Amyloid-Rich Low Grade Adenocarcinoma of the Parotid: Fine-Needle Aspiration Cytology With Histologic Correlations Grace C. H. Yang, M.D., F.I.A.C.,1* William I. Kuhel, M.D.,2 and Theresa Scognamiglio, M.D.1
Amyloid deposits are unexpected in salivary gland tumors. A 60year-old woman presented with a 1.8 cm, slow-growing parotid mass. Both fine-needle aspiration and frozen section were misinterpreted as pleomorphic adenoma. The final pathology was amyloid-rich low grade adenocarcinoma of the parotid gland. The aspirates consisted of three components: mucin, amyloid, and tumor cells. The mucin was unusually thick, stringy, and metachromatic. The amyloid presented as innumerable concretions scattered solitarily or in small jigsaw puzzle-like aggregates, individually wrapped by tumor cells. The tumor cells had bland oval nuclei and scant-to-abundant cytoplasm, arranged in loosely cohesive small sheets. On histology, the tumor cells were arranged in interconnecting monolayered glands of a wide range of size with small patches of cellular regions composed of plump tumor cells. As the luminal mucin and amyloid deposits enlarged, the lining tumor cells became thin and flat. The glandular lumen molded amyloid concretions into different shapes and sizes. Atrophic or pyknotic tumor cells outlined the amyloid concretions with concentric laminations, reminiscent of corpora amylacea. Alcian blue positive luminal mucin, associated with newly formed amyloid, was present in mucinous regions of the tumor. This is the first description of cytologic features of amyloid-rich low grade adenocarcinoma of the parotid and the second case in the pathology literature. The literature of amyloidrich tumors was reviewed and the implication of the presence of abundant amyloid on the death of tumor cells suggested.
1 Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York 2 Department of Otorhinolaryngology, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York *Correspondence to: Grace C. H. Yang, MD, Papanicolaou Cytology Laboratory, New York Presbyterian Hospital-Weill Cornell Medical Center, 525 East 68 Street, Suite F-766, New York, NY 10065, USA. E-mail: [email protected] Received 3 July 2013; Revised 10 October 2013; Accepted 9 January 2014 DOI: 10.1002/dc.23099 Published online 18 February 2014 in Wiley Online Library (wileyonlinelibrary.com).
798
Diagnostic Cytopathology, Vol. 42, No 9
Diagn. Cytopathol. 2014;42:798–801.
C 2014 Wiley Periodicals, V
Inc.
Key Words: amyloid; salivary gland neoplasm; corpora amylacea; Cell death; low grade adenocarcinoma of parotid
Amyloid deposits are unexpected in salivary gland tumors. We recently encountered a case of amyloid-rich low grade adenocarcinoma of the parotid gland, misdiagnosed as pleomorphic adenoma in both fine-needle aspiration (FNA) cytology and frozen section, and would like to share our experience. This is the second such case in the pathology literature and the first description of cytopathologic features of this tumor.
