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Tumor-to-tumor metastasis: Warthin tumor as a recipient of lung carcinoma and of renal carcinoma – Report of two cases
ARTICLE IN PRESS Pathology – Research and Practice 206 (2010) 458–462
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.de/prp
Teaching cases
Tumor-to-tumor metastasis: Warthin tumor as a recipient of lung carcinoma and of renal carcinoma – Report of two cases Jan Laco a,, Petr Celakovsky b, David Kalfert b, Helena Hornychova a, Tomas Rybnikar b, Ales Ryska a a b
The Fingerland Department of Pathology, Charles University Faculty of Medicine and Faculty Hospital in Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic Department of Otorhinolaryngology, Charles University Faculty of Medicine and Faculty Hospital in Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
a r t i c l e in f o
S u m m a r y
Article history: Received 2 March 2009 Received in revised form 2 June 2009 Accepted 25 June 2009
Tumor-to-tumor metastasis is an exceedingly rare event with only about 100 cases reported in the English written literature. We report two cases of a 65-year-old man with duplicity of colonic and lung adenocarcinomas who presented with swelling of the left parotid gland, and of a 75-year-old man who presented with swelling of the right parotid gland. Microscopical and immunohistochemical examination showed metastasis of lung carcinoma and of renal carcinoma, respectively, to Warthin tumor as the first clinical manifestation of the malignancy in the latter case. To the best of our knowledge, such a phenomenon has not been reported so far. & 2009 Elsevier GmbH. All rights reserved.
Keywords: Tumor-to-tumor metastasis Warthin tumor Lung carcinoma Renal carcinoma Secondary tumors
Introduction Tumor-to-tumor metastasis is considered an extremely uncommon event with approximately 100 cases reported in the English written literature [6]. The most frequent donor malignancy is lung carcinoma, while the most frequent malignant recipient appears to be clear cell renal carcinoma [24]. Benign recipient tumors include mainly follicular adenoma of thyroid gland and adrenocortical adenoma, together comprising more than 50% of cases, while the malignant recipients include, besides clear cell renal carcinoma, colorectal, gastric and pancreatic adenocarcinomas, glioblastoma and endometrial and prostatic adenocarcinomas; in general, the recipient tumors are benign in 42% and malignant in 58% of cases [21]. Warthin tumor (WT) is the second most common benign salivary gland tumor occurring almost exclusively in the parotid gland, accounting for 15% of all its epithelial tumors [2]. Although it is included in the current WHO classification of salivary gland tumors as a true tumorous entity [2], its neoplastic origin has recently been questioned [25]. Tumors metastasizing to salivary glands are rare, comprising only about 5% of all their malignant neoplasms. Among the distant primaries, lung (especially, small cell type), breast and kidney carcinomas are the most common [2]. In addition, cutaneous
Corresponding author. Tel.: +420 495 832 548; fax: +420 495 832 004.
E-mail address: [email protected] (J. Laco). 0344-0338/$ - see front matter & 2009 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2009.06.013
squamous cell carcinoma and malignant melanoma may metastasize to the parotid gland as well [10,15,17,26]. We are not aware of any reported case of tumor-to-tumor metastasis with salivary gland tumor as a recipient.
Case reports Case 1 A 65-year-old polymorbid man presented at the time of diagnosis of lung adenocarcinoma (T4N2MX, left upper lobe, confirmed by computed tomography (CT) and by findings in cytologic smears from bronchial washing), with a painless freely movable swelling in the left parotideomasseteric area measuring 30 20 mm2. Ultrasound examination revealed a hypoechogenic mass measuring 25 15 mm2 in the left parotid gland. No cervical lymphadenopathy was present. The fine needle aspiration cytology (FNAC) examination of the lesion was not performed. During operation (left lateral parotidectomy), a tumor in the dorso-caudal part of the deep parotid lobe was identified, removed and sent together with the superficial lobe for microscopic examination. Staging CT examination revealed no lymphadenopathy in other anatomic areas (except for left hilar pulmonary lymph nodes) but showed an expansion in the right adrenal gland measuring 70 40 mm2, which was suspicious of primary adrenocortical carcinoma or metastatic carcinoma; the lesion was not biopsied. The patient was transferred to a regional hospital for adjuvant
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chemoradiotherapy (surgical treatment was not indicated) and was lost for further follow-up. Case 2 A 75-year-old man with unrelevant medical history presented with a six months-lasting painless swelling in the right parotideomasseteric area measuring 40 30 mm2. Ultrasound examination revealed a non-homogenous mass measuring 43 27 mm2 in the superficial lobe of the right parotid gland. No cervical lymphadenopathy was present. The FNAC examination was followed by right superficial parotidectomy. During operation, a tumor within the superficial parotid lobe was identified, removed and sent for microscopic examination. On the basis of microscopic findings in the parotidectomy specimen, staging CT examination was performed. It revealed a non-homogenous opacifying mass in the upper pole of left kidney measuring 65 59 mm2, which was suspicious of renal carcinoma. Right kidney showed no pathological changes. In addition, multiple lesions interpreted as metastases were detected in liver, in the lower lobe of right lung, in right adrenal gland and in lumbar vertebrae. No lymphadenopathy was found. All the findings were assessed as generalized primary renal carcinoma (T1bN0pM1), and palliative care with no surgical intervention was indicated.
