 15, gross cystic disease fluid protein-15; GFAP, glial fibrillary acidic protein; M, monoclonal; MEC, mucoepidermoid carcinoma component; P, polyclonal. higher in the high-grade component than in the low-grade component; the Ki-67 labeling index was 61.6% and 4.2% for the high- and low-grade components, respectively (Fig 2B and C). The tumor-cell DNA content was determined with image cytometry using the CAS 200 image analysis system (Becton- Dickinson, San Jose, CA) on Feulgen-stained sections of the low- and high-grade components separately. DNA ploidy analysis showed that the low-grade MEC component was composed of diploid cells and that the high-grade carcinoma component was composed of aneuploid cells (Fig 3). DISCUSSION Since Stanley et al 4 first reported a dedifferentiated variant of salivary gland acinic cell carcinoma in 1988, dedifferentiation of other low-grade salivary gland carcinomas has been described, including adenoid cystic carcinoma, 7,10 epithelial-myoepithelial carcinoma, 8 and polymorphous lowgrade adenocarcinoma. 9 In such dedifferentiated tumors, the dedifferentiated element, which may be either undifferentiated carcinoma or poorly differentiated adenocarcinoma, lacks the original distinctive, well-differentiated growth pattern. In our case of dedifferentiation in a low-grade MEC in the parotid gland, the tumor consisted of a typical low-grade MEC, a high-grade anaplastic undifferentiated carcinoma, and a transitional zone. In our case, it is likely that the high-grade component developed through dedifferentiation from a low-grade MEC of the parotid gland. In MEC, the phenomenon of dedifferentiation is extremely rare, and we believe that the current report is the first formal description of it. Dedifferentiation can already be present when an untreated (primary) low-grade salivary gland tumor is detected, or it can develop in a recurrent lesion, sometimes after postoperative radiotherapy Evans, 12 in his series of MECs, described a case that underwent a change into anaplastic carcinoma after irradiation of the initial tumor. Although this case is a possible example of dedifferentiated MEC, it was not reported as dedifferentiated carcinoma. Spindle cell sarcomatoid MEC has been described in a single case report. 13 Epithelial islands in this tumor were composed of high-grade, poorly differentiated MEC cells, but a low-grade MEC component was not identified. Before the diagnosis of dedifferentiated MEC is made, several salivary gland tumors that have biphasic morphologic features should be considered. Also, metastatic undifferentiated carcinoma from a distant site should be excluded. Our patient had no history of a previous or coexistent malignancy. Rarely, foci of a low-grade neoplasm are present within a high-grade MEC, suggesting that the latter element develops through tumor progression. 14 In such instances, a few mucinproducing cells should be detected in the high-grade MEC component. In our case, the high-grade element (anaplastic undifferentiated carcinoma) was completely devoid of the distinctive features of MEC. Nuclear atypia and pleomorphism of more than moderate degree, frequent mitoses, and extensive necrosis, as seen in our case, are not typical of MEC of any grade. 12,15 When these features are present, the differential diagnosis should include other high-grade tumors. 12,15 The tumor in our case had initially been diagnosed as a high-grade adenosquamous carcinoma. Unlike adenosquamous carcinoma, however, the high-grade element in our case showed no evidence of squamous differentiation. The presence of a transitional zone between the low-grade MEC component and the high-grade carcinoma component differentiates the tumor in our case from a collision tumor. Mutation of the p53 gene or p53 overexpression (or both) has been implicated in dedifferentiation of adenoid cystic carcinoma 7,10 but not of acinic cell carcinoma. 5,6 Because the overexpression of p53 and HER-2/neu was not shown in our case, the molecular-genetic changes involved in the pathway of dedifferentiation in MEC remain to be elucidated. In dedifferentiated variants of salivary gland carcinomas, differences in DNA ploidy pattern and cell proliferation have been reported between the low- and high-grade components. 6-8,10 In the present case, we documented the alterations of these differences together with differences in carcinoembryonic antigen staining patterns. The distinct heterogeneity within the tumor would support the diagnosis of a dedifferentiated variant of MEC. It generally is accepted that dedifferentiated carcinomas are associated with a poor clinical outcome. 3,11 Although our patient was alive 10 years after the initial diagnosis, the twicerecurrent carcinoma within a short period testifies to the clinical aggressiveness of the tumor. The history of twicerecurrent neoplasm emphasizes the importance of not undertreating dedifferentiated MEC. However, additional case studies are needed to clarify the biologic behavior of this rare neoplasm and its suitable treatment. 1070