Case History A 60-year-old woman was incidentally found to have a 1.8 cm left parotid mass on a CT scan of the paranasal sinuses that was obtained for evaluation of chronic sinusitis. An MR of the neck performed 18 months later demonstrated that the parotid mass was 1.4 cm and heterogeneous. Ultrasound demonstrated a 1.9 cm hypoechoic, well-circumscribed mass with partially calcified rim. An ultrasound-guided FNA was performed and airR stain (Dade dried aspirate smears stained with Diff-QuikV Behring, Newark, DE) and Ultrafast Papanicolaou stain (Richard-Allan, Kalamazoo, MI).1 The FNA diagnosis was pleomorphic adenoma with cylindromatous stroma. The FNA was described having epithelial cells with abundant cytoplasm and bland nuclei in sheets associated with innumerable blue cylindromatous stroma and metachromatic chondroid myxoid stroma. The parotid mass was resected by means of a partial parotidectomy with dissection and preservation of the C 2014 WILEY PERIODICALS, INC. V
Diagnostic Cytopathology DOI 10.1002/dc
AMYLOID-RICH LOW GRADE ADENOCARCINOMA OF THE PAROTID
Fig. 1. Cytologic features of amyloid-rich low grade adenocarcinoma of the parotid. A: Innumerable dark blue amyloid concretions mixed with wisps of metachromatic mucin were observed at low magnification. FNA smear, Diff-Quik 403. B: Tumor cells (arrows) intimately associated with metachromatic mucin and rigid, dark blue aggregates of amyloid concretions. FNA smear, Diff-Quik 1003. C:Tumor cells associated with abnormally thick strands of metachromatic mucin. Inset: plump tumor cells. FNA smear, Diff-Quik 1003, inset: 4003. D: Numerous dark amyloid concretions, scattered singly or in jigsaw puzzle-like aggregates (arrow). Wisps of translucent violet mucin were present in the background. Inset: amyloid concretion, incompletely coated with pyknotic tumor cells. FNA smear, Ultrafast Papanicolaou 403 inset: 4003. E: At medium magnification jigsaw puzzle-like aggregates of amyloid concretions found to be within glandular lumens, associated with loosely cohesive tumor cells, separated by smearing. Note the wisps of translucent violet mucin in the background. FNA smear, Ultrafast Papanicolaou 1003. F: A naked, irregular shaped, blue amyloid concretion with concentric lamination (arrow) and a dark brown amyloid concretion, associated with tumor cells at the top and thin strands of mucin at the bottom. The tumor cells with bland oval nuclei in this area had variable amount of cytoplasm, ranged from scanty to abundant. FNA smear, Ultrafast Papanicolaou 4003. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
facial nerve. The surgical pathology laboratory received a 5.0 cm 3 2.5 cm 3 2.0 cm salivary gland tissue with attached fat. The specimen was sectioned to reveal a 1.7 cm 3 1.5 cm 3 1.2 cm well-circumscribed, firm, tan mass with a variegated cut surface. One representative section was submitted for frozen section, which was reported as pleomorphic adenoma. Examination of the paraffin-fixed permanent sections showed findings that were diagnostic for an amyloid-rich low grade adenocarcinoma with 0.6 cm microinvasion at the periphery of the main tumor. The surgical margin was clean and there was no lymphovascular invasion. A skull base-to-thigh positron emission tomographyoˆ– computed tomography (PET/CT) scan that was obtained one month after the surgery did not show evidence of persistent disease at the primary site or any evidence of regional or distant metastases. The patient underwent radiation therapy for three months and was doing well without complaints at follow-up examination by the surgeon.
Cytological Findings The aspirates consisted of three components: mucin, amyloid, and tumor cells. On Diff-Quik stained FNA smears, the dark
blue substance, thought to be cylindromatous stroma, was amyloid concretions (Fig. 1A). The metachromatic substance, thought to be chondroid myxoid stroma, was abnormally thick stringy mucin (Figs. 1A–C). The epithelial cells with abundant cytoplasm and bland nuclei (Fig. 1C inset), thought to be plasmacytoid myoepithelial cells, were low grade adenocarcinoma cells. On Ultrafast Papanicolaou stained FNA smears, there were numerous amyloid concretions, wrapped by tumor cells, scattered singly and in jigsaw-puzzled like aggregates, mixed with wisps of purple mucin (Fig. 1D). The smaller amyloid concretions were laminated, and stained light blue (Fig. 1E), while the larger thicker amyloid concretions stained dark with bluish-brown hue (Fig. 1E). On higher magnification, the wisps of purple mucin becomes more conspicuous and the neoplastic epithelial cells were arranged in loosely cohesive small monolayered sheets with bland nuclei and abundant cytoplasm (Fig. 1F).
Histopathologic Findings The tumor was well-circumscribed with pushing growth pattern (Fig. 2A). Interconnecting monolayered glands ranging from minute to gigantic were demonstrated by cytokeratin immunostain. Diagnostic Cytopathology, Vol. 42, No 9
799
Diagnostic Cytopathology DOI 10.1002/dc
YANG ET AL.