Fig. 1. The cytologic smear shows polygonal cells with enlarged nuclei with ¨ pseudoinclusions and with bluish cytoplasm (May-Grunwal–Giemsa stain, original magnification 400 ).
Materials and methods + The air-dried smears were stained using the May-Grunwald–Giemsa method The specimens were immediately fixed in formalin, embedded in paraffin and routinely processed. Indirect immunohistochemistry using monoclonal/polyclonal antibodies against cytokeratins (CK) (clone AE1/AE3, 1:50), cytokeratin 7 (CK7) (clone OV-TL 12/30, 1:50), cytokeratin 20 (CK20) (clone Ks20.8, 1:25), epithelial membrane antigen (EMA) (clone E29, 1:800), carcinoembryonic antigen (CEA) (clone II-7, 1:800), CD10 (clone 56C6, 1:50), vimentin (clone V9, 1: 50), S100 protein (S100) (polyclonal, 1: 6,000), HMB45 (clone HMB45, 1:50), Melan A (clone A103, 1:200), prostatic specific antigen (PSA) (clone ER-PR8, 1:50) and thyroid transforming factor 1 (TTF1) (clone 8G7G3/1, 1:25) was performed. The source of CD10 was Novocastra (Newcastle, United Kingdom), the source of all other antibodies was Dako (Glostrup, Denmark). Antigen retrieval was performed in a water bath for 40 min at 97 1C in the target retrieval buffers at different pH values – at pH 6.0 (buffer S1700) for CK, CK20, CEA and S100, and at pH 9.9 (buffer S3308) for CD10 and PSA. For CK7, vimentin, Melan A and TTF-1, the tissue was processed in the microwave vacuum histoprocessor RHS 1 (Milestone) at pH 6.0 at 120 1C for 4 min. Endogenous peroxidase activity was inhibited by immersing the sections in 3% hydrogene peroxide. Finally, the sections were incubated with EnVision+ Dual Link System-HRP (Dako). The reaction was visualized using diaminobenzidine.
Results Case 1 The cytologic smears from bronchial washing showed clusters of polygonal cells with enlarged, slightly irregular nuclei with occasional pseudoinclusions and with bluish cytoplasm; their nucleocytoplasmic ratio was increased (Fig. 1). Grossly, the tumor was well-circumscribed and firm, measuring 30 25 20 mm3. On cross section, the lesion was of whitish
Fig. 2. Nests consisting of atypical cells with eosinophilic to clear cytoplasm (right) are close to slit-like spaces lined by oncocytic epithelium within lymphoid stroma (left) (HE, original magnification 400 ).
color and mainly solid with small cystic spaces at the periphery, filled with yellowish fluid. Microscopically, two different components were identified (Fig. 2). The main one consisted of solid, cribriform and/or tubular nests of irregular polygonal cells with occasional comedo-type necroses separated by desmoplastic stroma (Fig. 3a). The cells featured enlarged irregular nuclei with nucleoli and eosinophilic to clear cytoplasm. The mitotic rate reached 8–9 mitotic figures/10 HPF; atypical mitoses were present as well. In addition, peripherally, there were tubular, slit-like and cystopapillary structures lined by cytologically bland partially flattened, partially bi-layered oncocytic epithelium (Fig. 3b); in between, there was lymphoid tissue with occasional presence of small germ centers. Behind fibrous capsule of the lesion, there was a small rim of lipomatous serous salivary gland with no remarkable changes. Immunohistochemically, the malignant component showed diffuse expression of CK, CK7, EMA and TTF1, whereas the oncocytic epithelium displayed CK+/CK7+/EMA+/TTF1-profile (Fig. 3c, d). The proof of CK20, CEA, PSA, S100, HMB45 and Melan A was negative in both components. Interestingly, three incidentally found intraglandular lymph nodes in the superficial parotid lobe featured no metastatic involvement. Based on the histological appearance and immunohistochemical profile, the diagnosis of lung adenocarcinoma metastasizing to WT was established.
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Fig. 3. (a) Solid nests frequently displayed comedo-type necroses (HE, original magnification 400 ). (b) Tubular and cystic structures lined by bi-layered oncocytic epithelium within lymphoid stroma (HE, original magnification 400 ). (c) Diffuse expression of cytokeratin 7 in both components (original magnification 400 ). (d) Diffuse expression of thyroid transforming factor-1 in the clear cell component (bottom), while the oncocytic epithelium remains negative (top) (original magnification 400 ).
