- Email: [email protected]
Hep Par 1 in gastric and bowel carcinomas: an immunohistochemical study
Pathology (2002 ) 34, pp. 423– 426
ANATOMICAL
PATHOLOGY
Hep Par 1 in gastric and bowel carcinomas: an immunohistochemical study D. VILLARI, R. CARUSO , M. GROSSO , E. VITARELLI , M. RIGHI
AND
G. BARRESI
Department of Human Pathology, Polyclinic Pad.D, University of Messina, Messina, Italy
Summary Aims: Hep Par 1 has been described as a specific marker of hepatocellular differentiation and its immunohistochemica l use has been suggested as a helpful tool for hepatocellular carcinoma (HCC) diagnosis. Most metastatic liver tumours come from the gastrointestinal tract and usually can be distinguished from HCC only through histology. We evaluated by immunohistochemistry the specificity of Hep Par 1, studying the presence of the epitope that reacts with Hep Par 1 in primary gastric and colorectal cancers. Methods: A series of 39 cases of primary gastric and 18 cases of colorectal carcinoma were selected. Twenty-six of the 39 gastric carcinomas were of the intestinal type, six of the diffuse type, three of the mixed type and five had hepatoid differentiation. Two of the 18 colorectal adenocarcinomas were well differentiated, 14 moderately differentiated, one poorly differentiated and one was of the mucinous type. Five- mm sections were stained by immunohistochemistr y using Hep Par 1 as primary antibody. Results: Immunohistochemical staining was observed in 26 gastric carcinomas (69%) and nine large bowel carcinomas (50%). Fifteen of the 26 positive-stained gastric cancers were of intestinal type, four of diffuse type and two of mixed type cases. All of the five hepatoid type cases stained positively. Two of the nine positively stained colorectal cancers were well differentiated, six were moderately differentiated and one was a mucinous type adenocarcinoma. The staining pattern was cytoplasmic and granular as described in benign and malignant hepatocytes. The percentage of immunostained cells was graded as follows: 0 (no staining); 1 ( > 0–5%); 2 ( > 5–50%); 3 ( > 50%). Of the 26 positive gastric tumours, 13 showed a staining score of 1, eight scored 2, and five scored 3. Four of the nine positive intestinal carcinomas showed a staining score of 1, and five scored 2. Conclusions: Our results show that Hep Par 1 is a highly sensitive marker of hepatocellular differentiation as demonstrated by the expression in gastric tumours with hepatoid histotype. However, the frequent reaction with neoplastic cells of gastric and bowel carcinomas shows a low grade of specificity of this antibody. Key words: Hep Par 1, immunohistochemistry, hepatocellular carcinoma. Received 18 February, revised 24 May, accepted 27 May 2002
INTRODUCTION Most metastatic lesions of the liver come from the gastrointestinal tract and are difficult to distinguish from primary liver cancers solely on the basis of histological
features, particularly when judgment must be rendered on a small biopsy specimen.1 Consequently, the histopathological distinction of primary from secondary liver tumours is often difficult and requires additional steps such as immunohistochemical staining with specific markers of hepatocellular differentiation. Various immunohistochemical markers have been proposed for the identification of hepatocellular carcinoma ( HCC), including a-fetoprotein ( AFP), a-1-antitrypsin, monoclonal carcino-embryonic antigen ( CEA), polyclonal CEA, factor XIIIa, ferritin, albumin, cytokeratins 8, 18, 7 and 19 and neuroendocrine markers such as chromogranin. 1– 3 More recently, a monoclonal antibody, Hep Par 1, reacting with a hepatocyte-specific epitope that is a large molecule ( > 150 000 kDa ) resistant to formalin fixation and tissue processing, has been proposed as an immunohistochemical marker for the identification of HCC. This antigen has an organelle ( possibly mitochondrial) localisation as suggested by the diffuse cytoplasmic granular immunostaining pattern.2– 6 However, the hepatic specificity of the epitope has recently been questioned, as cases of gastrointestinal adenocarcinoma have been found reactive to Hep Par 1. 3– 5 In this study we evaluated by immunohistochemistry the presence of the epitope that binds Hep Par 1 in primary gastric carcinomas and primary large bowel carcinomas. Our aim was to determine the entity of Hep Par 1 reactivity in gastrointestinal malignant neoplasms which, being potential metastatic liver tumours, could be misdiagnosed as primary liver tumours.