Fig. 2. Histologic features of amyloid-rich low grade adenocarcinoma of the parotid. A: Frozen section showed circumscribed pale tumor. Tissue section, H&E 203. B: Comparison of region 1 with minimal disruption of cytokeratin positive tumor cells and region 2 with extensive disruption of cytokeratin positive tumor cells. Note several naked amyloid concretions (*), devoid of cytokeratin positive tumor cells. Also note the patches of cellular regions, composed of densely packed small glands. AE1/AE3 cytokeratin immunohistochemistry, 403. C: The main tumor is composed of thin or atrophic glands engorged with luminal amyloid concretions. Inset: atrophic gland, lined by a few pyknotic nuclei surrounding the luminal amyloid concretion. Tissue section, H&E 1003. D: Deeper section revealed tumor pushing into parotid acini with desmoplastic reaction and heavy inflammatory response from lymphocytes (*). Tissue section, H&E 203. E: The invasive part of the tumor is composed of minute amyloid deposits surrounded by plump viable tumor cells. Some glands contained scalloped luminal eosinophilic amyloid deposit (*), suggesting fibrillogenesis. Tissue section, H&E 4003. F: Transition from cellular region to mucin and amyloid rich region. (1) Cellular region with plump tumor cells with abundant cytoplasm and the beginning of small luminal mucin. (2–3) Mucinous region with newly formed amyloid concretions. The mucin was alcian blue positive, but mucicarmine negative. The amyloid concretions were periodic acid Schiff (PAS) positive and Congo red positive with concentric fibrillary apple green birefringience under polarized light. Tissue section, 1003, F1–F2: H&E, F3: Alcian blue/PAS, F4: Congo red. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
The densely packed minute glands represented the cellular region. Many areas showed the disappearance of coating tumor cells around amyloid concretions (Fig. 2B2). The main tumor was pale, due to luminal amyloid deposition and compressed thin glands, barely visible at scanning magnification (Fig. 2C). Deeper cut revealed a 0.6 cm focus of invasion with desmoplastic reaction and heavy lymphocytic infiltration (Fig. 2D). Invasive portion of the tumor contained plump tumor cells with minute luminal amyloid deposits with scalloped edge (Fig. 2E). The tumor cells in the cellular region were plump with abundant cytoplasm (Fig. 2F1). The tumor cells in the mucinous region and amyloid-rich region were flat and as thin as the nucleus (Fig. 2F2). The abnormal mucin stained pale pink on hematoxylin and eosin and was alcian blue positive (Fig. 2F3) but mucicarmine negative. The amyloid deposits stained positive with Congo red and exhibited apple green concentric fibrillary birefringience under cross-polarizing filters (Fig. 2F4).
Discussion Massive deposition of b-fibrillary bodies (i.e., amyloid) within the lumen of low grade adenocarcinoma of the 800
Diagnostic Cytopathology, Vol. 42, No 9
parotid gland was first reported in 1983 by David and Kim.2 The 5 cm tumor was excised from a 68-year-old African-American man who remained free of disease two years post-treatment. Amyloid has also been reported in acinic cell carcinoma3,4 and Warthin’s tumor5 of the parotid gland, and tubular carcinoma of palate minor salivary gland.6 Salivary gland tumors with numerous psammoma bodies, morphologically similar to amyloid concretions, were reported. However, no Congo red stain was performed in these cases. This included a case of unusually slow growing oncocytic adenoma of the parotid in the histopathology literature,7 and two cases of acinic cell carcinoma in the cytopathology literature.8,9 David and Kim2 proposed that amyloid deposition of low grade adenocarcinoma of the parotid resulted from apoptosis of tumor cells, with progressive release and confluence of cytoplasmic intermediate filaments. More recently, Drut and Gimenez4 also proposed that the globular amyloid deposits in a 5 cm acinic cell carcinoma of the parotid resulted from the accumulation of residual masses of apoptotic tumor cells. We have an alternative hypothesis, and propose that amyloid deposition occurred prior to cell death and amyloid deposition induced tumor
Diagnostic Cytopathology DOI 10.1002/dc
AMYLOID-RICH LOW GRADE ADENOCARCINOMA OF THE PAROTID
cell death for the following two reasons. First, the presence of minute amyloid deposits within the lumen of plump, viable tumor cells with no sign of degeneration (Fig. 2E). Second, amyloid-like fibrils may not be amyloid, such as Congo red-negative fibrillary glomerulopathy.10 Prior authors cited the ultrastructural similarity of amyloid fibrils and cytoplasmic fibrils as evidence that amyloid deposits were derived from dying cells.2,4 Amyloid fibrils are inappropriately folded versions of endogenous proteins and polypeptides present naturally in the body, or endogenous proteins or peptides secreted by tumor. In addition to medullary thyroid carcinoma that produce amyloid resulted from inappropriately folded calcitonin,11 other amyloid-producing tumors include calcifying epithelial odontogenic tumors that secrete inappropriately folded ameloblastin,12 pituitary adenomas that secrete inappropriately folded growth hormone13 or prolactin,14 and B-cell lymphoproliferative disorders that secrete inappropriately folded light chain.15 In conclusion, we propose the sequence of events in this tumor as follows. Tumor cells secreted inappropriate folded luminal mucin which became amyloid. Continual expansion of luminal amyloid caused tumor cell death. Amyloidinduced cell death impeded the aggressiveness of tumor.