Fig. 4. Solid clear cell component with small areas of fresh hemorrhage (left) close to cystic structures with eosinophilic content within lymphoid stroma (HE, original magnification 200 ).
necroses were not identified. The second component consisted of tubular and cystopapillary formations lined by cytologically bland bi-layered oncocytic epithelium within lymphoid tissue containing occasional germ centers (Fig. 5b). Within the cystic spaces, eosinophilic proteinaceous material was seen. Immunohistochemically, the clear cell component showed diffuse expression of CK, EMA, CD10 (Fig. 5c) and vimentin, whereas CK7 staining was negative (Fig. 5d). The oncocytic epithelium of tubular and cystopapillary formations showed CK+/CK7+/EMA+ profile. The proof of CK20, CEA, PSA, TTF-1, S100, HMB-45 and Melan A was negative in both components. On microscopy, the piece of attached salivary gland tissue showed slightly lipomatous serous salivary gland with no other remarkable changes. Based on the histological appearance and immunohistochemical profile, the diagnosis of conventional clear cell renal carcinoma (grade III acc. Fuhrman) metastasizing to WT was established.
Case 2 Discussion Since the FNAC smears showed only blood, they were considered non-diagnostic. Grossly, the tumor was well-circumscribed, measuring 30 30 20 mm3. On cross section, the lesion was of light brownish color with multiple small cystic spaces. In addition, solid whitish foci with small areas of fresh hemorrhage were present throughout the tumor. A piece of salivary gland tissue measuring 20 10 10 mm3 was attached at one pole. Microscopically, two different lesions were intermingled throughout the lesion (Fig. 4). The first component consisted of solid formations of atypical cells with enlarged irregular vesicular nuclei with eosinophilic nucleoli evident at magnification 100 and with pale to clear cytoplasm (Fig. 5a). The mitotic rate reached 2–3 mitotic figures/10 HPF. Thin fibrous septa endowed by prominent sinusoid-like vessels separated the cells into large nests. Areas of fresh hemorrhage were frequently found, whereas
Tumor-to-tumor metastasis is an exceedingly rare event if the Campbell’s criteria are strictly followed [3]. These comprise: (i) presence of at least two primary tumors with the recipient being a true neoplasm; (ii) exclusion of direct ingrowth or tumor emboli and (iii) exclusion of metastatic tumor of lymph nodes involved by lymphoproliferative disease. While the last two criteria are undoubtely fulfilled in both of our cases, the first criterion requires additional comments on the true biologic nature of WT. Despite the fact that WT has been recognized for more than 100 years, its precise etiopathogenesis remains unclear. Regarding risk factors, only smoking has been accepted [11]. The interesting findings of the possible role of Epstein-Barr virus [12] and Kaposi sarcoma virus [4] (KSV, HHV-8) need to be elucidated by further studies.
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Fig. 5. (a) Solid component consisting of atypical cells with irregular nuclei and clear cytoplasm (HE, original magnification 400 ). (b) Cystic structures lined by bi-layered oncocytic epithelium within lymphoid stroma with a small germ center (HE, original magnification 400 ). (c) Diffuse expression of CD10 in the clear cell component (right), while oncocytic epithelium (left) is negative (original magnification 400 ). (d) Expression of cytokeratin 7 in oncocytic epithelium (top and left), while the clear cell component (bottom and right) remains negative (original magnification 400 ).
Although WT is currently listed in the WHO classification of salivary gland tumors [2] in the category of true benign neoplasms, the finding of polyclonality of both epithelial and stromal components has led some authors to the conclusion that WT should be regarded as a hyperplastic/reactive tumor-like condition arising from the embryonic inclusions of the salivary gland tissue in the intra- or peri-parotid lymph nodes [25]. However, it should be noted that polyclonality is still consistent with a true neoplastic origin of the lesion as demonstrated in more than twenty different tumor types [20]. Recently, several molecular studies have revealed important findings supporting the concept of the true neoplastic nature of WT by proof of t(11;19) reciprocal translocation, leading to the generation of a novel CRTC1/MECT1-MAML2 fusion oncogene [16]. Thus, it seems that WT may well be a heterogenous group of lesions with a different pathogenesis and clinical outcome as documented by occasional malignant transformation of WT, including mucoepidermoid carcinoma [23,27]. Since the lymphoid stroma of WT shares both microscopic and immunohistochemical features of normal or reactive lymph nodes, it may, although rarely, show changes commonly seen in lymph nodes, e.g. tuberculosis [18], granulomatous reactions seen after imaging procedures [9] or after FNAC [22], as well as lymphomas – both Hodgkin [1] and non-Hodgkin types. The latter include MALT-type lymphoma [14], diffuse large B-cell lymphoma [8], peripheral T-cell lymphoma, NOS [13], and, most commonly, low-grade follicular lymphoma [7,19]. These findings may support the hypothesis of nodal origin of WT. In our cases, the differential diagnosis is mainly with malignant transformation of a pre-existing WT. The epithelial component of WT may, following various insults (trauma, FNAC), exhibit squamous and/or goblet cell metaplasia [5]. These are harmless, benign changes which, however, may cytologically very closely mimic features of mucoepidermoid carcinoma, rarely reported to arise from WT [23], and cause a real diagnostic pitfall for the cytologist. The expression of TTF-1 and CD10 in the
