Metastatic Hepatocellular Carcinoma of the Breast, Simulating Gynecomastia: Diagnosis by Fine-Needle Aspiration Biopsy Oscar Nappi, M.D.,Gerard0 Ferrara, M.D.,Giovanni lanniello, M.D.,and Mark R. Wick, M.D.
Hepatocellular carcinoma (HCC) may uncommonly present with distant metastasis in the absence of a documented neoplasm in the liver. The authors herein describe the case of a 60-year-old man wiih cirrhosis who developed unilateral enlargement of the breast and a subareolar mass. This problem was clinically thought to rejwesent gynecomastia, but a mammary fine-needle aspiration biopsy demonstrated a malignant epithelial neoplasm composed of large granular amphophilic cells. Bile pigment was visualized in the tumor on aspirate smears and cell block preparations; immunostains showed reactivity for cytokeratin and alpha-fetoprotein, but there was no positivity for epithelial membrane antigen, gross cystic disease fluid protein-IS, vimentin, estrogen receptors, progesterone receptors, or SI 00 protein. These results indicated a diagnosis of metastatic HCC, which was subsequently conjirmed by computed tomography of the abdomen. Diagn Cytopathol 1992;8:588-592. 0 1992 wiley-Liss, Inc Key Words: Hepatic neoplasms; Fine-needle aspiration; Immunocytology
Uncommonly, hepatocellular carcinoma (HCC) may present with metastasis to a distant anatomic site in the absence of a documented mass in the liver. 1-3 The pathologic diagnosis of HCC is difficult in this setting and often reiquires the application of specialized morphologic studies. Because the presence of cirrhosis may obscure the radiographic delineation of a hepatic neoplasm-particularly if it is relatively small’-the existence of end-stage liver disease is also a potentially confounding clinical factor in this context. We herein report a case where a male patient with cirrhosis developed enlargement of one breast, because of intramammary metastasis of an occult HCC. He was __ ]Received October 30, 1991. Accepted March 20, 1992. IFrom the Departments of Pathology and Internal Medicine, General City Hospital, Benevento, Italy, and the Department of Pathology, Washington University SchooI of Medicine, St. Louis, MO. Address reprint requests to Dr. M.R. Wick, Division of Surgical Pathology, Barnes Hospital, Washington University School of Medicine, One Barnes Hospital Plaza, St. Louis, M O 63 110.
588
Diagnostic Cytopathology, Vol 8, No 6
presumed to have simple gynecomastia related to hepatogenic endocrinopathy, until fine-needle aspiration biopsy (FNAB) revealed the true nature of his breast lesion. To the best of our knowledge, there are no examples of similar cases in the prior literature on FNAB cytopathology.
Report of a Case A 60-yr-old man found a painless subareolar mass in his right breast by self-examination. It had increased in size to 3.5 cm over a 3-wk period, and he consulted a physician because of this feature. The patient had been assigned a diagnosis of hepatic cirrhosis 7 yr previously, based on abnormal levels of alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and the results of a liver biopsy. He had intermittently shown clinical symptoms of hepatic insufficiency in the interim and was found to have antihepatitis C virus antibody in his serum. Physical examination demonstrated typical findings of long-standing liver disease, including palmar erythema, telangiectasias of the skin, testicular atrophy, and hepatosplenomegaly. The aforementioned mammary mass was palpable as a firm, mobile lesion beneath the right nipple. The opposite breast was slightly enlarged as well, but no discrete tumefactions were detectable in it. No evidence was found of ascites, peripheral edema, or jaundice, and there were no abdominal masses. Results of screening biochemical and hematologic tests were unchanged, compared with those obtained in previous evaluations. A chest X-ray was interpreted as unremarkable. A tentative diagnosis of unilateral gynecomastia was made clinically, but a fine-needle aspiration biopsy (FNAB) of the right breast was undertaken to confirm this impression. This unexpectedly revealed a metastatic adenocarcinoma that was strongly suggestive of a hepatic origin on morphologic grounds (see below). In light of this information, computed tomography of the abdomen was performed with intravenous administration of radiologic 0 1992 WILEY-LISS, INC
HCC SIMULATING GYNECOMASTIA
contrast material. The latter procedure disclosed a 5 cm vascular mass in the right hepatic lobe, consistent in appearance with HCC, but did not show metastases to intraabdominal lymph nodes. A bone scan also yielded normal results. Because of documented metastasis to the breast and his generally tenuous medical condition, the patient was not considered to be a candidate for surgical resection of his hepatic neoplasm. He is being given appropriate chemotherapy and is still alive with persistent but stable tumor growth.