MATERIALS AND METHODS Tissue blocks from formalin-fixed, paraffin-embedded surgical specimens, resected from 39 patients with gastric carcinoma and 18 patients with colorectal adenocarcinoma, were retrieved from files of the Department of Human Pathology at the University of Messina, Italy. According to Lauren classification, gastric carcinomas were histologically classified as intestinal type ( 26 cases ), diffuse type ( five cases ), mixed type ( three cases) and with hepatoid differentiation ( five cases) . Moreover, colorectal adenocarcinomas were classified into well ( two cases ), moderately ( 14 cases ) and poorly ( one case) differentiated, as well as mucinous type ( one case ). Paraffin sections from normal liver tissue and from well differentiated HCCs, previously tested for Hep Par 1, were utilised as positive controls. Five-mm thick sections for each block were mounted on 3-aminopropyl triethoxysilane coated ( Sigma, USA) slides. Microwave-stimulated antigen retrieval was performed in 10 mM citrate buffer, at pH 6.0. Endogenous peroxidase was blocked with 0.3% H2O2 in absolute methanol for 30 min at room temperature ( RT). Successively, the sections were incubated overnight at 4°C with mouse monoclonal Hep Par 1 antibody ( clone OCH1
ISSN 0031–3025 printed/ ISSN 1465– 3931 online/ 02/ 050423 – 04 © 2002 Royal College of Pathologists of Australasia DOI:10.1080/ 0031302021000009333
424
Pathology (2002 ), 34, October
VILLARI et al.
TABLE 1
Detection of Hep Par 1 in gastric carcinomas Staining score
Gastric carcinomas Intestinal type Diffuse type Mixed type Hepatoid type
Positive rate
1
2
3
66.6% ( 26/ 39) 57.6% ( 15/ 26) 15.3% ( 4/ 26 ) 7.6% ( 2/ 26 ) 19.2% ( 5/ 26 )
13 7 2 1 3
8 6 0 1 1
5 2 2 0 1
E5.2.10; Dako, Denmark) at the dilution of 1:80 as previously reported.5,7,8 Following incubation with the primary antibody, a streptavidin– biotin– peroxidase method was employed ( Universal LSAB kit; Dako). Finally, 3,39 diaminobenzidine tetrahydrochloride- H2 O2 substrate solution was applied for 10 min, at RT in the dark. All slides were slightly counterstained with Mayer’s haematoxylin. As negative control, the primary antibody was replaced by PBS. The assessment of immunostained sections was performed on a consensus basis by two pathologists ( DV and RC), using a double-heade d microscope; the percentage of stained cells was graded as follows: 0 ( no staining ); 1 ( > 0– 5% ); 2 ( > 5– 50% ); 3 ( > 50% ).
RESULTS All of the obtained data are summarised in Tables 1 and 2. The staining pattern of Hep Par 1 in neoplastic cells of gastric and colorectal carcinomas was granular and diffuse throughout the cytoplasm ( Fig. 1a-d). Immunohistochemical staining was observed in 26 of 39 gastric carcinomas. Fifteen of the positive cases were intestinal type, four were diffuse type and two were mixed type. Seven intestinal type cases stained with a score of 1, while six cases stained with a score of 2 and two cases stained with a score of 3. Two diffuse type cases stained with an intensity of 1, while two cases stained with a score of 3. Two of the mixed type cases stained positively with a score of 1 and 2, respectively. All five hepatoid adenocarcinomas were stained, three of them with a staining score of 1, one with a staining score of 2 and one with a staining score of 3. Nine of the 18 colorectal adenocarcinomas stained positively. Two of positive cases were well differentiated, six were moderately differentiated and one was of the mucinous type. Both well differentiated type cases stained with a score of 1. One of the moderately differentiated cases stained with a score of 1 and five of the moderately differentiated cases stained with a score of 2. None of the poorly differentiated cases stained positively. The mucinous type case stained with a score of 1.
TABLE 2
A diffuse, granular cytoplasmic staining was encountered in normal liver tissue, while diffuse staining with variable intensity from cell to cell was seen in HCC control sections.