4 CASE STUDIES FIGURE 3. DNA histogram by digital image analysis showing a diploid (DNA index, 1.00) and an aneuploid DNA (DNA index, 1.29) pattern in (A) the low-grade mucoepidermoid carcinoma component and (B) high-grade carcinoma component, respectively. REFERENCES FIGURE 2. Immunohistochemistry. (A) Carcinoembryonic antigen is strongly expressed in the low-grade mucoepidermoid carcinoma component (on the right), but the high-grade anaplastic carcinoma component (on the left) is completely negative. Different Ki-67 (MIB-1) immunoreactivity can be noted between (B) the low-grade mucoepidermoid carcinoma component (labeling index, 4.2%) and (C) the high-grade anaplastic carcinoma component (labeling index, 61.6%). 1. Goode RK, Auclair PL, Ellis GL: Mucoepidermoid carcinoma of the major salivary glands: Clinical and histopathologic analysis of 234 cases with evaluation of grading criteria. Cancer 82: , Brandwein MS, Ivanov K, Wallace DI, et al: Mucoepidermoid carcinoma: A clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol 25: , Meis JM: Dedifferentiation in bone and soft-tissue tumors: A histological indicator of tumor progression. Pathol Annu 26:37-62, Stanley RJ, Weiland LH, Olsen KD, et al: Dedifferentiated acinic cell (acinous) carcinoma of the parotid gland. Otolaryngol Head Neck Surg 98: , Henley JD, Geary WA, Jackson CL, et al: Dedifferentiated acinic cell carcinoma of the parotid gland: A distinct rarely described entity. Hum Pathol 28: , Di Palma S, Corletto V, Lavarino C, et al: Unilateral aneuploid dedifferentiated acinic cell carcinoma associated with bilateral-low grade diploid acinic cell carcinoma of the parotid gland. Virchows Arch 434: , Cheuk W, Chan JK, Ngan RK: Dedifferentiation in adenoid cystic carcinoma of salivary gland: An uncommon complication associated with an accelerated clinical course. Am J Surg Pathol 23: , Alos L, Carrillo R, Ramos J, et al: High-grade carcinoma component in epithelial-myoepithelial carcinoma of salivary glands: Clinicopathological, immunohistochemical and flow-cytometric study of three cases. Virchows Arch 434: ,

5 9. Pelkey TJ, Mills SE: Histologic transformation of polymorphous lowgrade adenocarcinoma of salivary gland. Am J Clin Pathol 111: , Chau Y, Hongyo T, Aozasa K, et al: Dedifferentiation of adenoid cystic carcinoma: Report of a case implicating p53 gene mutation. Hum Pathol 32: , Zarbo RJ: Salivary gland neoplasia: A review for the practicing pathologist. Mod Pathol 15: , Evans HL: Mucoepidermoid carcinoma of salivary glands: A study of 69 cases with special attention to histologic grading. Am J Clin Pathol 81: , Love GL, Sarma DP: Spindle cell mucoepidermoid carcinoma of submandibular gland. J Surg Oncol 31:66-68, Ellis GL, Auclair PL: Tumors of the Salivary Glands. Washington, DC, Armed Forces Institute of Pathology, Rosai J: Ackerman s Surgical Pathology, 8th ed. St. Louis, MO, Mosby, 1996 AGGRESSIVE ANGIOMYXOMA: A SECOND CASE OF METASTASIS WITH PATIENT S DEATH STELLA BLANDAMURA, MD, JULIA CRUZ, MD, LOURDES FAURE VERGARA, MD, ISIDRO MACHADO PUERTO, MD, AND VITO NINFO, MD Aggressive angiomyxoma is a rare tumor that predominates in the female genital tract. Multiple relapses may occur in adjacent organs and tissues, but metastases have not been reported. We present a case of aggressive angiomyxoma in a young woman with multiple local recurrences that metastasized to the lungs, killing the patient. We document this case and report a similar one, found in the INTRODUCTION Aggressive angiomyxoma is a rare fibromyofibroblastic tumor that arises mainly in the vulva, perineum, and pelvis, most commonly in young patients. Histologically, the tumor has a bland appearance, with many blood vessels in a loose myxoid stroma and scanty mesenchymal spindle or stellate cells with delicate cytoplasmic processes. Because of its infiltrative behavior, complete surgical excision is difficult, and multiple recurrences occur in 70% of cases, often within a few years. The dependency of the tumor on hormonal state has been suggested, at least for some aggressive angiomyxomas. 1-3 Chromosomal abnormality involving chromosome 12, associated with rearrangement of HMGIC gene, has been reported. 4-6 Despite frequent recurrences, prognosis is generally good. One metastasizing aggressive angiomyxoma reported in a letter to the editor was not thoroughly documented. 7 We report an aggressive vulvar angiomyxoma with multiple local recurrences and pulmonary metastases and discuss the potential for unfavorable behavior by this neoplasm. literature, of a postmenopausal woman with pulmonary and mediastinic metastases. These cases may expand the current concepts of potential behavior of aggressive angiomyxoma. HUM PATHOL 34: Elsevier Inc. All rights reserved. Key words: aggressive angiomyxoma, female soft part tumors. and a second one was detected in September In May 2000, chest radiograms showed multiple lung metastases (Fig 1), and the patient died in January An autopsy histologically confirmed that the metastases were caused by aggressive angiomyxoma. HISTOLOGY The primary tumor was composed of spindle and stellate cells with ill-defined cytoplasm in an abundant myxoid stroma. Cellularity was low and quite uniformly distributed, with an increase around some vessels. Cells had round or oval nuclei, with small, centrally located nucleoli. The stroma was abundant, with prominent myxoid changes and small areas of erythrocyte extravasation. Vascularization was abundant, with variably sized vessels, ranging from small thin-walled capillaries to larger vessels with medial hypertrophy. Mitotic figures were absent, and there were no hemorrhagic or necrotic areas (Fig 2). Immunostaining was focally positive for desmin CASE REPORT A 27-year-old woman was hospitalized in September 1991 with a vulvar mass that was 10 cm in diameter. A resection was performed, and an aggressive angiomyxoma was diagnosed. Six years later (February 1997), a local relapse was detected, From the Department of Oncological and Surgical Sciences, Anatomic Pathology Section, University of Padua, Padua, Italy; the Department of Pathology, Oncology Institute, Havana, Cuba; the Department of Pathology, Hospital General Docente Màrtires del 9 de Abril, Sagua la Grande, Cuba; and the Department of Pathology, Hospital Hermanos Ameijiras, Ciudad de la Habana, Cuba. Accepted for publication June 17, Address correspondence and reprint requests to Stella Blandamura, MD, Istituto di Anatomia Patologica, Università di Padova, Via A. Gabelli 61, Padova, Italy Elsevier Inc. All rights reserved /03/ $30.00/0 doi: /s (03) Chest radiograph showing multiple lung metasta- FIGURE 1. ses. 1072