Materials and Methods Aspirates of the breast lesion were obtained using standard technique. Several air-dried smears were prepared, as well as others that were fixed immediately in absolute ethyl alcohol. These were stained in parallel with hematoxylin and eosin and the May-Griinwald-Giemsa method. The remaining aspirated material was processed as a cell block, fixed in 95% ethyl alcohol, and embedded in paraffin. Immunohistochemical studies were performed on the cell block specimen. Serial sections were cut at 5-pm intervals and mounted on glass slides coated with a chromealum mixture. They were deparaffinized in Americlear (American Scientific Products, McGaw Park, IL) and absolute ethyl alcohol, followed by immersion in 0.6% methanolic hydrogen peroxide solution for 45 min. Rehydration was accomplished in graded alcohol solutions, distilled water, and phosphate-buffered saline. Primary antibodies (Table I) to cytokeratins, epithelial membrane antigen (EMA), SlOO protein, gross cystic disease fluid protein-1 5 (GCDFP15), vimentin, estrogen receptor protein (ERP), progesterone receptor protein (PRP), and alpha-fetoprotein (AFP) were applied and sections were incubated at 4°C for 18 hr, in moisture chambers. Localization of antibody binding was visualized with the avidin-biotin-peroxidase complex (ABC) technique (4), using 3,3’-diaminobenzidine (0.25 mg/ml with 0.003% hydrogen peroxide) as the chromogen. Positive controls were represented by sections of stock neoplasms that were known to contain the determinants of interest. Sections of the breast mass also were stained with the ABC method after substitution of nonimmune rabbit serum and mouse ascites fluid for primary antibodies; these served as negative controls.
Results Cytologic and Histologic Findings Smears of the material obtained at FNAB of the breast showed the presence of single epithelial cells, or small cohesive groups of them, all of which demonstrated increased nucleocytoplasmic ratios (Fig. C- 1). Scattered green-brown pigment was apparent within cells, and it
Table I. Immunohistochemical Reagents Used in the Study of Metastatic Hepatocellular Carcinoma in the Breast Reagenta
Source
Anticytokeratinsb [AEl/AE3]
Dilution
Hybritech, Inc. San Diego, CA Becton-Dickinson Mountain View, CA Triton Biosciences Alameda, CA
1:150
Anti-epithelial membrane antigen [E29]
DakoPatts Co. Santa Barbara, CA
1 :1,000
Anti-gross cystic disease fluid protein-I5 [D6]
Signet Laboratories Dedham, MA
1:80
Anti-vimentin [V9]
BioCenex Laboratories Dublin, CA
1:800
Anti-alpha fetoprotein [AFP26]
Bioproducts For Science Indianapolis, IN
1:800
Anti-estrogen receptor protein [H222]
Abbott Laboratories Lisle, I L
1:2
Anti-progesterone receptor protein [MPRI]
Abbott Laboratories
1.4
[CAM 5.21 [MAK-6]
1:40
1:75
Anti-S100 protein
DakoPatts Co.
1:1,000
Universal ABC Elite Development Kits
Vector Laboratories Burlingame, CA
Prediluted
”All antibodies except for anti-S100 protein were murine hybridoma reagents. Anti-S100 protein was a rabbit antiserum. Clone numbers or commercial designations for monoclonal antibodies are provided in brackets. bAnticytokeratins were used as a mixture.
was focally seen in intercellular glandlike spaces. Cytoplasm was moderately abundant, amphophilic, and granular. Nuclei were generally round to oval with vesicular or coarsely clumped chromatin and prominent nucleoli; occasional binucleated or multinucleated cells were apparent as well (Fig. C-2). Scattered cells showed the presence of intranuclear cytoplasmic invaginations, which were amphophilic. Sections of the cell block material confirmed the cytologic appearances noted above and showed that the neoplastic cells were arranged in trabeculae, solid clusters, and glandlike configurations. The intercellular pigment noted in the smear preparations had the characteristics of bile in paraffin sections (Fig. C-3) in that it was homogeneous, yellow-green, seen within intercellular lumina, and stained positively with Fouchet’s method.