References
3. Ellis GL, Auclair PL. Tumors of the salivary glands. Atlas of tumor pathology. Third series. Fascicle 17. Washington, DC: AFIP; 1996. p 197. 4. Drut R, Gimenez PO. Acinic cell carcinoma of salivary gland with massive deposits of globular amyloid. Int J Surg Pathol 2008;16: 202–207. 5. David R, Buchner A. Corpora amylacea in adenolymphoma (Warthin’s tumor). Am J Clin Pathol 1978;69:173–175. 6. David R, Buchner A. Amyloid stroma in a tubular carcinoma of palatal salivary gland: A histochemical and ultrastructural study. Cancer 1978;41:1836–1844. 7. Feiner HD, Goldstein S, Ittman M, Pelton K, Jacobs J. Oncocytic adenoma of the parotid gland with psammoma bodies. Arch Pathol Lab Med 1986;110:640–644. 8. Bottles K, Lowhagen T. Psammoma bodies in the aspiration cytology smears of an acinic-cell tumor. Acta Cytol 1985;29:191–192. 9. Whitlatch SP. Psammoma bodies in fine-needle aspiration biopsies of acinic cell tumor. Diagn Cytopathol 1986;2:268–269. 10. Yang GCH, Nieto R, Stachura I, Gallo GR. Ultrastructural immunohistochemical localization of polyclonal IgG, C3, and amyloid P component on the Congo red-negative amyloid-like fibrils of fibrillary glomerulopathy. Am J Pathol 1992;141:409–419. 11. Sletten K, Westermark P, Natvig JB. Characterization of amyloid fibril proteins from medullary carcinoma of the thyroid. J Exp Med 1976;143:993–998. 12. Murphy CL, Kestler DP, Foster JS, et al. Odontogenic ameloblastassociated protein nature of the amyloid found in calcifying epithelial odontogenic tumors and unerupted tooth follicles. Amyloid 2008;15:89–95. 13. Iwase T, Nishizawa S, Baba S, et al. Intrasellar neuronal choristoma associated with growth hormone-producing pituitary adenoma containing amyloid deposits. Hum Pathol. 1995;26:925– 928.
1. Yang GCH, Alvarez II. Ultrafast Papanicolaou stain: An alternative preparation for fine-needle aspiration cytology. Acta Cytol 1995;39: 55–60.
14. Wiesli P, Br€andle M, Brandner S, Kollias SS, Bernays RL. Extensive spherical amyloid deposition presenting as a pituitary tumor. J Endocrinol Invest 2003;26:552–555.
2. David R, Kim KM. Beta-fibrillary bodies in low-grade adenocarcinoma of parotid gland: A histochemical and ultrastructural study. Hum Pathol 1982;13:1028–1035.
15. Hemmer PR, Topazian MD, Gertz MA, Abraham SC. Globular amyloid deposits isolated to the small bowel: A rare association with AL amyloidosis. Am J Surg Pathol 2007;31:141–145.