DISCUSSION Hep Par 1 stains the majority of HCCs, including hepatoblastomas and fibrolamellar variants, with a distinct granular cytoplasmic pattern.2,3,5,6,9 Focal staining has been reported in few cases of gastrointestinal malignancies and pancreatic adenocarcinomas.3,5 In the present study, we have documented positive immunostaining in neoplastic cells of gastric carcinomas ( 69% of the cases examined) and colorectal adenocarcinomas ( 50% of the cases examined). The reactivity for Hep Par 1 was diffuse and intense, similar to that observed in our control group of HCCs and previously described in primary malignancies of the liver.3,5 All of the neoplasms included in this study could be potentially metastatic to the liver. Moreover, Hep Par 1 immunoreactivity has been recently described in hepatoid adenocarcinomas of the stomach and has been considered as the expression of true hepatocellular differentiation in hepatoid foci outside the liver.7 Hepatoid tumours behave aggressively, irrespective of the anatomical site of origin, because of the extensive venous permeation and consequent metastasis. 10 The risk of a misdiagnosis in cases of hepatic metastases of hepatoid carcinomas is very high; therefore, the presence of Hep Par 1 immunoreactivity in a liver nodule should not always be considered evidence of primary hepatocellular carcinoma. Conversely, the absence of Hep Par 1 reactivity in a liver neoplasm is not always diagnostic for metastatic liver tumour as it has been demonstrated by the decreasing immunoreactivity to Hep Par 1 in HCC with reduced differentiation.4,11 All of the hepatoid adenocarcinomas included in this study stained positively for Hep Par 1 with a pattern that was more often focal, as described by Maitra et al. 7 Therefore, our results
Detection of Hep Par 1 in colorectal adenocarcinoma s Staining score
Colorectal carcinomas Well differentiated Moderately differentiated Mucinous type
Positive rate
1
2
3
50% ( 9/ 18 ) 22.2% ( 2/ 9) 66.6% ( 6/ 9) 1.1% ( 1/ 9)
4 2 1 1
5 0 5 0
0 0 0 0
IMMUNOEXPRESSION OF HEP PAR 1 IN GASTRIC AND BOWEL CARCINOMAS
425
Fig. 1 Hep Par 1 immunoexpression is evident in the cytoplasm of neoplastic cells: ( a) intestinal-type gastric carcinoma ( original magnification, ´20); ( b) mixed type ( intestinal and diffuse) gastric carcinoma ( original magnification, ´20 ); ( c) hepatoid carcinoma of stomach ( original magnification, ´40 ); ( d) well differentiated colorectal adenocarcinoma ( streptavidin–biotin immunoperoxidase stain, original magnification, ´20).
strongly suggest that Hep Par 1 reactivity in liver nodules should not be considered a peculiar immunohistochemical finding for hepatocellular carcinoma because it appears in gastric cancer as well as colorectal adenocarcinomas. The Hep Par 1 positivity encountered in gastric carcinoma can be explained by a common embryological derivation of both
liver and stomach from the foregut. Moreover, the positive immunoreaction for Hep Par 1 seen in colorectal adenocarcinomas is probably explained by the origin of the large bowel from primitive intestine, although from segments different to the liver. In fact, a variety of adult human malignancies not related to the gastrointestinal tract have
426
Pathology (2002 ), 34, October
VILLARI et al.
been found negative for Hep Par 1 reactivity.3 These data suggest a possible correlation between the presence of the epitope reacting with Hep Par 1 and the embryological origin of the tissue. In conclusion, Hep Par 1 is a highly sensitive marker of hepatocellular differentiation as demonstrated by its expression in gastric tumours of the hepatoid histotype. However, the reaction of Hep Par 1 with neoplastic cells of gastric and large bowel carcinomas reveals a low grade of specificity of this antibody, thus limiting its use as a marker for differential diagnosis between HCC and metastatic lesions arising from the gastrointestinal tract.
4.
5.
6.
7. Address for correspondence: Dr D. Villari, Department of Human Pathology, Policlinico Universitario, 98125 Messina, Italy. E-mail: [email protected]
References 1. Fucich LF, Cheles MK, Thung ST, Gerber MA, Marrogi AJ. Primary vs metastatic hepatic carcinoma. An immunohistochemical study of 34 cases. Arch Pathol Lab Med 1994; 118: 927– 30. 2. Leong AS-Y, Sormunen RT, Tsui WMS, Liew CT. Hep Par 1 and selected antibodies in the immunohistological distinction of hepatocellular carcinoma from cholangiocarcinoma, combined tumors and metastatic carcinoma. Histopathology 1998; 33: 318– 24. 3. Wennerberg AE, Nalesnik MA, Coleman WB. Hepatocyte paraffin 1:
8. 9.