malignant tissues in our cases, however, favors the metastatic pulmonary and renal nature, respectively, since primary tumors of salivary gland are always TTF-1 and CD10 negative. A metastasis of Warthin-like papillary thyroid carcinoma (PTC), which may show TTF-1 positivity, enters the differential diagnosis in Case 1 as well. However, the nuclear characteristics of the malignant cells were not diagnostic of PTC. In addition, ultrasound examination showed no lesion in the thyroid gland. In general, since the most frequent metastasizing malignancies include lung, breast, renal, colorectal and prostatic carcinomas and malignant melanoma, the immunohistochemical panel of CK, CK7, CK20, TTF1, estrogen and progesterone receptors, gross cystic disease fluid protein 15, CD10, vimentin, CDX-2, PSA, S100, HMB45 and Melan A will solve the issue in cases similar to ours in the vast majority of cases. In the herein presented cases, it is not possible to decide whether it represents lung, respectively renal carcinoma metastasizing to the, whatsoever small, pre-existing WT, or if the areas resembling WT have arisen from salivary gland inclusions in the lymph node as a reactive response to the metastatic deposits. Since the evolution of WT is typically very slow, we favor the former hypothesis. In addition, since the non-malignant tissue displayed in both cases tubular, slit-like and even cystopapillary formations lined by at least partially evident bi-layered oncocytic epithelium, we consider these findings adequate to fulfill the diagnostic criteria of WT. Why the three lymph nodes in the superficial parotid lobe in Case 1 were uninvolved by metastases remains unclear. In addition, the staging CT showed no lymphadenopathy in other anatomic areas, except for regional hilar lymph nodes of left lung. Thus, we can – based on these unique particular cases – only speculate that the presence of epithelial structures of WT within the lymph node stroma made it perhaps more susceptible to homing of circulating tumor cells of the lung and the renal carcinoma. In summary, we present previously unreported unique cases of tumor-to-tumor metastasis of lung and of renal carcinomas into WT. Whatever the true biologic dignity of WT may be, the herein presented findings can be regarded as stage pM1 of both the lung
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and the renal carcinoma for oncological and therapeutical purposes.
Acknowledgement Supported by Research project of the Ministry of Health of the Czech Republic No. 00179906. References [1] S. Badve, G. Evans, S. Mady, M. Coppen, J. Sloane, A case of Warthin0 s tumour with coexistent Hodgkin0 s disease, Histopathology 22 (1993) 280–281. [2] L. Barnes, J.W. Eveson, P. Reichart, D. Sidransky, WHO classification of tumours. Pathology and genetics, in: Head and Neck Tumours, IARCPress, Lyon, 2005, pp. 263–265 et 281. [3] L.V. Campbell Jr., E. Gilbert, C.R. Chamberlain Jr., A.L. Watne, Metastases of cancer to cancer, Cancer 22 (1968) 635–643. [4] E. Dalpa, V. Gourvas, S. Baritaki, S. Miyakis, V. Samaras, C. Barbatis, G. Sourvinos, D.A. Spandidos, High prevalence of human herpes virus 8 (HHV-8) in patients with Warthin0 s tumors of the salivary gland, J. Clin. Virol. 42 (2008) 182–185. [5] S. Di Palma, R.H. Simpson, A. Skalova, M. Michal, Metaplastic (infarcted) Warthin0 s tumour of the parotid gland: a possible consequence of fine needle aspiration biopsy, Histopathology 35 (1999) 432–438. [6] O. Fadare, V. Parkash, P.N. Fiedler, A.B. Mayerson, B. Asiyanbola, Tumor-totumor metastasis to a thyroid follicular adenoma as the initial presentation of a colonic adenocarcinoma, Pathol. Int. 5 (2005) 574–579. [7] R. Giardini, M. Mastore, Follicular non Hodgkin0 s lymphoma in adenolymphoma: report of a case, Tumori 76 (1990) 212–215. [8] S. Gorai, T. Numata, S. Kawada, M. Nakano, J. Tamaru, T. Kobayashi, Malignant lymphoma arising from heterotopic Warthin0 s tumor in the neck: case report a review of the literature, Tohoku J. Exp. Med. 212 (2007) 199–205. [9] K. Hamper, G. Seifert, Changes in the salivary glands following sialography. Differential diagnosis of granulomatous reactions, Pathologe 8 (1987) 65–72 (in German). [10] R.W. Hinerman, D.J. Indelicato, R.J. Amdur, C.G. Morris, J.W. Werning, M. Vaysberg, J. Kirwan, W.M. Mendenhall, Cutaneous squamous cell carcinoma metastatic to parotid-area lymph nodes, Laryngoscope 118 (2008) 1989–1996.
