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Home , Angioma, Angiosarcoma, Cavernous hemangioma, Hemangioendothelioma, Hemangioma, Lesion

The Korean Journal of 2006; 40: 361-7

Immunohistochemical Characteristics of Kaposi and its Mimicries

Kyoung Bun Lee∙Hye Seung Lee1 Background : The differential diagnosis of Kaposi sarcoma includes many that range Hee Eun Lee∙So Yeon Park1 from benign disease to malignant tumors. However, little information is available about the Jin Haeng Chung1 immunohistochemical characteristics of Kaposi sarcoma. Methods : The expressions of 13 Gheeyoung Choe1∙Woo Ho Kim various proteins (HHV-8 LNA-1, Ki-67, bcl-2, p53, CD31, CD34, factor VIII, D2-40, vimentin, Kye Yong Song2 SMA, S-100, EMA, and c-kit) were evaluated immunohistochemically in 49 vascular tumors including 16 Kaposi , 8 , 2 , and 23 benign vascular tumors with using the tissue array method. Results : All 16 cases of Kaposi sarcoma Department of Pathology, Seoul National University College of Medicine, Seoul; showed nuclear staining for HHV-8 LNA-1, whereas all the cases of and benign 1Department of Pathology, Seoul National vascular were negative for HHV-8 LNA-1 (p<0.001). All Kaposi sarcoma were positive University Bundang Hospital, Sungnam; for D2-40, which is a marker of lymphatic differentiation, but 25% of the benign vascular lesions 2Department of Pathology, Chung-Ang and 30.4% of the angiosarcoma were positive for D2-40 (p<0.001). The mean proliferation University College of Medicine, Seoul, index as assessed by Ki-67 immunostaining revealed no difference between the benign and Korea malignant vascular lesions (p>0.05). No Kaposi sarcoma showed a bcl-2 expression, but 62.5% of the angiosarcomas and 21.7% of the benign vascular tumors had bcl-2 expressions (p= Received : August 17, 2006 0.005). Conclusions : Immunohistochemical detection of HHV-8 LNA-1 and D2-40 are use- Accepted : September 19, 2006 ful tools to differentiate Kaposi sarcoma from other vascular tumors. Corresponding Author Hye Seung Lee, M.D. Department of Pathology, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Sungnam 463-707, Korea Tel: 031-787-7714 Fax: 031-787-4012 Key Words : Sarcoma, Kaposi; Herpesvirus 8, human; Latent nuclear antigen; Monoclonal E-mail: [email protected] antibody D2-40; Immunohistochemistry

Kaposi sarcoma was described as ‘‘idiopathic multiple pigment- and pyogenic should be distinguished.1,7 ed sarcoma of the ’’ by Kaposi in 1872 and it was known as More advanced and cellular lesions must be differentiated from a relatively rare tumor of the elderly until the advent of acquired cutaneous angiosarcoma, aneurysmal fibrous histiocytoma, spin- immunodeficiency syndrome (AIDS) and organ transplantation.1 dle cell , dermatofibrosarcoma protuberans and vas- In 1994, detection of a viral DNA fragment in Kaposi sarcoma cular or pilar leiomyomas.1,7 By performing immunohistochem- tissue was reported and this virus was called Kaposi sarcoma-asso- ical staining for endothelial cell markers such as CD31 and CD34, ciated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8).2,3 Kaposi sarcoma can be differentiated from nonvascular spindle The virus has been revealed to be present in all cases of Kaposi cell . Therefore, the difficulty in the diagnosing Kaposi sarcoma.4 KSHV/HHV-8 is also found in lymphoproliferative sarcoma usually occurs in differentiating it from benign vascu- disorders like primary effusion lymphoma and multicentric Castle- lar tumors and angiosarcoma. man’s disease.5,6 Detection of KSHV/HHV8 in a is diagnostic for the The differential diagnosis of Kaposi sarcoma includes variable Kaposi sarcoma and molecular methods have traditionally been , depending on the histopathological stages. For the early used to identify KSHV/HHV8. Polymerase chain reaction ampli- lesions, benign vascular proliferation diseases such as acroangio- fication (PCR), direct in situ hybridization and reverse transcrip- dermatitis (stasis dermatitis), benign lymphangioendothelioma, tase (RT) in situ PCR have been used to detect the viral genes.6,8,9 targetoid hemosiderotic hemangioma, immature , bacillary Monoclonal antibody to HHV-latent nuclear antigen-1 (LNA-1),

