Carcinoma in Basal Cell Adenoma of the Parotid Gland

PATHOLOGY

RESEARCH AND PRACTICE

© Gustav Fischer Verlag

Carcinoma in Basal Cell Adenoma of the Parotid Gland Toshitaka Nagao 1, Isamu Sugano 1 , Yasuo Ishida 1, Osamu Matsuzaki 2 , Akiyoshi Konno 3 , Yoichiro Kondo 4 and Koichi Nagao 1 1 Department of Surgical Pathology, Teikyo University, School of Medicine, Ichihara Hospital, Ichihara, Japan; 2Department of Surgical Pathology, Chiba Cancer Center Hospital; 3Department of Otolaryngology and the 4Department of Pathology, Chiba University, School of Medicine, Chiba, Japan

Summary

Introduction

Malignant transformation of basal cell adenoma (BCA) of the parotid gland is rarely reported, and when occurred, may principally become manifest as a malignant basaloid tumor, i.e. basal cell adenocarcinoma or adenoid cystic carcinoma. We describe herein three cases of non-basaloid carcinoma arising in BCA. The incidence of this malignant tumor was 0.2% of all parotid gland tumors and 4.3% ofBCAs in our series. One case was salivary duct carcinoma showing histologic evidence of transition between malignant and benign elements. The remaining two cases were well-encapsulated parotid gland tumors, which were composed of BCA and scattered foci of malignant transformation. Malignant components were adenocarcinoma, not otherwise specified (NOS), and sometimes intermixed with neoplastic myoepithelial cells included BCA cells. These two cases were regarded to be intracapsular carcinoma in BCA. BCA components showed solid, tubular and trabecular arrangements. The patients' prognosis was quite variable among these three cases; the first case died of disease after 27 months, whereas the latter two cases are alive and well for 4 and 10 years after surgery. Ki-67 labeling index indicated that cell proliferative activity was at least five times higher in carcinomas than BCAs. Non-basaloid carcinomas such as salivary duct carcinoma or adenocarcinoma, NOS, do develop in BCAs as in the case of a pleomorphic adenoma with malignant transformation, though the incidence may be extremely rare.

Basal cell adenoma (BCA) is a newly categorized entity which is discriminated from the other types of monomorphic adenomas in the second version of the World Health Organization classification of the salivary gland tumors [29]. BCA is distinctly separable from pleomorphic adenoma (PA) because of its uniform proliferation of tumor cells in contrast to diverse histopathologic features commonly seen in the latter tumors. BCA accounts for 1.5 to 7.5 percent of salivary gland tumors and the most common site is the parotid gland [10, 17, 24]. Although carcinoma arising from a PA is not an exceptional event but a well-recognized entity [10, 20, 23, 29, 31], malignant transformations in monomorphic adenomas such as Warthin's tumor [22, 26J, BCA [4, 6, 16, 21] and sebaceous lymphadenoma [13J, have rarely been reported. Regarding malignancy in BCA, only malignant basaloid type tumor has hitherto been described [4, 6, 16, 21]. However, basaloid tumors, i.e. BCA, basal cell adenocarcinoma and solid type of adenoid cystic carcinoma, are of a confusing concept, especially with respect to their mutual relationship and differential diagnosis [5, 8, 10, 11, 15]. In this paper, we present three rare cases of non-basaloid carcinoma arising from BCA in the parotid gland with histologic, immunohistochemical and ultrastructural evaluations.

Key words: Basal cell adenoma - Salivary duct carcinoma - Adenocarcinoma - Parotid gland - Salivary gland Pathol. Res. Pract. 193: 171-178(1997)

Material and Methods Seventy cases of BCA were selected from 1277 surgically resected cases of primary parotid gland tumors deposited in 0344-0338/97/0193-0171 $5.00/0

172 . T. Nagao et al. Table I. Antibodies used in this study Antibody

Source

Clonality

Dilution

Cytokeratin (KLI) Cytokeratin (5/6/8/18) Epithelial membrane antigen Smooth muscle actin S-Ioo protein Vimentin BRST-I Carcinoembryonic antigen Ki-67 (MIB-I)