[11] C.A. Kotwall, Smoking as an etiologic factor in the development of Warthin0 s tumor of the parotid gland, Am. J. Surg. 164 (1992) 646–647. [12] C.J. Laane, A.H. Murr, A.N. Mhatre, K.D. Jones, A.K. Lalwani, Role of EpsteinBarr virus and cytomegalovirus in the etiology of benign parotid tumors, Head Neck 24 (2002) 443–450. [13] H.X. Liu, Y.M. Sun, Peripheral T-cell lymphoma, NOS arising in Warthin tumor: report of a case, Zhonghua Bing Li Xue Za Zhi 37 (2008) 425. [14] G. Marioni, R. Marchese-Ragona, F. Marino, A. Poletti, G. Ottaviano, C. de Filippis, A. Staffieri, MALT-type lymphoma and Warthin0 s tumour presenting in the same parotid gland, Acta Otolaryngol. 124 (2004) 318–323. [15] M. Mesa, J.L. Quesada, J. Pinas, Metastasis of amelanotic melanoma of unknown origin in the parotid gland, Br. J. Oral Maxillofac. Surg., in press. [16] I.D. O0 Neil, New insights into the nature of Warthin0 s tumour, J. Oral Pathol. Med. 38 (2009) 145–149. + ¨ E. Stauffer, P. Zbaren, Metastatic disease to the [17] M. Nuyens, J. Schupbach, parotid gland, Otolaryngol. Head Neck Surg. 135 (2006) 844–848. ¨ ¨ ur, ¨ Mycobacterium tuberculosis [18] C. Ozcan, D.D. Apa, G. Aslan, S. Gulhan, K. Gor infection within parotid gland Warthin tumor, J. Craniofac. Surg. 19 (2008) 1561–1565. [19] Ch.K. Park, J.T. Manning, H. Battifora, L.J. Medeiros, Follicle center lymphoma and Warthin tumor involving the same anatomic site, Am. J. Clin. Pathol. 113 (2000) 113–119. [20] B.L. Parsons, Many different tumor types have polyclonal tumor origin: evidence and implications, Mutat. Res. 659 (2008) 232–247. [21] J.F. Richardson, I. Katayama, Neoplasm to neoplasm metastasis. An acidophil adenoma harbouring metastatic carcinoma: a case report, Arch. Pathol. 91 (1971) 135–139. [22] A. Ryˇska, G. Seifert, Adenolymphoma (Warthin0 s tumor) with multiple sarcoid-like granulomas, Pathol. Res. Pract. 195 (1999) 835–839. [23] G. Seifert, Carcinomas in pre-existing Warthin tumors (cystadenolymphomas) of the parotid gland – classification, pathogenesis, differential diagnosis, Pathologe 18 (1997) 359–367 (in German). [24] A. Sella, J.Y. Ro, Renal cell cancer: best recipient of tumor-to-tumor metastasis, Urology 30 (1987) 35–38. [25] A. Teymoortash, J.A. Werner, Tissue that has lost its track: Warthin’s tumour, Virchows Arch. 446 (2005) 585–588. [26] M.J. Veness, S. Porceddu, C.E. Palme, G.J. Morgan, Cutaneous head and neck squamous cell carcinoma metastatic to parotid and cervical lymph nodes, Head Neck 29 (2007) 621–631. [27] J.D. Williamson, B.H. Simmons, A. el-Naggar, L.J. Medeiros, Mucoepidermoid carcinoma involving Warthin tumor. A report of five cases and review of the literature, Am. J. Clin. Pathol. 114 (2000) 564–570.
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.de/prp
Teaching cases
Tumor-to-tumor metastasis: Warthin tumor as a recipient of lung carcinoma and of renal carcinoma – Report of two cases Jan Laco a,, Petr Celakovsky b, David Kalfert b, Helena Hornychova a, Tomas Rybnikar b, Ales Ryska a a b
The Fingerland Department of Pathology, Charles University Faculty of Medicine and Faculty Hospital in Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic Department of Otorhinolaryngology, Charles University Faculty of Medicine and Faculty Hospital in Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
a r t i c l e in f o
S u m m a r y
Article history: Received 2 March 2009 Received in revised form 2 June 2009 Accepted 25 June 2009
Tumor-to-tumor metastasis is an exceedingly rare event with only about 100 cases reported in the English written literature. We report two cases of a 65-year-old man with duplicity of colonic and lung adenocarcinomas who presented with swelling of the left parotid gland, and of a 75-year-old man who presented with swelling of the right parotid gland. Microscopical and immunohistochemical examination showed metastasis of lung carcinoma and of renal carcinoma, respectively, to Warthin tumor as the first clinical manifestation of the malignancy in the latter case. To the best of our knowledge, such a phenomenon has not been reported so far. & 2009 Elsevier GmbH. All rights reserved.