10. 11.
a monoclonal antibody that reacts with hepatocytes and can be used for differential diagnosis of hepatic tumors. Am J Pathol 1993; 143: 1050– 4. Demetris AJ, Seaberg EC, Wennerberg A, Ionellie J, Michalopoulos G. Ductular reaction after submassive necrosis in humans. Special emphasis on analysis of ductular hepatocytes. Am J Pathol 1996; 149: 439– 48. Minervini MI, Demetris AJ, Lee RG, Carr BI, Madariaga J, Nalesnik MA. Utilization of hepatocyte-specific antibody in the immunocytochemical evaluation of liver tumors. Mod Pathol 1997; 10: 686– 92. Wu PC, Fang WSJ, Lau VKT, Lai CL, Lo CK, Lau JYN. Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers. Clinical and biological implications. Am J Pathol 1996; 149: 1167–75. Maitra A, Murakata LA, Albores-Saavedra J. Immunoreactivity for hepatocyte paraffin 1 antibody in hepatoid adenocarcinomas of the gastrointestinal tract. Am J Clin Pathol 2001; 115: 689– 94. Albores-Saavedra J, Hoang MP, Murakata LA, Sinkre P, Yaziji H. Atypical bile duct adenoma, clear cell type. A previously undescribed tumor of the liver. Am J Surg Pathol 2001; 25: 956– 60. Fasano M, Theise ND, Nalesnik M, et al. Immunohistochemica l evaluation of hepatoblastomas with use of the hepatocyte-specifi c marker, hepatocyte paraffin 1, and the polyclonal anti-carcinoembryonic antigen. Mod Pathol 1998; 11: 934– 8. Nagai E, Ueyama T, Takashi Y, Tsuneyoshi M. Hepatoid adenocarcinoma of the stomach. Cancer 1993; 72: 1827–35. Kumagai I, Masuda T, Sato S, Ishikawa K. Immunoreactivity to monoclonal antibody, Hep Par 1, in human hepatocellular carcinomas according to histopathological grade and histological pattern. Hepatol Res 2001; 20: 312–9.
ANATOMICAL
PATHOLOGY
Hep Par 1 in gastric and bowel carcinomas: an immunohistochemical study D. VILLARI, R. CARUSO , M. GROSSO , E. VITARELLI , M. RIGHI
AND
G. BARRESI
Department of Human Pathology, Polyclinic Pad.D, University of Messina, Messina, Italy
Summary Aims: Hep Par 1 has been described as a specific marker of hepatocellular differentiation and its immunohistochemica l use has been suggested as a helpful tool for hepatocellular carcinoma (HCC) diagnosis. Most metastatic liver tumours come from the gastrointestinal tract and usually can be distinguished from HCC only through histology. We evaluated by immunohistochemistry the specificity of Hep Par 1, studying the presence of the epitope that reacts with Hep Par 1 in primary gastric and colorectal cancers. Methods: A series of 39 cases of primary gastric and 18 cases of colorectal carcinoma were selected. Twenty-six of the 39 gastric carcinomas were of the intestinal type, six of the diffuse type, three of the mixed type and five had hepatoid differentiation. Two of the 18 colorectal adenocarcinomas were well differentiated, 14 moderately differentiated, one poorly differentiated and one was of the mucinous type. Five- mm sections were stained by immunohistochemistr y using Hep Par 1 as primary antibody. Results: Immunohistochemical staining was observed in 26 gastric carcinomas (69%) and nine large bowel carcinomas (50%). Fifteen of the 26 positive-stained gastric cancers were of intestinal type, four of diffuse type and two of mixed type cases. All of the five hepatoid type cases stained positively. Two of the nine positively stained colorectal cancers were well differentiated, six were moderately differentiated and one was a mucinous type adenocarcinoma. The staining pattern was cytoplasmic and granular as described in benign and malignant hepatocytes. The percentage of immunostained cells was graded as follows: 0 (no staining); 1 ( > 0–5%); 2 ( > 5–50%); 3 ( > 50%). Of the 26 positive gastric tumours, 13 showed a staining score of 1, eight scored 2, and five scored 3. Four of the nine positive intestinal carcinomas showed a staining score of 1, and five scored 2. Conclusions: Our results show that Hep Par 1 is a highly sensitive marker of hepatocellular differentiation as demonstrated by the expression in gastric tumours with hepatoid histotype. However, the frequent reaction with neoplastic cells of gastric and bowel carcinomas shows a low grade of specificity of this antibody. Key words: Hep Par 1, immunohistochemistry, hepatocellular carcinoma. Received 18 February, revised 24 May, accepted 27 May 2002