Diagnostic Cytopathology, Vol. 42, No 9
801
Amyloid deposits are unexpected in salivary gland tumors. A 60year-old woman presented with a 1.8 cm, slow-growing parotid mass. Both fine-needle aspiration and frozen section were misinterpreted as pleomorphic adenoma. The final pathology was amyloid-rich low grade adenocarcinoma of the parotid gland. The aspirates consisted of three components: mucin, amyloid, and tumor cells. The mucin was unusually thick, stringy, and metachromatic. The amyloid presented as innumerable concretions scattered solitarily or in small jigsaw puzzle-like aggregates, individually wrapped by tumor cells. The tumor cells had bland oval nuclei and scant-to-abundant cytoplasm, arranged in loosely cohesive small sheets. On histology, the tumor cells were arranged in interconnecting monolayered glands of a wide range of size with small patches of cellular regions composed of plump tumor cells. As the luminal mucin and amyloid deposits enlarged, the lining tumor cells became thin and flat. The glandular lumen molded amyloid concretions into different shapes and sizes. Atrophic or pyknotic tumor cells outlined the amyloid concretions with concentric laminations, reminiscent of corpora amylacea. Alcian blue positive luminal mucin, associated with newly formed amyloid, was present in mucinous regions of the tumor. This is the first description of cytologic features of amyloid-rich low grade adenocarcinoma of the parotid and the second case in the pathology literature. The literature of amyloidrich tumors was reviewed and the implication of the presence of abundant amyloid on the death of tumor cells suggested.
1 Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York 2 Department of Otorhinolaryngology, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York *Correspondence to: Grace C. H. Yang, MD, Papanicolaou Cytology Laboratory, New York Presbyterian Hospital-Weill Cornell Medical Center, 525 East 68 Street, Suite F-766, New York, NY 10065, USA. E-mail: [email protected] Received 3 July 2013; Revised 10 October 2013; Accepted 9 January 2014 DOI: 10.1002/dc.23099 Published online 18 February 2014 in Wiley Online Library (wileyonlinelibrary.com).
798
Diagnostic Cytopathology, Vol. 42, No 9
Diagn. Cytopathol. 2014;42:798–801.
C 2014 Wiley Periodicals, V
Inc.
Key Words: amyloid; salivary gland neoplasm; corpora amylacea; Cell death; low grade adenocarcinoma of parotid
Amyloid deposits are unexpected in salivary gland tumors. We recently encountered a case of amyloid-rich low grade adenocarcinoma of the parotid gland, misdiagnosed as pleomorphic adenoma in both fine-needle aspiration (FNA) cytology and frozen section, and would like to share our experience. This is the second such case in the pathology literature and the first description of cytopathologic features of this tumor.
Case History A 60-year-old woman was incidentally found to have a 1.8 cm left parotid mass on a CT scan of the paranasal sinuses that was obtained for evaluation of chronic sinusitis. An MR of the neck performed 18 months later demonstrated that the parotid mass was 1.4 cm and heterogeneous. Ultrasound demonstrated a 1.9 cm hypoechoic, well-circumscribed mass with partially calcified rim. An ultrasound-guided FNA was performed and airR stain (Dade dried aspirate smears stained with Diff-QuikV Behring, Newark, DE) and Ultrafast Papanicolaou stain (Richard-Allan, Kalamazoo, MI).1 The FNA diagnosis was pleomorphic adenoma with cylindromatous stroma. The FNA was described having epithelial cells with abundant cytoplasm and bland nuclei in sheets associated with innumerable blue cylindromatous stroma and metachromatic chondroid myxoid stroma. The parotid mass was resected by means of a partial parotidectomy with dissection and preservation of the C 2014 WILEY PERIODICALS, INC. V
Diagnostic Cytopathology DOI 10.1002/dc
AMYLOID-RICH LOW GRADE ADENOCARCINOMA OF THE PAROTID