Immunotech S.A., Marseille, France Novocastra Lab., Newcastle, UK DAKO, Glostrup, Denmark Nichirei, Tokyo, Japan Nichirei, Tokyo, Japan DAKO, Glostrup, Denmark Signet Lab., Dedham, MA DAKO, Glostrup, Denmark Immunotech S.A., Marseille, France

Monoclonal Monoclonal Monoclonal Monoclonal Polyclonal Monoclonal Monoclonal Monoclonal Monoclonal

(1 :50) (1:100) (1:100) Prediluted Prediluted (1 :50)

the files of Chiba University Hospital and other hospitals in Chiba perfecture, Japan, between 1953 and 1994. Among these BCA cases, three cases consistent with carcinoma in BCA were identified. Several step tissue sections were fixed on 10% formalin and processed using routine histologic techniques. For electron microscopy, although only one case was available for examination, the material was fixed in 3% glutaraldehyde in phosphate buffer at 4°C, post-fixed in 1% osmium tetroxide, stained in blocks with uranyl acetate and embedded in Epon-812. Ultrathin sections were stained with lead citrate and examined in a JEM-12ooEX electron microscope (lEOL, Tokyo, Japan). For immunohistochemistry, the deparaffinized and rehydrated slides were boiled in 10 mM citrate buffer, pH 6.0, for 20 min in a microwave oven. After cooling for 30 min, they were incubated with the primary antibody for 15 h at 4 0c. The primary antibodies used in this study are listed in Table I. The labeled streptavidin-biotin peroxidase method was used for detection, employing 3,3' -diaminobenzidine as the chromogen. The sections were slightly counterstained with hematoxylin. The percentage of Ki-67positive cells was determined by counting at least 1000 tumor cells and recorded as Ki-67 labeling index (LI).

Results The incidence of BCA was 5.5%, and malignant transformation in BCA was 0.2% of all parotid gland tumors and 4.3% of all BCAs in our series. Although a membranous variant of BCA is known to coexist with skin adnexal tumor [16, 37], no patients had a salivary gland-skin diathesis in our series. Clinical Findings

Case 1: A 61-year-old man presented with pain in the right parotid region and right facial nerve palsy. Physical examination revealed a mass in the right parotid area measuring 35x30 mm. A total parotidectomy with transplantation of the facial nerve was done. Postoperatively the patient received 40 Gy of radiation. Fourteen months later, recurrence developed in the right submandibular area and metastases were found in the ver-

(1:10)

(1 :50) (1: 100)

tebral bone. In spite of extensive radiotherapy, he died 27 months after surgery. Case 2: A 74-year-old man had a 6-month history of an enlarging and painless left-sided parotid mass. On examination there was a firm mass measuring 45x31 mm without any evidence of fixation to the adjacent tissue and facial nerve palsy. A subtotal parotidectomy was done without an additional therapy. He is alive with no evidence of recurrent disease for 4 years after the surgery. Case 3: A 62-year-old man had a 7-year history of a right parotid gland mass. Intraoperative examination revealed that the facial nerve was fixed with the mass. A subtotal parotidectomy with partial facial nerve resection was performed. On examination the mass was firm measuring 60x50 mm. He received no additional therapy and no evidence of recurrence 10 years later. Pathologic Findings

In Case 1, the tumor was widely distributed in the parotid gland without any encapsulation, measuring 30x30x25 mm. Histologically, two distinctly different areas were identified within the same tumor (Fig. lA-C). The major portion was composed of many distended duct-like structures filled with atypical cells with eosinophilic cytoplasm and prominent nucleoli. The tumor cells showed cribriform, papillary, or solid growth pattern. Apocrine-like metaplasia was seen when they displayed papillary arrangement along the dilated cystic wall (Fig. 1C). Occasionally, central portion of the cell cluster underwent comedo-like necrosis (Fig. 1A). These histologic features were consistent with salivary duct carcinoma [7, 10, 19, 29]. The carcinoma cells invaded into the adjacent parotid gland and adipose tissue. Perineural and lymphovenous invasions were evident. There was a different tumor mass measuring 4x5 mm at the central portion of the above mentioned carcinoma tissue. The tumor cells in this portion consisted of solid and trabecular growth of basaloid cells (Fig. 1B) that had no nuclear atypism or pleomorphism.