INTRODUCTION Most metastatic lesions of the liver come from the gastrointestinal tract and are difficult to distinguish from primary liver cancers solely on the basis of histological
features, particularly when judgment must be rendered on a small biopsy specimen.1 Consequently, the histopathological distinction of primary from secondary liver tumours is often difficult and requires additional steps such as immunohistochemical staining with specific markers of hepatocellular differentiation. Various immunohistochemical markers have been proposed for the identification of hepatocellular carcinoma ( HCC), including a-fetoprotein ( AFP), a-1-antitrypsin, monoclonal carcino-embryonic antigen ( CEA), polyclonal CEA, factor XIIIa, ferritin, albumin, cytokeratins 8, 18, 7 and 19 and neuroendocrine markers such as chromogranin. 1– 3 More recently, a monoclonal antibody, Hep Par 1, reacting with a hepatocyte-specific epitope that is a large molecule ( > 150 000 kDa ) resistant to formalin fixation and tissue processing, has been proposed as an immunohistochemical marker for the identification of HCC. This antigen has an organelle ( possibly mitochondrial) localisation as suggested by the diffuse cytoplasmic granular immunostaining pattern.2– 6 However, the hepatic specificity of the epitope has recently been questioned, as cases of gastrointestinal adenocarcinoma have been found reactive to Hep Par 1. 3– 5 In this study we evaluated by immunohistochemistry the presence of the epitope that binds Hep Par 1 in primary gastric carcinomas and primary large bowel carcinomas. Our aim was to determine the entity of Hep Par 1 reactivity in gastrointestinal malignant neoplasms which, being potential metastatic liver tumours, could be misdiagnosed as primary liver tumours.
MATERIALS AND METHODS Tissue blocks from formalin-fixed, paraffin-embedded surgical specimens, resected from 39 patients with gastric carcinoma and 18 patients with colorectal adenocarcinoma, were retrieved from files of the Department of Human Pathology at the University of Messina, Italy. According to Lauren classification, gastric carcinomas were histologically classified as intestinal type ( 26 cases ), diffuse type ( five cases ), mixed type ( three cases) and with hepatoid differentiation ( five cases) . Moreover, colorectal adenocarcinomas were classified into well ( two cases ), moderately ( 14 cases ) and poorly ( one case) differentiated, as well as mucinous type ( one case ). Paraffin sections from normal liver tissue and from well differentiated HCCs, previously tested for Hep Par 1, were utilised as positive controls. Five-mm thick sections for each block were mounted on 3-aminopropyl triethoxysilane coated ( Sigma, USA) slides. Microwave-stimulated antigen retrieval was performed in 10 mM citrate buffer, at pH 6.0. Endogenous peroxidase was blocked with 0.3% H2O2 in absolute methanol for 30 min at room temperature ( RT). Successively, the sections were incubated overnight at 4°C with mouse monoclonal Hep Par 1 antibody ( clone OCH1
ISSN 0031–3025 printed/ ISSN 1465– 3931 online/ 02/ 050423 – 04 © 2002 Royal College of Pathologists of Australasia DOI:10.1080/ 0031302021000009333
424
Pathology (2002 ), 34, October
VILLARI et al.
TABLE 1
Detection of Hep Par 1 in gastric carcinomas Staining score
Gastric carcinomas Intestinal type Diffuse type Mixed type Hepatoid type
Positive rate
1
2
3
66.6% ( 26/ 39) 57.6% ( 15/ 26) 15.3% ( 4/ 26 ) 7.6% ( 2/ 26 ) 19.2% ( 5/ 26 )
13 7 2 1 3
8 6 0 1 1
5 2 2 0 1
E5.2.10; Dako, Denmark) at the dilution of 1:80 as previously reported.5,7,8 Following incubation with the primary antibody, a streptavidin– biotin– peroxidase method was employed ( Universal LSAB kit; Dako). Finally, 3,39 diaminobenzidine tetrahydrochloride- H2 O2 substrate solution was applied for 10 min, at RT in the dark. All slides were slightly counterstained with Mayer’s haematoxylin. As negative control, the primary antibody was replaced by PBS. The assessment of immunostained sections was performed on a consensus basis by two pathologists ( DV and RC), using a double-heade d microscope; the percentage of stained cells was graded as follows: 0 ( no staining ); 1 ( > 0– 5% ); 2 ( > 5– 50% ); 3 ( > 50% ).