Fig. 1. Cytologic features of amyloid-rich low grade adenocarcinoma of the parotid. A: Innumerable dark blue amyloid concretions mixed with wisps of metachromatic mucin were observed at low magnification. FNA smear, Diff-Quik 403. B: Tumor cells (arrows) intimately associated with metachromatic mucin and rigid, dark blue aggregates of amyloid concretions. FNA smear, Diff-Quik 1003. C:Tumor cells associated with abnormally thick strands of metachromatic mucin. Inset: plump tumor cells. FNA smear, Diff-Quik 1003, inset: 4003. D: Numerous dark amyloid concretions, scattered singly or in jigsaw puzzle-like aggregates (arrow). Wisps of translucent violet mucin were present in the background. Inset: amyloid concretion, incompletely coated with pyknotic tumor cells. FNA smear, Ultrafast Papanicolaou 403 inset: 4003. E: At medium magnification jigsaw puzzle-like aggregates of amyloid concretions found to be within glandular lumens, associated with loosely cohesive tumor cells, separated by smearing. Note the wisps of translucent violet mucin in the background. FNA smear, Ultrafast Papanicolaou 1003. F: A naked, irregular shaped, blue amyloid concretion with concentric lamination (arrow) and a dark brown amyloid concretion, associated with tumor cells at the top and thin strands of mucin at the bottom. The tumor cells with bland oval nuclei in this area had variable amount of cytoplasm, ranged from scanty to abundant. FNA smear, Ultrafast Papanicolaou 4003. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
facial nerve. The surgical pathology laboratory received a 5.0 cm 3 2.5 cm 3 2.0 cm salivary gland tissue with attached fat. The specimen was sectioned to reveal a 1.7 cm 3 1.5 cm 3 1.2 cm well-circumscribed, firm, tan mass with a variegated cut surface. One representative section was submitted for frozen section, which was reported as pleomorphic adenoma. Examination of the paraffin-fixed permanent sections showed findings that were diagnostic for an amyloid-rich low grade adenocarcinoma with 0.6 cm microinvasion at the periphery of the main tumor. The surgical margin was clean and there was no lymphovascular invasion. A skull base-to-thigh positron emission tomographyoˆ– computed tomography (PET/CT) scan that was obtained one month after the surgery did not show evidence of persistent disease at the primary site or any evidence of regional or distant metastases. The patient underwent radiation therapy for three months and was doing well without complaints at follow-up examination by the surgeon.
Cytological Findings The aspirates consisted of three components: mucin, amyloid, and tumor cells. On Diff-Quik stained FNA smears, the dark
blue substance, thought to be cylindromatous stroma, was amyloid concretions (Fig. 1A). The metachromatic substance, thought to be chondroid myxoid stroma, was abnormally thick stringy mucin (Figs. 1A–C). The epithelial cells with abundant cytoplasm and bland nuclei (Fig. 1C inset), thought to be plasmacytoid myoepithelial cells, were low grade adenocarcinoma cells. On Ultrafast Papanicolaou stained FNA smears, there were numerous amyloid concretions, wrapped by tumor cells, scattered singly and in jigsaw-puzzled like aggregates, mixed with wisps of purple mucin (Fig. 1D). The smaller amyloid concretions were laminated, and stained light blue (Fig. 1E), while the larger thicker amyloid concretions stained dark with bluish-brown hue (Fig. 1E). On higher magnification, the wisps of purple mucin becomes more conspicuous and the neoplastic epithelial cells were arranged in loosely cohesive small monolayered sheets with bland nuclei and abundant cytoplasm (Fig. 1F).
Histopathologic Findings The tumor was well-circumscribed with pushing growth pattern (Fig. 2A). Interconnecting monolayered glands ranging from minute to gigantic were demonstrated by cytokeratin immunostain. Diagnostic Cytopathology, Vol. 42, No 9
799
Diagnostic Cytopathology DOI 10.1002/dc
YANG ET AL.