Immunohistochemical Observations The tumor cells in the paraffin-embedded cell block showed diffuse reactivity for cytokeratin (Fig. C-4), but uniformly lacked EMA (Fig. C-5). They likewise were not labeled by anti-vimentin or with antibodies to GCDFP15, SlOO protein, ERP, and PRP. Cytoplasmic immunopositivity was observed for AFP, in a heterogeneous Diagnostic Cytopathology. Vol 8, No 6
589
Fig. C-1
Fig. C-2
Fig. C-3
Fig. c-4
Fig. C-5
Fig. C-6
Figs. C-1-C-6. Fig. C-1. Clustered cells with granular cytoplasm and large nucleocytoplasmic ratios, in FNAB of the right breast mass in this case. (H&E, X 250). Fig. C-2. Prominent nucleoli, occasional binucleation, and focal intracytoplasmic pigment are seen in this cluster of tumor cells. (H&E, X400). Fig. C-3. Cell block preparation of fine-needle breast aspirate showing disposition of tumor cells in nests and cords with obvious intercellular bile plugs. (H&E, X 160). Fig. C-4. Diffuse immunoreactivity for cytokeratin, in metastatic hepatocellular carcinoma. (ABC anticytokeratin immunoslain, X 160). Fig. C-5. Negativity for epithelial membrane antigen (EMA) in metastatic hepatocellular carcinoma. (ABC anti-EMA immunostain, X 160). Fig. C-6. Heterogeneous positivity for alpha-fetoprotein (AFP) in metastatic hepatocellular carcinoma. (ABC anti-AFP immunostain, X 160).
HCC SIMULATING GYNECOMASTIA
mosaic pattern (Fig. C-6). Positive and negative controls stained appropriately.
Discussion Metastatic neoplasms in the breast are relatively uncommon and usually appear in the context of disseminated spread of a known malignancy.' Rarely, such tumors can be the initial manifestation of occult malignant melanoma or carcinoma of the lung. Heretofore, we have been able to find only one report of HCC that was shown to involve the mammary gland through the use of FNAB. Silverman et aL6documented such a case concerning a woman who was already known to have a hepatic neoplasm. The capacity for HCC to present itself with distant metastasisin the absence of a clinically overt mass in the liver-has indeed been reported, but this tumor most often involves the bones or lungs in this setting.'-1° Because FNAB of breast lesions is now a widely practiced procedure, an increasing number of publications have addressed the differential diagnostic problems that may be encountered therein. 6, "-I6 Primary and metastatic mammary neoplasms can be difficult to distinguish from one another in selected cases, and this problem is heightened by the fact that hormonal treatment given for other malignant tumors may play a pathogenetic role in neoplasia of the breast. For example, reports have been made of mammary carcinomas occurring in men who have received diethyl-stilbestrol for prostatic cancer.I7 In this specific context, it may be vexing to separate primary breast tumors from metastatic prostatic carcinomas that show the cytologic effects of hormonal therapy.15 In fact, the case we have described does show some similarities to the scenario noted above. Men with hepatic cirrhosis are known to have elevated levels of estrogenic compounds in serum, 18,19 and they are subject to the development of gynecomastia as a r e ~ u l t . Moreover, '~ the possibility of primary breast cancer also must be considered in such patients on the same conceptual ground^.'^ Therefore, FNAB is certainly advisable to resolve clinical uncertainty surrounding these eventualities. Our case showed extremely convincing cytologic and histologic evidence of hepatocellular differentiation, because of the presence of bile formation by the tumor.*' Otherwise, the microscopic recognition of HCC can be challenging, and a sizable number of alternative diagnoses are raised by the morphologic picture of a large granularcell epithelioid malignancy. In the breast, these would include primary apocrine carcinoma or epithelioid angiosarcoma, metastatic malignant melanoma, and secondary deposits of other adenocarcinomas. 5,",12,15,16 The presence of intranuclear invaginations-as seen in the lesion under discussion-is a nonspecific finding and may be observed in several of these pathologic entities.21 It is in this domain that immunohistochemical analyses 'r6