Keywords: Tumor-to-tumor metastasis Warthin tumor Lung carcinoma Renal carcinoma Secondary tumors
Introduction Tumor-to-tumor metastasis is considered an extremely uncommon event with approximately 100 cases reported in the English written literature [6]. The most frequent donor malignancy is lung carcinoma, while the most frequent malignant recipient appears to be clear cell renal carcinoma [24]. Benign recipient tumors include mainly follicular adenoma of thyroid gland and adrenocortical adenoma, together comprising more than 50% of cases, while the malignant recipients include, besides clear cell renal carcinoma, colorectal, gastric and pancreatic adenocarcinomas, glioblastoma and endometrial and prostatic adenocarcinomas; in general, the recipient tumors are benign in 42% and malignant in 58% of cases [21]. Warthin tumor (WT) is the second most common benign salivary gland tumor occurring almost exclusively in the parotid gland, accounting for 15% of all its epithelial tumors [2]. Although it is included in the current WHO classification of salivary gland tumors as a true tumorous entity [2], its neoplastic origin has recently been questioned [25]. Tumors metastasizing to salivary glands are rare, comprising only about 5% of all their malignant neoplasms. Among the distant primaries, lung (especially, small cell type), breast and kidney carcinomas are the most common [2]. In addition, cutaneous
Corresponding author. Tel.: +420 495 832 548; fax: +420 495 832 004.
E-mail address: [email protected] (J. Laco). 0344-0338/$ - see front matter & 2009 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2009.06.013
squamous cell carcinoma and malignant melanoma may metastasize to the parotid gland as well [10,15,17,26]. We are not aware of any reported case of tumor-to-tumor metastasis with salivary gland tumor as a recipient.
Case reports Case 1 A 65-year-old polymorbid man presented at the time of diagnosis of lung adenocarcinoma (T4N2MX, left upper lobe, confirmed by computed tomography (CT) and by findings in cytologic smears from bronchial washing), with a painless freely movable swelling in the left parotideomasseteric area measuring 30 20 mm2. Ultrasound examination revealed a hypoechogenic mass measuring 25 15 mm2 in the left parotid gland. No cervical lymphadenopathy was present. The fine needle aspiration cytology (FNAC) examination of the lesion was not performed. During operation (left lateral parotidectomy), a tumor in the dorso-caudal part of the deep parotid lobe was identified, removed and sent together with the superficial lobe for microscopic examination. Staging CT examination revealed no lymphadenopathy in other anatomic areas (except for left hilar pulmonary lymph nodes) but showed an expansion in the right adrenal gland measuring 70 40 mm2, which was suspicious of primary adrenocortical carcinoma or metastatic carcinoma; the lesion was not biopsied. The patient was transferred to a regional hospital for adjuvant
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chemoradiotherapy (surgical treatment was not indicated) and was lost for further follow-up. Case 2 A 75-year-old man with unrelevant medical history presented with a six months-lasting painless swelling in the right parotideomasseteric area measuring 40 30 mm2. Ultrasound examination revealed a non-homogenous mass measuring 43 27 mm2 in the superficial lobe of the right parotid gland. No cervical lymphadenopathy was present. The FNAC examination was followed by right superficial parotidectomy. During operation, a tumor within the superficial parotid lobe was identified, removed and sent for microscopic examination. On the basis of microscopic findings in the parotidectomy specimen, staging CT examination was performed. It revealed a non-homogenous opacifying mass in the upper pole of left kidney measuring 65 59 mm2, which was suspicious of renal carcinoma. Right kidney showed no pathological changes. In addition, multiple lesions interpreted as metastases were detected in liver, in the lower lobe of right lung, in right adrenal gland and in lumbar vertebrae. No lymphadenopathy was found. All the findings were assessed as generalized primary renal carcinoma (T1bN0pM1), and palliative care with no surgical intervention was indicated.
Fig. 1. The cytologic smear shows polygonal cells with enlarged nuclei with ¨ pseudoinclusions and with bluish cytoplasm (May-Grunwal–Giemsa stain, original magnification 400 ).
Materials and methods + The air-dried smears were stained using the May-Grunwald–Giemsa method The specimens were immediately fixed in formalin, embedded in paraffin and routinely processed. Indirect immunohistochemistry using monoclonal/polyclonal antibodies against cytokeratins (CK) (clone AE1/AE3, 1:50), cytokeratin 7 (CK7) (clone OV-TL 12/30, 1:50), cytokeratin 20 (CK20) (clone Ks20.8, 1:25), epithelial membrane antigen (EMA) (clone E29, 1:800), carcinoembryonic antigen (CEA) (clone II-7, 1:800), CD10 (clone 56C6, 1:50), vimentin (clone V9, 1: 50), S100 protein (S100) (polyclonal, 1: 6,000), HMB45 (clone HMB45, 1:50), Melan A (clone A103, 1:200), prostatic specific antigen (PSA) (clone ER-PR8, 1:50) and thyroid transforming factor 1 (TTF1) (clone 8G7G3/1, 1:25) was performed. The source of CD10 was Novocastra (Newcastle, United Kingdom), the source of all other antibodies was Dako (Glostrup, Denmark). Antigen retrieval was performed in a water bath for 40 min at 97 1C in the target retrieval buffers at different pH values – at pH 6.0 (buffer S1700) for CK, CK20, CEA and S100, and at pH 9.9 (buffer S3308) for CD10 and PSA. For CK7, vimentin, Melan A and TTF-1, the tissue was processed in the microwave vacuum histoprocessor RHS 1 (Milestone) at pH 6.0 at 120 1C for 4 min. Endogenous peroxidase activity was inhibited by immersing the sections in 3% hydrogene peroxide. Finally, the sections were incubated with EnVision+ Dual Link System-HRP (Dako). The reaction was visualized using diaminobenzidine.