Fig. 2. Histologic features of amyloid-rich low grade adenocarcinoma of the parotid. A: Frozen section showed circumscribed pale tumor. Tissue section, H&E 203. B: Comparison of region 1 with minimal disruption of cytokeratin positive tumor cells and region 2 with extensive disruption of cytokeratin positive tumor cells. Note several naked amyloid concretions (*), devoid of cytokeratin positive tumor cells. Also note the patches of cellular regions, composed of densely packed small glands. AE1/AE3 cytokeratin immunohistochemistry, 403. C: The main tumor is composed of thin or atrophic glands engorged with luminal amyloid concretions. Inset: atrophic gland, lined by a few pyknotic nuclei surrounding the luminal amyloid concretion. Tissue section, H&E 1003. D: Deeper section revealed tumor pushing into parotid acini with desmoplastic reaction and heavy inflammatory response from lymphocytes (*). Tissue section, H&E 203. E: The invasive part of the tumor is composed of minute amyloid deposits surrounded by plump viable tumor cells. Some glands contained scalloped luminal eosinophilic amyloid deposit (*), suggesting fibrillogenesis. Tissue section, H&E 4003. F: Transition from cellular region to mucin and amyloid rich region. (1) Cellular region with plump tumor cells with abundant cytoplasm and the beginning of small luminal mucin. (2–3) Mucinous region with newly formed amyloid concretions. The mucin was alcian blue positive, but mucicarmine negative. The amyloid concretions were periodic acid Schiff (PAS) positive and Congo red positive with concentric fibrillary apple green birefringience under polarized light. Tissue section, 1003, F1–F2: H&E, F3: Alcian blue/PAS, F4: Congo red. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
The densely packed minute glands represented the cellular region. Many areas showed the disappearance of coating tumor cells around amyloid concretions (Fig. 2B2). The main tumor was pale, due to luminal amyloid deposition and compressed thin glands, barely visible at scanning magnification (Fig. 2C). Deeper cut revealed a 0.6 cm focus of invasion with desmoplastic reaction and heavy lymphocytic infiltration (Fig. 2D). Invasive portion of the tumor contained plump tumor cells with minute luminal amyloid deposits with scalloped edge (Fig. 2E). The tumor cells in the cellular region were plump with abundant cytoplasm (Fig. 2F1). The tumor cells in the mucinous region and amyloid-rich region were flat and as thin as the nucleus (Fig. 2F2). The abnormal mucin stained pale pink on hematoxylin and eosin and was alcian blue positive (Fig. 2F3) but mucicarmine negative. The amyloid deposits stained positive with Congo red and exhibited apple green concentric fibrillary birefringience under cross-polarizing filters (Fig. 2F4).
Discussion Massive deposition of b-fibrillary bodies (i.e., amyloid) within the lumen of low grade adenocarcinoma of the 800
Diagnostic Cytopathology, Vol. 42, No 9
parotid gland was first reported in 1983 by David and Kim.2 The 5 cm tumor was excised from a 68-year-old African-American man who remained free of disease two years post-treatment. Amyloid has also been reported in acinic cell carcinoma3,4 and Warthin’s tumor5 of the parotid gland, and tubular carcinoma of palate minor salivary gland.6 Salivary gland tumors with numerous psammoma bodies, morphologically similar to amyloid concretions, were reported. However, no Congo red stain was performed in these cases. This included a case of unusually slow growing oncocytic adenoma of the parotid in the histopathology literature,7 and two cases of acinic cell carcinoma in the cytopathology literature.8,9 David and Kim2 proposed that amyloid deposition of low grade adenocarcinoma of the parotid resulted from apoptosis of tumor cells, with progressive release and confluence of cytoplasmic intermediate filaments. More recently, Drut and Gimenez4 also proposed that the globular amyloid deposits in a 5 cm acinic cell carcinoma of the parotid resulted from the accumulation of residual masses of apoptotic tumor cells. We have an alternative hypothesis, and propose that amyloid deposition occurred prior to cell death and amyloid deposition induced tumor
Diagnostic Cytopathology DOI 10.1002/dc
AMYLOID-RICH LOW GRADE ADENOCARCINOMA OF THE PAROTID
cell death for the following two reasons. First, the presence of minute amyloid deposits within the lumen of plump, viable tumor cells with no sign of degeneration (Fig. 2E). Second, amyloid-like fibrils may not be amyloid, such as Congo red-negative fibrillary glomerulopathy.10 Prior authors cited the ultrastructural similarity of amyloid fibrils and cytoplasmic fibrils as evidence that amyloid deposits were derived from dying cells.2,4 Amyloid fibrils are inappropriately folded versions of endogenous proteins and polypeptides present naturally in the body, or endogenous proteins or peptides secreted by tumor. In addition to medullary thyroid carcinoma that produce amyloid resulted from inappropriately folded calcitonin,11 other amyloid-producing tumors include calcifying epithelial odontogenic tumors that secrete inappropriately folded ameloblastin,12 pituitary adenomas that secrete inappropriately folded growth hormone13 or prolactin,14 and B-cell lymphoproliferative disorders that secrete inappropriately folded light chain.15 In conclusion, we propose the sequence of events in this tumor as follows. Tumor cells secreted inappropriate folded luminal mucin which became amyloid. Continual expansion of luminal amyloid caused tumor cell death. Amyloidinduced cell death impeded the aggressiveness of tumor.