have proven to be a valuable adjunct to conventional cytomorphology. It is known that HCC usually exhibits a disparity in its expression of two common epithelial markers, namely, cytokeratin and EMA.ZZThis observation is a helpful clue to immunohistologic identification, because other somatic carcinomas typically are reactive for both determinants.2z Moreover, the presence of positivity for ERP and AFP is potentially shared by both HCC and breast cancers, 23-2s although reactivity for the latter of these proteins is admittedly much more common in hepatocellular neoplasms.2sGCDFP- 15 and SlOO protein are not present in HCC and therefore represent additional "breast-related'' discriminants that should be used in a case such as this one. In summary, we have documented an unusual presentation of hepatocellular carcinoma with mammary metastasis, which was clinically thought to represent gynecomastia in a patient with cirrhosis. The diagnostic value of FNAB in this setting, with adjunctive immunohistologic studies, lends further support to the general utility of these procedures in the assessment of lesions of the breast. 26927
References I . Anthony PP: Tumors and tumor-like lesions of the liver and biliary tract. In: MacSween RNM, Anthony PP, Scheuer PJ, eds). Pathology of the liver. New York: Chnrchill-Livingstone, 1987; 574645. 2. Okuda K: Clinical aspects of hepatocellular carcinoma: analysis of 134 cases. In: (Okuda K, Peters RL, eds). Hepatocellular carcinoma. New York: John Wiley & Sons, 1976: 387-436. 3. Edmonson HA, Craig JR: Neoplasms of the liver. In: Schiff L, Schiff ER, eds. Diseases of the liver. Philadelphia: Lippincott, 1987: 110958.
4. Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase com-
5. 6.
7. 8. 9.
10.
11. 12.
13.
14.
plex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 1981; 29577-80. Hajdu SI, Urban JA. Cancer metastatic to the breast. Cancer 1972; 29: I69 1-6. Silverman JF, Feldman PS, Cove11 JL, Frable WJ. Fine needle aspiration cytology of neoplasms metastatic to the breast. Acta Cytol 1987; 31:291-300. Chakrovorty RC, Makoui C. Symptomatic bone metastases from occult primary liver cancer. Digest Dis 1977; 22:471-3. Ma LT, Hui PK, Lee NW. Hepatocellular carcinoma in the mandible: a case report. J Hong Kong Med Assoc 1985; 37:37-40. Ng IOL, Leung CY, H o JWC. Fine needle aspiration cytologic diagnosis of a symptomatic bony metastasis from an occult hepatocellular carcinoma: a case report. Diagn Cytopathol 1990; 6: 127-9. Talerman A, Magyar E. Hepatocellular carcinoma presenting with pathologic fracture due to bone metastases. Cancer 1973; 32:147781. Bhagat P, Kline TS. The male breast and malignant neoplasms: diagnosis by aspiration biopsy cytology. Cancer 1990; 65:233841. Kline TS, Joshi LP, Huntcr SN. Fine needle aspiration of the breast: diagnosis and pitfalls: a review of 3,545 cases. Cancer 1979; 49:145864. Landon G, Sniege N, Ordonez NG, Mackay B. Carcinoid metastatic to breast diagnosed by fine needle aspiration biopsy. Diagn Cytopatho1 1987; 3:23&3. Lozowski MS, Faegenburg D, Mishriki Y, Lundy J. Carcinoid Diagnostic Cytopathology, Vol 8, No 6
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15.
16.
17.
18 19. 20.