Results Case 1 The cytologic smears from bronchial washing showed clusters of polygonal cells with enlarged, slightly irregular nuclei with occasional pseudoinclusions and with bluish cytoplasm; their nucleocytoplasmic ratio was increased (Fig. 1). Grossly, the tumor was well-circumscribed and firm, measuring 30 25 20 mm3. On cross section, the lesion was of whitish
Fig. 2. Nests consisting of atypical cells with eosinophilic to clear cytoplasm (right) are close to slit-like spaces lined by oncocytic epithelium within lymphoid stroma (left) (HE, original magnification 400 ).
color and mainly solid with small cystic spaces at the periphery, filled with yellowish fluid. Microscopically, two different components were identified (Fig. 2). The main one consisted of solid, cribriform and/or tubular nests of irregular polygonal cells with occasional comedo-type necroses separated by desmoplastic stroma (Fig. 3a). The cells featured enlarged irregular nuclei with nucleoli and eosinophilic to clear cytoplasm. The mitotic rate reached 8–9 mitotic figures/10 HPF; atypical mitoses were present as well. In addition, peripherally, there were tubular, slit-like and cystopapillary structures lined by cytologically bland partially flattened, partially bi-layered oncocytic epithelium (Fig. 3b); in between, there was lymphoid tissue with occasional presence of small germ centers. Behind fibrous capsule of the lesion, there was a small rim of lipomatous serous salivary gland with no remarkable changes. Immunohistochemically, the malignant component showed diffuse expression of CK, CK7, EMA and TTF1, whereas the oncocytic epithelium displayed CK+/CK7+/EMA+/TTF1-profile (Fig. 3c, d). The proof of CK20, CEA, PSA, S100, HMB45 and Melan A was negative in both components. Interestingly, three incidentally found intraglandular lymph nodes in the superficial parotid lobe featured no metastatic involvement. Based on the histological appearance and immunohistochemical profile, the diagnosis of lung adenocarcinoma metastasizing to WT was established.
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Fig. 3. (a) Solid nests frequently displayed comedo-type necroses (HE, original magnification 400 ). (b) Tubular and cystic structures lined by bi-layered oncocytic epithelium within lymphoid stroma (HE, original magnification 400 ). (c) Diffuse expression of cytokeratin 7 in both components (original magnification 400 ). (d) Diffuse expression of thyroid transforming factor-1 in the clear cell component (bottom), while the oncocytic epithelium remains negative (top) (original magnification 400 ).
Fig. 4. Solid clear cell component with small areas of fresh hemorrhage (left) close to cystic structures with eosinophilic content within lymphoid stroma (HE, original magnification 200 ).
necroses were not identified. The second component consisted of tubular and cystopapillary formations lined by cytologically bland bi-layered oncocytic epithelium within lymphoid tissue containing occasional germ centers (Fig. 5b). Within the cystic spaces, eosinophilic proteinaceous material was seen. Immunohistochemically, the clear cell component showed diffuse expression of CK, EMA, CD10 (Fig. 5c) and vimentin, whereas CK7 staining was negative (Fig. 5d). The oncocytic epithelium of tubular and cystopapillary formations showed CK+/CK7+/EMA+ profile. The proof of CK20, CEA, PSA, TTF-1, S100, HMB-45 and Melan A was negative in both components. On microscopy, the piece of attached salivary gland tissue showed slightly lipomatous serous salivary gland with no other remarkable changes. Based on the histological appearance and immunohistochemical profile, the diagnosis of conventional clear cell renal carcinoma (grade III acc. Fuhrman) metastasizing to WT was established.
Case 2 Discussion Since the FNAC smears showed only blood, they were considered non-diagnostic. Grossly, the tumor was well-circumscribed, measuring 30 30 20 mm3. On cross section, the lesion was of light brownish color with multiple small cystic spaces. In addition, solid whitish foci with small areas of fresh hemorrhage were present throughout the tumor. A piece of salivary gland tissue measuring 20 10 10 mm3 was attached at one pole. Microscopically, two different lesions were intermingled throughout the lesion (Fig. 4). The first component consisted of solid formations of atypical cells with enlarged irregular vesicular nuclei with eosinophilic nucleoli evident at magnification 100 and with pale to clear cytoplasm (Fig. 5a). The mitotic rate reached 2–3 mitotic figures/10 HPF. Thin fibrous septa endowed by prominent sinusoid-like vessels separated the cells into large nests. Areas of fresh hemorrhage were frequently found, whereas
Tumor-to-tumor metastasis is an exceedingly rare event if the Campbell’s criteria are strictly followed [3]. These comprise: (i) presence of at least two primary tumors with the recipient being a true neoplasm; (ii) exclusion of direct ingrowth or tumor emboli and (iii) exclusion of metastatic tumor of lymph nodes involved by lymphoproliferative disease. While the last two criteria are undoubtely fulfilled in both of our cases, the first criterion requires additional comments on the true biologic nature of WT. Despite the fact that WT has been recognized for more than 100 years, its precise etiopathogenesis remains unclear. Regarding risk factors, only smoking has been accepted [11]. The interesting findings of the possible role of Epstein-Barr virus [12] and Kaposi sarcoma virus [4] (KSV, HHV-8) need to be elucidated by further studies.