References
3. Ellis GL, Auclair PL. Tumors of the salivary glands. Atlas of tumor pathology. Third series. Fascicle 17. Washington, DC: AFIP; 1996. p 197. 4. Drut R, Gimenez PO. Acinic cell carcinoma of salivary gland with massive deposits of globular amyloid. Int J Surg Pathol 2008;16: 202–207. 5. David R, Buchner A. Corpora amylacea in adenolymphoma (Warthin’s tumor). Am J Clin Pathol 1978;69:173–175. 6. David R, Buchner A. Amyloid stroma in a tubular carcinoma of palatal salivary gland: A histochemical and ultrastructural study. Cancer 1978;41:1836–1844. 7. Feiner HD, Goldstein S, Ittman M, Pelton K, Jacobs J. Oncocytic adenoma of the parotid gland with psammoma bodies. Arch Pathol Lab Med 1986;110:640–644. 8. Bottles K, Lowhagen T. Psammoma bodies in the aspiration cytology smears of an acinic-cell tumor. Acta Cytol 1985;29:191–192. 9. Whitlatch SP. Psammoma bodies in fine-needle aspiration biopsies of acinic cell tumor. Diagn Cytopathol 1986;2:268–269. 10. Yang GCH, Nieto R, Stachura I, Gallo GR. Ultrastructural immunohistochemical localization of polyclonal IgG, C3, and amyloid P component on the Congo red-negative amyloid-like fibrils of fibrillary glomerulopathy. Am J Pathol 1992;141:409–419. 11. Sletten K, Westermark P, Natvig JB. Characterization of amyloid fibril proteins from medullary carcinoma of the thyroid. J Exp Med 1976;143:993–998. 12. Murphy CL, Kestler DP, Foster JS, et al. Odontogenic ameloblastassociated protein nature of the amyloid found in calcifying epithelial odontogenic tumors and unerupted tooth follicles. Amyloid 2008;15:89–95. 13. Iwase T, Nishizawa S, Baba S, et al. Intrasellar neuronal choristoma associated with growth hormone-producing pituitary adenoma containing amyloid deposits. Hum Pathol. 1995;26:925– 928.
1. Yang GCH, Alvarez II. Ultrafast Papanicolaou stain: An alternative preparation for fine-needle aspiration cytology. Acta Cytol 1995;39: 55–60.
14. Wiesli P, Br€andle M, Brandner S, Kollias SS, Bernays RL. Extensive spherical amyloid deposition presenting as a pituitary tumor. J Endocrinol Invest 2003;26:552–555.
2. David R, Kim KM. Beta-fibrillary bodies in low-grade adenocarcinoma of parotid gland: A histochemical and ultrastructural study. Hum Pathol 1982;13:1028–1035.
15. Hemmer PR, Topazian MD, Gertz MA, Abraham SC. Globular amyloid deposits isolated to the small bowel: A rare association with AL amyloidosis. Am J Surg Pathol 2007;31:141–145.
Diagnostic Cytopathology, Vol. 42, No 9
801