21.
tumor metastatic to breast diagnosed by fine needle aspiration. Acta Cytol 1989; 33:1914. Schmitt FC, Tani E, Skoog L. Cytology and immunohistochemistry of bilateral breast metastases from prostatic cancer. Acta Cytol 1989; 33:899-902. Sniege N, Zachariah S, Fanning T, Dekmezian RH, Ordonez NG. Fine needle aspiration cytology of metastatic neoplasms in the breast. Am J Clin Pathol 1989; 92:27-35. Schlappack OK, Braun 0, Maier U. Report of two cases of male breast cancer after prolonged estrogen treatment for prostatic carcinoma. Cancer Detec Prev 1986; 9:319-22. Treves N. Gynecomastia. Cancer 1958; 11:1083-1102 Cavanaugh J, Niewochner CB, Nuttal FQ. Gynecomastia and cirrhosis of the liver. Arch Intern Med 1990; 150:563-5. Tao LC, Ho CS, McLoughlin MJ, Evans WK, Donat EE. Cytologic diagnosis of hepatocellular carcinoma by fine needle aspiration biopsy. Cancer 1984; 53:547-52. Gritsman AY, Popok SM, Ro JY, Dekmentian RH, Weber RS. Renal cell carcinoma with intranuclear inclusions metastatic to thyroid: a diagnostic problem in aspiration cytology. Diagn Cytopathol 1988; 4:125-9.
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Diagnostic Cytopathology, Vol 8,No 6
22. Swanson PE. Monoclonal antibodies to human milk fat globule proteins. In: Wick MR, Siegal GP, eds. Monoclonal antibodies in diagnostic immunohistochemistry. New York: Marcel Dekker, 1988: 227-83. 23. Shintaku IP, Said JW. Detection of estrogen receptors in routinely processed formalin-fixed paraffin embedded sections of breast carcinoma. Am J Clin Pathol 1987; 87:161-7. 24. Nagasue N, Kohno H, Chang YC, Yamanoi A, Nakamura T, Yukaya H, Hayashi T. Clinicopathologic comparison between estrogen receptor-positive and -negative hepatocellular carcinomas. Ann Surg 1990; 212:150-4. 25. Kloppel G, Caselitz J. Epithelial tumor markers: oncofetal antigens (carcinoembryonic antigen, alpha-fetoprotein, and epithelial membrane antigen). In: Seifert G , ed. Morphological tumor markers. Berlin: Springer-Verlag, 1987: 103-32. 26. Wick MR. Lillemoe TJ, Copland GT, Swanson PE, Manivel JC, Kiang DT: Gross cystic disease fluid protein-15 as a marker for breast cancer. Hum Pathol 1989; 20:281-7. 27. Drier JK, Swanson PE, Cherwitz DL, Wick MR. SlOO protein inimunoreactivity in poorly-differentiated carcinomas. Arch Pathol Lab Med 1987; 111:447-52.
Hepatocellular carcinoma (HCC) may uncommonly present with distant metastasis in the absence of a documented neoplasm in the liver. The authors herein describe the case of a 60-year-old man wiih cirrhosis who developed unilateral enlargement of the breast and a subareolar mass. This problem was clinically thought to rejwesent gynecomastia, but a mammary fine-needle aspiration biopsy demonstrated a malignant epithelial neoplasm composed of large granular amphophilic cells. Bile pigment was visualized in the tumor on aspirate smears and cell block preparations; immunostains showed reactivity for cytokeratin and alpha-fetoprotein, but there was no positivity for epithelial membrane antigen, gross cystic disease fluid protein-IS, vimentin, estrogen receptors, progesterone receptors, or SI 00 protein. These results indicated a diagnosis of metastatic HCC, which was subsequently conjirmed by computed tomography of the abdomen. Diagn Cytopathol 1992;8:588-592. 0 1992 wiley-Liss, Inc Key Words: Hepatic neoplasms; Fine-needle aspiration; Immunocytology
Uncommonly, hepatocellular carcinoma (HCC) may present with metastasis to a distant anatomic site in the absence of a documented mass in the liver. 1-3 The pathologic diagnosis of HCC is difficult in this setting and often reiquires the application of specialized morphologic studies. Because the presence of cirrhosis may obscure the radiographic delineation of a hepatic neoplasm-particularly if it is relatively small’-the existence of end-stage liver disease is also a potentially confounding clinical factor in this context. We herein report a case where a male patient with cirrhosis developed enlargement of one breast, because of intramammary metastasis of an occult HCC. He was __ ]Received October 30, 1991. Accepted March 20, 1992. IFrom the Departments of Pathology and Internal Medicine, General City Hospital, Benevento, Italy, and the Department of Pathology, Washington University SchooI of Medicine, St. Louis, MO. Address reprint requests to Dr. M.R. Wick, Division of Surgical Pathology, Barnes Hospital, Washington University School of Medicine, One Barnes Hospital Plaza, St. Louis, M O 63 110.