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Fig. 5. (a) Solid component consisting of atypical cells with irregular nuclei and clear cytoplasm (HE, original magnification 400 ). (b) Cystic structures lined by bi-layered oncocytic epithelium within lymphoid stroma with a small germ center (HE, original magnification 400 ). (c) Diffuse expression of CD10 in the clear cell component (right), while oncocytic epithelium (left) is negative (original magnification 400 ). (d) Expression of cytokeratin 7 in oncocytic epithelium (top and left), while the clear cell component (bottom and right) remains negative (original magnification 400 ).
Although WT is currently listed in the WHO classification of salivary gland tumors [2] in the category of true benign neoplasms, the finding of polyclonality of both epithelial and stromal components has led some authors to the conclusion that WT should be regarded as a hyperplastic/reactive tumor-like condition arising from the embryonic inclusions of the salivary gland tissue in the intra- or peri-parotid lymph nodes [25]. However, it should be noted that polyclonality is still consistent with a true neoplastic origin of the lesion as demonstrated in more than twenty different tumor types [20]. Recently, several molecular studies have revealed important findings supporting the concept of the true neoplastic nature of WT by proof of t(11;19) reciprocal translocation, leading to the generation of a novel CRTC1/MECT1-MAML2 fusion oncogene [16]. Thus, it seems that WT may well be a heterogenous group of lesions with a different pathogenesis and clinical outcome as documented by occasional malignant transformation of WT, including mucoepidermoid carcinoma [23,27]. Since the lymphoid stroma of WT shares both microscopic and immunohistochemical features of normal or reactive lymph nodes, it may, although rarely, show changes commonly seen in lymph nodes, e.g. tuberculosis [18], granulomatous reactions seen after imaging procedures [9] or after FNAC [22], as well as lymphomas – both Hodgkin [1] and non-Hodgkin types. The latter include MALT-type lymphoma [14], diffuse large B-cell lymphoma [8], peripheral T-cell lymphoma, NOS [13], and, most commonly, low-grade follicular lymphoma [7,19]. These findings may support the hypothesis of nodal origin of WT. In our cases, the differential diagnosis is mainly with malignant transformation of a pre-existing WT. The epithelial component of WT may, following various insults (trauma, FNAC), exhibit squamous and/or goblet cell metaplasia [5]. These are harmless, benign changes which, however, may cytologically very closely mimic features of mucoepidermoid carcinoma, rarely reported to arise from WT [23], and cause a real diagnostic pitfall for the cytologist. The expression of TTF-1 and CD10 in the
malignant tissues in our cases, however, favors the metastatic pulmonary and renal nature, respectively, since primary tumors of salivary gland are always TTF-1 and CD10 negative. A metastasis of Warthin-like papillary thyroid carcinoma (PTC), which may show TTF-1 positivity, enters the differential diagnosis in Case 1 as well. However, the nuclear characteristics of the malignant cells were not diagnostic of PTC. In addition, ultrasound examination showed no lesion in the thyroid gland. In general, since the most frequent metastasizing malignancies include lung, breast, renal, colorectal and prostatic carcinomas and malignant melanoma, the immunohistochemical panel of CK, CK7, CK20, TTF1, estrogen and progesterone receptors, gross cystic disease fluid protein 15, CD10, vimentin, CDX-2, PSA, S100, HMB45 and Melan A will solve the issue in cases similar to ours in the vast majority of cases. In the herein presented cases, it is not possible to decide whether it represents lung, respectively renal carcinoma metastasizing to the, whatsoever small, pre-existing WT, or if the areas resembling WT have arisen from salivary gland inclusions in the lymph node as a reactive response to the metastatic deposits. Since the evolution of WT is typically very slow, we favor the former hypothesis. In addition, since the non-malignant tissue displayed in both cases tubular, slit-like and even cystopapillary formations lined by at least partially evident bi-layered oncocytic epithelium, we consider these findings adequate to fulfill the diagnostic criteria of WT. Why the three lymph nodes in the superficial parotid lobe in Case 1 were uninvolved by metastases remains unclear. In addition, the staging CT showed no lymphadenopathy in other anatomic areas, except for regional hilar lymph nodes of left lung. Thus, we can – based on these unique particular cases – only speculate that the presence of epithelial structures of WT within the lymph node stroma made it perhaps more susceptible to homing of circulating tumor cells of the lung and the renal carcinoma. In summary, we present previously unreported unique cases of tumor-to-tumor metastasis of lung and of renal carcinomas into WT. Whatever the true biologic dignity of WT may be, the herein presented findings can be regarded as stage pM1 of both the lung
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and the renal carcinoma for oncological and therapeutical purposes.
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