Carcinoma in Basal Cell Adenoma . 173

Fig. 1. Case 1. A) Low-power view showing a transitional area (middle) from basal cell adenoma (left) to salivary duct carcinoma (right). Note comedo-like necrosis in salivary duct carcinoma. B) Basal cell adenoma (left) and transitional zone (right). Basal cell adenoma is characterized by monotonous tubular and solid arrangements of basaloid cells, whereas basaloid cells and carcinoma cells are intimately admixed in transitional zone. C) Salivary duct carcinoma with intracystic papillary projections showing apocrine-like metaplasia. Immunostaining for smooth muscle actin (SMA) (D), Ki-67 (E) and BRST-l (F). D) Carcinoma cells are surrounded by SMA-positive cells. E) Many carcinoma cells are immunostained for Ki-67 in the transitional zone than basal cell adenoma (upper portion). F) BRDT-I is positive for almost all carcinoma cells in transitional zone. By contrast, no immunostaining cells are seen in the basal cell adenoma (upper portion).

174 . T. Nagao et al.

Fig. 2. Case 2. A) Low-power view showing a basal cell adenoma (left lower portion) from adenocarcinoma (right). B-1) Basal cell adenoma showing solid and trabecular growth ofbasaloid cells with scattered small lumens. B-2) An area of malignant transformation. Carcinoma cells have eosinophilic cytoplasms and prominent nucleoli surrounded by basaloid cells. A mitotic figure is seen (arrow). Immunostaining for vimentin (C), Ki-67 (D), and BRST-I (E).

E

C) Carcinoma cells are surrounded by vimentin-positive cells. D) Many carcinoma cells are positive for Ki-67. E) Almost all carcinoma cells are positive for BRST-I, while basal cell adenoma are negative.

Myxochondromatous stroma characteristically observed in pleomorphic adenoma was absent. We considered this area as being BCA. There was a distinctive area in which carcinoma and BCA cells were intermixed within the same cell nest encompassed by basaloid cells (Fig. lB). Also observed were transitional cells between BCA and carcinoma.

Cases 2 and 3 had largely similar histologic features with some differences. Both tumors were of a well-circumscribed mass with thick fibrous capsule. In the tumors, three distinctly different cell types were identified: BCA composed of basaloid and cuboidal cells without any atypia (Fig. 2B-l, 3A, B); and atypical cells which had distinct nucleoli, an elevated cytoplasmic

Carcinoma in Basal Cell Adenoma . 175

Fig. 3. Case 3. A) Basal cell adenoma showing trabecular arrangement in loose stroma with marked vasodilataion. B) Solid and insular pattern with squamous differentiation recognized as "eddies" and peripheral palisading are evident in basal cell adenoma. C) Transitional area between basal cell adenoma and adenocarcinoma. Carcinoma cells with fused glandular structure surrounded by basaloid cells. D) Glandular structure of carcinoma cells with hyalinizing fibrous stroma. Immunostaining for cytokeratin (E), carcinoembryonic antigen (CEA) (F), and Ki-67 (G). E) Cytokeratin is positive in carcinoma cells but not in surrounded basaloid cells. F) Apical portion and luminal contents of carcinoma cells expressing CEA. G) Many Ki-67 positive cells are seen in carcinoma portion.

176 . T. Nagao et aI.

Fig. 4. Case 3. Electron micrograph of a cell nest intermixed with carcinoma cells and basal cell adenoma cells. Except for vacuoles, carcinoma cells contain rather sparse cytoplasmic organelles. They are apparently surrounded by flat benign cells showing myoepithelial cell differentiation. Many lysosome-like organelles seen in carcinoma cell (inset).