588
Diagnostic Cytopathology, Vol 8, No 6
presumed to have simple gynecomastia related to hepatogenic endocrinopathy, until fine-needle aspiration biopsy (FNAB) revealed the true nature of his breast lesion. To the best of our knowledge, there are no examples of similar cases in the prior literature on FNAB cytopathology.
Report of a Case A 60-yr-old man found a painless subareolar mass in his right breast by self-examination. It had increased in size to 3.5 cm over a 3-wk period, and he consulted a physician because of this feature. The patient had been assigned a diagnosis of hepatic cirrhosis 7 yr previously, based on abnormal levels of alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and the results of a liver biopsy. He had intermittently shown clinical symptoms of hepatic insufficiency in the interim and was found to have antihepatitis C virus antibody in his serum. Physical examination demonstrated typical findings of long-standing liver disease, including palmar erythema, telangiectasias of the skin, testicular atrophy, and hepatosplenomegaly. The aforementioned mammary mass was palpable as a firm, mobile lesion beneath the right nipple. The opposite breast was slightly enlarged as well, but no discrete tumefactions were detectable in it. No evidence was found of ascites, peripheral edema, or jaundice, and there were no abdominal masses. Results of screening biochemical and hematologic tests were unchanged, compared with those obtained in previous evaluations. A chest X-ray was interpreted as unremarkable. A tentative diagnosis of unilateral gynecomastia was made clinically, but a fine-needle aspiration biopsy (FNAB) of the right breast was undertaken to confirm this impression. This unexpectedly revealed a metastatic adenocarcinoma that was strongly suggestive of a hepatic origin on morphologic grounds (see below). In light of this information, computed tomography of the abdomen was performed with intravenous administration of radiologic 0 1992 WILEY-LISS, INC
HCC SIMULATING GYNECOMASTIA
contrast material. The latter procedure disclosed a 5 cm vascular mass in the right hepatic lobe, consistent in appearance with HCC, but did not show metastases to intraabdominal lymph nodes. A bone scan also yielded normal results. Because of documented metastasis to the breast and his generally tenuous medical condition, the patient was not considered to be a candidate for surgical resection of his hepatic neoplasm. He is being given appropriate chemotherapy and is still alive with persistent but stable tumor growth.
Materials and Methods Aspirates of the breast lesion were obtained using standard technique. Several air-dried smears were prepared, as well as others that were fixed immediately in absolute ethyl alcohol. These were stained in parallel with hematoxylin and eosin and the May-Griinwald-Giemsa method. The remaining aspirated material was processed as a cell block, fixed in 95% ethyl alcohol, and embedded in paraffin. Immunohistochemical studies were performed on the cell block specimen. Serial sections were cut at 5-pm intervals and mounted on glass slides coated with a chromealum mixture. They were deparaffinized in Americlear (American Scientific Products, McGaw Park, IL) and absolute ethyl alcohol, followed by immersion in 0.6% methanolic hydrogen peroxide solution for 45 min. Rehydration was accomplished in graded alcohol solutions, distilled water, and phosphate-buffered saline. Primary antibodies (Table I) to cytokeratins, epithelial membrane antigen (EMA), SlOO protein, gross cystic disease fluid protein-1 5 (GCDFP15), vimentin, estrogen receptor protein (ERP), progesterone receptor protein (PRP), and alpha-fetoprotein (AFP) were applied and sections were incubated at 4°C for 18 hr, in moisture chambers. Localization of antibody binding was visualized with the avidin-biotin-peroxidase complex (ABC) technique (4), using 3,3’-diaminobenzidine (0.25 mg/ml with 0.003% hydrogen peroxide) as the chromogen. Positive controls were represented by sections of stock neoplasms that were known to contain the determinants of interest. Sections of the breast mass also were stained with the ABC method after substitution of nonimmune rabbit serum and mouse ascites fluid for primary antibodies; these served as negative controls.