RESULTS All of the obtained data are summarised in Tables 1 and 2. The staining pattern of Hep Par 1 in neoplastic cells of gastric and colorectal carcinomas was granular and diffuse throughout the cytoplasm ( Fig. 1a-d). Immunohistochemical staining was observed in 26 of 39 gastric carcinomas. Fifteen of the positive cases were intestinal type, four were diffuse type and two were mixed type. Seven intestinal type cases stained with a score of 1, while six cases stained with a score of 2 and two cases stained with a score of 3. Two diffuse type cases stained with an intensity of 1, while two cases stained with a score of 3. Two of the mixed type cases stained positively with a score of 1 and 2, respectively. All five hepatoid adenocarcinomas were stained, three of them with a staining score of 1, one with a staining score of 2 and one with a staining score of 3. Nine of the 18 colorectal adenocarcinomas stained positively. Two of positive cases were well differentiated, six were moderately differentiated and one was of the mucinous type. Both well differentiated type cases stained with a score of 1. One of the moderately differentiated cases stained with a score of 1 and five of the moderately differentiated cases stained with a score of 2. None of the poorly differentiated cases stained positively. The mucinous type case stained with a score of 1.
TABLE 2
A diffuse, granular cytoplasmic staining was encountered in normal liver tissue, while diffuse staining with variable intensity from cell to cell was seen in HCC control sections.
DISCUSSION Hep Par 1 stains the majority of HCCs, including hepatoblastomas and fibrolamellar variants, with a distinct granular cytoplasmic pattern.2,3,5,6,9 Focal staining has been reported in few cases of gastrointestinal malignancies and pancreatic adenocarcinomas.3,5 In the present study, we have documented positive immunostaining in neoplastic cells of gastric carcinomas ( 69% of the cases examined) and colorectal adenocarcinomas ( 50% of the cases examined). The reactivity for Hep Par 1 was diffuse and intense, similar to that observed in our control group of HCCs and previously described in primary malignancies of the liver.3,5 All of the neoplasms included in this study could be potentially metastatic to the liver. Moreover, Hep Par 1 immunoreactivity has been recently described in hepatoid adenocarcinomas of the stomach and has been considered as the expression of true hepatocellular differentiation in hepatoid foci outside the liver.7 Hepatoid tumours behave aggressively, irrespective of the anatomical site of origin, because of the extensive venous permeation and consequent metastasis. 10 The risk of a misdiagnosis in cases of hepatic metastases of hepatoid carcinomas is very high; therefore, the presence of Hep Par 1 immunoreactivity in a liver nodule should not always be considered evidence of primary hepatocellular carcinoma. Conversely, the absence of Hep Par 1 reactivity in a liver neoplasm is not always diagnostic for metastatic liver tumour as it has been demonstrated by the decreasing immunoreactivity to Hep Par 1 in HCC with reduced differentiation.4,11 All of the hepatoid adenocarcinomas included in this study stained positively for Hep Par 1 with a pattern that was more often focal, as described by Maitra et al. 7 Therefore, our results
Detection of Hep Par 1 in colorectal adenocarcinoma s Staining score
Colorectal carcinomas Well differentiated Moderately differentiated Mucinous type
Positive rate
1
2
3
50% ( 9/ 18 ) 22.2% ( 2/ 9) 66.6% ( 6/ 9) 1.1% ( 1/ 9)
4 2 1 1
5 0 5 0
0 0 0 0
IMMUNOEXPRESSION OF HEP PAR 1 IN GASTRIC AND BOWEL CARCINOMAS
425
Fig. 1 Hep Par 1 immunoexpression is evident in the cytoplasm of neoplastic cells: ( a) intestinal-type gastric carcinoma ( original magnification, ´20); ( b) mixed type ( intestinal and diffuse) gastric carcinoma ( original magnification, ´20 ); ( c) hepatoid carcinoma of stomach ( original magnification, ´40 ); ( d) well differentiated colorectal adenocarcinoma ( streptavidin–biotin immunoperoxidase stain, original magnification, ´20).