ratio, eosinophilic cytoplasm, and a high mitotic rate (Fig. 2B-2, 3C, D). Basaloid cells showed solid, trabecular and tubular growth, and became cuboidal thereby producing small acinar lumens (Fig. 2B-l). The basaloid cell nest frequently showed peripheral palisading (Fig. 3B). In Case 3, squamous eddies were evident within the cell nest or end of the trabecular cell cord (Fig. 3B). The trabecular structure was sometimes accompanied by microcystic stromal alteration with marked vasodilatation (Fig. 3A). On the other hand, carcinoma cells formed a fused, sometimes dilated, gland structure, which was accompanied by basaloid cells arranged along the peripheral interface of the epithelial nests (Fig. 2A, B-2, 3C). Sometimes, carcinoma cells showed solid cell clusters (Fig. 2A). Furthermore, the carcinoma cells showed invasive growth with hyalinization, where they were unaccompanied by basaloid cells (Fig. 3D). We considered that these malignant components were adenocarcinoma, not otherwise specified (NOS) [10, 25, 29]. The malignant transformations seemed to develop multifocally throughout the tumor mass. No capsular invasions, however, were observed. Carcinoma cells had no mucin production revealed by mucicarmin staining, as examined so far. Immunohistochemically, cytokeratins and epithelial membrane antigen were demonstrated in BCA cells situated at the inner and luminal side of cell nests, and almost all carcinoma cells in the three cases (Fig. 3E). Conversely, smooth muscle actin (SMA), S-100 protein, and vimentin, an indicator for myoepithelial cell differentiation [2, 14J, tended to localize in peripheral

BCA cells adjacent to the connective tissue. Carcinoma cells were negative for these antibodies in all the cases. At the transitional zone between BCA and carcinoma, carcinoma cell nests were surrounded by basaloid cells, which were positive for SMA (Fig. ID), S-100 protein and vimentin (Fig. 2C). Focally, the luminal aspect of cell borders and intraluminal secretion of BCAs and adenocarcinomas, but not salivary duct carcinoma, showed positive reaction for carcinoembryonic antigen (Fig. 3F). Ki-67, a marker for cell proliferation [28J, was positively stained more frequently in carcinoma cells than in BCA cells. Ki-67 LI of carcinoma cells and BCA cells was 30.8% and 1.7% in Case I (Fig. IE), 17.4% and 3.1% in Case 2 (Fig. 2D), and 22.5% and 3.1 % in Case 3 (Fig. 3G), respectively. Most of the salivary duct carcinoma cells and apical portion, as well as luminal contents of adenocarcinoma, NOS, were strongly positive for BRST-l, which is raised against breast ductal carcinomas and consequently referred to as breast-specific markers, while BCA cells were only focally stained with luminal pattern (Fig. IF, 2E). In Case 3, electron microscopy revealed that carcinoma cells had a clear nucleus with a prominent nucleolus and usually contained sparse cytoplasmic organelles. Many lysosome-like corpuscles were occasionally observed. Sometimes, they were arranged to produce luminal structure with apical microvilli. In BCA area, two different cells were largely identified; basaloid and ductal cells. The former had thin cytoplasmic process with well-formed hemidesmosomes and fine filaments similar to those seen in normal myoepithelial cells. In the

Carcinoma in Basal Cell Adenoma . 177 transitional area, carcinoma cells were apparently surrounded by these basaloid cells with a thick basement membrane (Fig. 4).

Discussion Kleinsasser and Klein first described BCAs, which are an encapsulated, slow-growing, purely epithelial neoplasm composed of what appeared to be basal cells [17}. BCA is a relatively uncommon tumor and its incidence was 5.5% among parotid gland tumors in our series, which is somewhat higher than that reported by other investigators [10, l7}. The reason for this discrepancy is unknown but geographic and racial factors seem to be influential. In the AFIP series, the incidence of carcinoma in PA is 8.5% of all PA [lOJ and 4.5% in our previously reported data [23}. In comparison, malignant transformation in BCA is an apparently rare event. The age of the patients having carcinoma in BCA was higher than all BCAs [24J. As in PA, malignant transformation may occur on the basis of long standing presence of BCA [20, 31]. According to our experience, the tumor size of carcinoma in BCA is relatively larger when compared with that of benign BCA [24J. Reports of malignant basaloid salivary gland tumors are rare, due, in part, to the confusing terminology. In fact, they have variably referred to as basaloid salivary carcinoma [4J, hybrid BCA and adenoid cystic carcinoma [1, 11, 30J, basal cell adenocarcinoma [8, 9J, basal cell carcinoma [19 J, basaloid carcinoma [12J, and carcinoma ex monomorphic adenoma [21}. Of these, there is clear documentation for basal cell adenocarcinoma arising in major salivary glands, which is a relatively new entity defined as a malignant counterpart of BCA [8, 9}. The most important diagnostic feature for separating basal cell adenocarcinoma from BCA is the infiltrative growth pattern. Ellis and Wiscovitch considered that most basal cell adenocarcinomas probably arise de novo. Luna et aI., however, reported a series of eight basaloid carcinomas arising from basal cell adenomas [21]. Some investigators have described adenoid cystic carcinomas coexisting with BCA and regarded BCA as a benign counterpart of adenoid cystic carcinoma [5J, while some others consider that the two lesions and their histologic aspect are completely independent from each other [9}. Furthermore, Ellis and Auclair proposed in AFIP fascicle that hybrid BCA-adenoid cystic carcinoma occurring in infants is probably best reclassified as sialoblastoma, another newly described entity [10}. Thus, histogenetic correlations among basaloid tumors are still controversial. Whatever the event, our cases unequivocally showed the emergence of non-basaloid carcinomas from BCAs, along with an apparent transitional zone between benign and malignant areas.