Results Cytologic and Histologic Findings Smears of the material obtained at FNAB of the breast showed the presence of single epithelial cells, or small cohesive groups of them, all of which demonstrated increased nucleocytoplasmic ratios (Fig. C- 1). Scattered green-brown pigment was apparent within cells, and it
Table I. Immunohistochemical Reagents Used in the Study of Metastatic Hepatocellular Carcinoma in the Breast Reagenta
Source
Anticytokeratinsb [AEl/AE3]
Dilution
Hybritech, Inc. San Diego, CA Becton-Dickinson Mountain View, CA Triton Biosciences Alameda, CA
1:150
Anti-epithelial membrane antigen [E29]
DakoPatts Co. Santa Barbara, CA
1 :1,000
Anti-gross cystic disease fluid protein-I5 [D6]
Signet Laboratories Dedham, MA
1:80
Anti-vimentin [V9]
BioCenex Laboratories Dublin, CA
1:800
Anti-alpha fetoprotein [AFP26]
Bioproducts For Science Indianapolis, IN
1:800
Anti-estrogen receptor protein [H222]
Abbott Laboratories Lisle, I L
1:2
Anti-progesterone receptor protein [MPRI]
Abbott Laboratories
1.4
[CAM 5.21 [MAK-6]
1:40
1:75
Anti-S100 protein
DakoPatts Co.
1:1,000
Universal ABC Elite Development Kits
Vector Laboratories Burlingame, CA
Prediluted
”All antibodies except for anti-S100 protein were murine hybridoma reagents. Anti-S100 protein was a rabbit antiserum. Clone numbers or commercial designations for monoclonal antibodies are provided in brackets. bAnticytokeratins were used as a mixture.
was focally seen in intercellular glandlike spaces. Cytoplasm was moderately abundant, amphophilic, and granular. Nuclei were generally round to oval with vesicular or coarsely clumped chromatin and prominent nucleoli; occasional binucleated or multinucleated cells were apparent as well (Fig. C-2). Scattered cells showed the presence of intranuclear cytoplasmic invaginations, which were amphophilic. Sections of the cell block material confirmed the cytologic appearances noted above and showed that the neoplastic cells were arranged in trabeculae, solid clusters, and glandlike configurations. The intercellular pigment noted in the smear preparations had the characteristics of bile in paraffin sections (Fig. C-3) in that it was homogeneous, yellow-green, seen within intercellular lumina, and stained positively with Fouchet’s method.
Immunohistochemical Observations The tumor cells in the paraffin-embedded cell block showed diffuse reactivity for cytokeratin (Fig. C-4), but uniformly lacked EMA (Fig. C-5). They likewise were not labeled by anti-vimentin or with antibodies to GCDFP15, SlOO protein, ERP, and PRP. Cytoplasmic immunopositivity was observed for AFP, in a heterogeneous Diagnostic Cytopathology. Vol 8, No 6
589
Fig. C-1
Fig. C-2
Fig. C-3
Fig. c-4
Fig. C-5
Fig. C-6
Figs. C-1-C-6. Fig. C-1. Clustered cells with granular cytoplasm and large nucleocytoplasmic ratios, in FNAB of the right breast mass in this case. (H&E, X 250). Fig. C-2. Prominent nucleoli, occasional binucleation, and focal intracytoplasmic pigment are seen in this cluster of tumor cells. (H&E, X400). Fig. C-3. Cell block preparation of fine-needle breast aspirate showing disposition of tumor cells in nests and cords with obvious intercellular bile plugs. (H&E, X 160). Fig. C-4. Diffuse immunoreactivity for cytokeratin, in metastatic hepatocellular carcinoma. (ABC anticytokeratin immunoslain, X 160). Fig. C-5. Negativity for epithelial membrane antigen (EMA) in metastatic hepatocellular carcinoma. (ABC anti-EMA immunostain, X 160). Fig. C-6. Heterogeneous positivity for alpha-fetoprotein (AFP) in metastatic hepatocellular carcinoma. (ABC anti-AFP immunostain, X 160).