strongly suggest that Hep Par 1 reactivity in liver nodules should not be considered a peculiar immunohistochemical finding for hepatocellular carcinoma because it appears in gastric cancer as well as colorectal adenocarcinomas. The Hep Par 1 positivity encountered in gastric carcinoma can be explained by a common embryological derivation of both
liver and stomach from the foregut. Moreover, the positive immunoreaction for Hep Par 1 seen in colorectal adenocarcinomas is probably explained by the origin of the large bowel from primitive intestine, although from segments different to the liver. In fact, a variety of adult human malignancies not related to the gastrointestinal tract have
426
Pathology (2002 ), 34, October
VILLARI et al.
been found negative for Hep Par 1 reactivity.3 These data suggest a possible correlation between the presence of the epitope reacting with Hep Par 1 and the embryological origin of the tissue. In conclusion, Hep Par 1 is a highly sensitive marker of hepatocellular differentiation as demonstrated by its expression in gastric tumours of the hepatoid histotype. However, the reaction of Hep Par 1 with neoplastic cells of gastric and large bowel carcinomas reveals a low grade of specificity of this antibody, thus limiting its use as a marker for differential diagnosis between HCC and metastatic lesions arising from the gastrointestinal tract.
4.
5.
6.
7. Address for correspondence: Dr D. Villari, Department of Human Pathology, Policlinico Universitario, 98125 Messina, Italy. E-mail: [email protected]
References 1. Fucich LF, Cheles MK, Thung ST, Gerber MA, Marrogi AJ. Primary vs metastatic hepatic carcinoma. An immunohistochemical study of 34 cases. Arch Pathol Lab Med 1994; 118: 927– 30. 2. Leong AS-Y, Sormunen RT, Tsui WMS, Liew CT. Hep Par 1 and selected antibodies in the immunohistological distinction of hepatocellular carcinoma from cholangiocarcinoma, combined tumors and metastatic carcinoma. Histopathology 1998; 33: 318– 24. 3. Wennerberg AE, Nalesnik MA, Coleman WB. Hepatocyte paraffin 1:
8. 9.
10. 11.
a monoclonal antibody that reacts with hepatocytes and can be used for differential diagnosis of hepatic tumors. Am J Pathol 1993; 143: 1050– 4. Demetris AJ, Seaberg EC, Wennerberg A, Ionellie J, Michalopoulos G. Ductular reaction after submassive necrosis in humans. Special emphasis on analysis of ductular hepatocytes. Am J Pathol 1996; 149: 439– 48. Minervini MI, Demetris AJ, Lee RG, Carr BI, Madariaga J, Nalesnik MA. Utilization of hepatocyte-specific antibody in the immunocytochemical evaluation of liver tumors. Mod Pathol 1997; 10: 686– 92. Wu PC, Fang WSJ, Lau VKT, Lai CL, Lo CK, Lau JYN. Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers. Clinical and biological implications. Am J Pathol 1996; 149: 1167–75. Maitra A, Murakata LA, Albores-Saavedra J. Immunoreactivity for hepatocyte paraffin 1 antibody in hepatoid adenocarcinomas of the gastrointestinal tract. Am J Clin Pathol 2001; 115: 689– 94. Albores-Saavedra J, Hoang MP, Murakata LA, Sinkre P, Yaziji H. Atypical bile duct adenoma, clear cell type. A previously undescribed tumor of the liver. Am J Surg Pathol 2001; 25: 956– 60. Fasano M, Theise ND, Nalesnik M, et al. Immunohistochemica l evaluation of hepatoblastomas with use of the hepatocyte-specifi c marker, hepatocyte paraffin 1, and the polyclonal anti-carcinoembryonic antigen. Mod Pathol 1998; 11: 934– 8. Nagai E, Ueyama T, Takashi Y, Tsuneyoshi M. Hepatoid adenocarcinoma of the stomach. Cancer 1993; 72: 1827–35. Kumagai I, Masuda T, Sato S, Ishikawa K. Immunoreactivity to monoclonal antibody, Hep Par 1, in human hepatocellular carcinomas according to histopathological grade and histological pattern. Hepatol Res 2001; 20: 312–9.