In general, BCAs are histologically subclassified into tubular, trabecular, solid and membranous type [10, 29}. Ductal cell differentiation occurs variable in BCA according to its subtypes. For example, tubular type of BCA has most prominently ductal cell differentiation. It seems that the degree of ductal cell population does not relate to the occurrence of malignant transformation in BCA because ductal cell is not so noticeable in our cases. It is reported that the incidence of basaloid carcinoma arising from BCA is especially high in the membranous type, which is also referred to as dermal analogue type [3J, with the salivary-dermal tumor diathesis [4, 16, 2l}. In our present cases, however, BCA components comprised no membranous feature and patients had no cutaneous tumors. In carcinomas in PA, various histologic patterns have been shown to develop including undifferentiated carcinoma, adenocarcinoma, NOS, squamous cell carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma and salivary duct carcinoma [19,23, 31]. In our cases, malignant components of carcinoma in BCA were salivary duct carcinoma and adenocarcinoma, NOS. Salivary duct carcinoma is a rare malignant tumor and its prognosis is very poor [7, 19}. Indeed, our patient died 27 months after surgery in Case 1. Although carcinomas in PA are obviously infiltrative, when confined within the capsule, they are further categorized as intracapsular carcinoma [29}. Cases 2 and 3 were thus considered to be the intracapsular carcinoma in BCA. Prognoses of these cases were quite favorable similar to that of intracapsular carcinomas in PA [20}. However, these lesions may progress to manifest invasive carcinoma as Case 1. Occasionally, in carcinomas in PA, there may be a transitional zone of intermediate features between the benign PA and carcinomatous components [20}. Similarly, our present cases also showed that malignant areas coexisted with small cell nests and tubules sometimes intermixed with myoepithelial differentiated BCA cells. Carcinoma cells might have first proliferative replacing of ductular cells, because the ductular architecture of BCA was focally preserved. Gradually, they might grow destroying BCA cell nests with hyalinization. It is also described that the invasion of tumor cells into hyalinized stroma within the PA is one of the important hallmarks of the criteria for the occurrence of malignant transformation [23, 31J, It has been already reported that BRST-1, one of the breast cancer markers, is positive for salivary duct carcinoma [7}. Since BRST-1 was strongly expressed not only in the salivary duct carcinoma of Case 1 but also in adenocarcinoma, NOS, of Case 2 and 3, whereas only focal expressions were confirmed in BCA areas, the possibility may exist that this staining is useful to examine malignant transformation in BCA. Electron microscopically, carcinoma cells had many large vacuoles, regarded as lysosomes, which may correspond in part to BRST-l positive material. As Ki-67 LI was at least five times higher in carcinomas than BCAs, this cell prolif-

178 . T. Nagao et al. erative activity marker may also help us to distinguish between malignant and benign counterparts. To the best of our knowledge, this is the first report to demonstrate that malignant transformation of non-basaloid carcinoma does actually occur, though the incidence may be quite rare. Acknowledgements: We wish to thank Mr. Shigeru Munakata, Mr. Kenichi Hasegawa, and Mr. Akira Asoh, Department of Surgical Pathology, Teikyo University, School of Medicine, Ichihara Hospital, for technical assistance.

17. 18. 19.

20.

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