HCC SIMULATING GYNECOMASTIA
mosaic pattern (Fig. C-6). Positive and negative controls stained appropriately.
Discussion Metastatic neoplasms in the breast are relatively uncommon and usually appear in the context of disseminated spread of a known malignancy.' Rarely, such tumors can be the initial manifestation of occult malignant melanoma or carcinoma of the lung. Heretofore, we have been able to find only one report of HCC that was shown to involve the mammary gland through the use of FNAB. Silverman et aL6documented such a case concerning a woman who was already known to have a hepatic neoplasm. The capacity for HCC to present itself with distant metastasisin the absence of a clinically overt mass in the liver-has indeed been reported, but this tumor most often involves the bones or lungs in this setting.'-1° Because FNAB of breast lesions is now a widely practiced procedure, an increasing number of publications have addressed the differential diagnostic problems that may be encountered therein. 6, "-I6 Primary and metastatic mammary neoplasms can be difficult to distinguish from one another in selected cases, and this problem is heightened by the fact that hormonal treatment given for other malignant tumors may play a pathogenetic role in neoplasia of the breast. For example, reports have been made of mammary carcinomas occurring in men who have received diethyl-stilbestrol for prostatic cancer.I7 In this specific context, it may be vexing to separate primary breast tumors from metastatic prostatic carcinomas that show the cytologic effects of hormonal therapy.15 In fact, the case we have described does show some similarities to the scenario noted above. Men with hepatic cirrhosis are known to have elevated levels of estrogenic compounds in serum, 18,19 and they are subject to the development of gynecomastia as a r e ~ u l t . Moreover, '~ the possibility of primary breast cancer also must be considered in such patients on the same conceptual ground^.'^ Therefore, FNAB is certainly advisable to resolve clinical uncertainty surrounding these eventualities. Our case showed extremely convincing cytologic and histologic evidence of hepatocellular differentiation, because of the presence of bile formation by the tumor.*' Otherwise, the microscopic recognition of HCC can be challenging, and a sizable number of alternative diagnoses are raised by the morphologic picture of a large granularcell epithelioid malignancy. In the breast, these would include primary apocrine carcinoma or epithelioid angiosarcoma, metastatic malignant melanoma, and secondary deposits of other adenocarcinomas. 5,",12,15,16 The presence of intranuclear invaginations-as seen in the lesion under discussion-is a nonspecific finding and may be observed in several of these pathologic entities.21 It is in this domain that immunohistochemical analyses 'r6
have proven to be a valuable adjunct to conventional cytomorphology. It is known that HCC usually exhibits a disparity in its expression of two common epithelial markers, namely, cytokeratin and EMA.ZZThis observation is a helpful clue to immunohistologic identification, because other somatic carcinomas typically are reactive for both determinants.2z Moreover, the presence of positivity for ERP and AFP is potentially shared by both HCC and breast cancers, 23-2s although reactivity for the latter of these proteins is admittedly much more common in hepatocellular neoplasms.2sGCDFP- 15 and SlOO protein are not present in HCC and therefore represent additional "breast-related'' discriminants that should be used in a case such as this one. In summary, we have documented an unusual presentation of hepatocellular carcinoma with mammary metastasis, which was clinically thought to represent gynecomastia in a patient with cirrhosis. The diagnostic value of FNAB in this setting, with adjunctive immunohistologic studies, lends further support to the general utility of these procedures in the assessment of lesions of the breast. 26927
References I . Anthony PP: Tumors and tumor-like lesions of the liver and biliary tract. In: MacSween RNM, Anthony PP, Scheuer PJ, eds). Pathology of the liver. New York: Chnrchill-Livingstone, 1987; 574645. 2. Okuda K: Clinical aspects of hepatocellular carcinoma: analysis of 134 cases. In: (Okuda K, Peters RL, eds). Hepatocellular carcinoma. New York: John Wiley & Sons, 1976: 387-436. 3. Edmonson HA, Craig JR: Neoplasms of the liver. In: Schiff L, Schiff ER, eds. Diseases of the liver. Philadelphia: Lippincott, 1987: 110958.
4. Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase com-
5. 6.
7. 8. 9.
10.
11. 12.
13.
14.
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