361 362 Kyoung Bun Lee Hye Seung Lee Hee Eun Lee, et al. which is a protein encoded by the open reading frame-73 (ORF- MATERIALS AND METHODS 73) of the viral genome, has recently become commercially avail- able and it is suitable for performing immunohistochemistry on Patient selection formalin fixed tissues. LNA-1 is expressed predominantly dur- ing viral latency, and it interacts with p53 and suppresses the Forty-nine cases of vascular tumors from the files of the Depart- transcriptional activity and ability of p53 to induce apoptosis.10 ment of Pathology, Seoul National University Hospital in Seoul Furthermore, LNA-1 binds to the retinoblastoma (rb) protein and the Seoul National University Bundang Hospital in Gyeong- in the ‘pocket lesion’ to free a gene regulatory protein called E2F gi, Korea were examined in this study. Sixteen Kaposi sarcomas, and this acts as a transcription co-factor that activates the tran- eight angiosarcomas, two hemangioendotheliomas were includ- scription of genes that are involved in cell cycle progression.11 ed in low to high grade malignant groups. Twen- Although KSHV/HHV-8 infection has an important role in ty three benign vascular lesions included three acroangiodermati- the pathogenesis of the Kaposi sarcoma, whether Kaposi sarco- tis, two , four capillary , three cav- ma originates from blood vessels or lymphatic endothelial cells ernous hemangiomas, one cherry , one hemangioma, one is controversial. Several studies have shown that vascular endothe- intravascular histiocytosis, and eight pyogenic . lial cell markers like CD31 and factor VIII were present in Kaposi sarcoma,12 and this supports the origin of Kaposi sarcoma from Tissue array methods blood vessels. On the other hand, the presence of selective lym- phatic endothelial cell markers such as vascular endothelial growth All of the tissues were evaluated using tissue-array methods. factor receptor-3 (VEGF-3) and podoplanin and the absence of Core tissue (2 mm in diameter) of the tumors were taken specific PAL-E antigen in the ultra- from individual paraffin-embedded tissues and they were arranged structual features are the evidences against the origin of Kaposi in a new recipient paraffin block (tissue array block) using a tre- sarcoma from blood vessels, rather suggesting the lymphatic phine apparatus (Superbiochips Laboratories, Seoul, Korea).22 endothelial cell origin.13-15 An adequate case for inclusion into the study was defined as a In this study, we compared the immunohistochemical charac- tumor occupying more than 10% of the core area. teristics of Kaposi sarcoma with other vascular lesions that mimic the Kaposi sarcoma. To this purpose, we selected the molecular Immunohistochemistry markers that confirmed the status of KSHV/HHV8 infection, the cell type, the proliferation activity of the tumor cells and Formalin-fixed, paraffin-embedded four- m thick sections tumor related protein. Monoclonal antibody to HHV8-LNA-1 from the tissue-array block were deparaffinized and dehydrated. was immunohisochemically applied on formalin fixed tissue for Immunohistochemical staining against 13 various antigens was the detection of KSHV/HHV8. For the cell type, vascular endo- performed using a streptavidin peroxidase procedure after an thelial cell markers (CD31, CD34 and factor VIII), a selective antigen retrieval process. Table 2 presents the antibodies used lymphatic endothelial cell marker named D2-40,16 other mes- in this study and the antigen retrieval methods. enchymal cell makers (alpha- actin (SMA) and The percentage of Ki-67 positive tumor cells was used as the S-100 protein) and epithelial membrane antigen (EMA) were proliferation index. The cut-off value for p53 was based on the tested. In addition, we assessed the expression pattern of other previously established cut-off values.23 For the other proteins, markers including Ki-67, bcl-2, p53 and c-kit. Ki-67 is com- the immunostaining pattern of each case was scored as positive monly used for the evaluation of the cellular proliferation activ- (strong staining), weakly positive (faint staining) or negative ity in diagnostic pathology, and bcl-2, c-kit and p53 are tumor (absence of staining), and the percentage of positive neoplastic related proteins that are involved in controlling the cell death cells was counted. For statistical analysis of this data, the results and intracellular signaling. The expression of the above proteins of immunostaining were considered to be positive if 10% or in Kaposi sarcoma has been individually examined in various more of the neoplastic cells were strongly stained. previous studies with the variable results,17-21 but this is the first For the immunostaining for HHV-8 LNA-1, we used the study in which the various protein markers that are routinely human control slide for immunohistochemisty (Superbiochips used in pathologic diagnosis were all checked together for mak- Laboratories, Seoul, Korea).24 The expression of HHV-8 LNA-1 ing the differential diagnosis of vascular lesions. was not found in all the neoplastic or non-neoplastic tissues in- Immunohistochemical Characteristics of Kaposi Sarcoma Compared with Its Mimics 363

cluding the skin, breast, pancreas, , , , acquired immune deficiency disease (AIDS), diabetes mellitus, , salivary gland, bile duct, , gallbladder, colon, kidney, medication and autoimmune disease. Four patients’ serum prostate, seminal vesicle, testis, uterus, placenta, adrenal gland, samples were anti-HIV positive. Two cases showed multiple thyroid, brain and their various tumors. lesions and the others showed single lesion. Case nine had metas- tasis to the tonsil from the skin. The distribution of histologic Statistics stage was not different according to the HIV serology or the immune status. The 2 test or the student-T test was used to compare the ex- pression pattern between Kaposi sarcoma and the other vascular Immunohistochemistry of HHV-8 LNA-1 tumors. The results were considered as statistically significant at p values of <0.05. All statistical analyses were conducted using All sixteen cases of Kaposi sarcoma (100%) showed nuclear the SPSS11.0 (SPSS, Chicago, IL). staining for HHV-8 LNA-1, whereas all the cases of angiosar- coma and the other benign vascular tumors were negative for this antigen (p<0.001). HHV-8 LNA-1 staining had a sensitivi- RESULTS ty of 100% and specificity of 100% for detecting Kaposi sarco- ma. The positive staining was always diffuse in distribution and Clinicopathological features of Kaposi sarcoma strong in density (Fig. 1A-C).

The clinicopathological features of the Kaposi sarcoma patients Immunohistochemistry of the cell type proteins are listed in Table 1. The mean age of the 16 patients was 56.5± 16.0 years (age range: 24 to 82). Fourteen patients were male The results of immunostaining for the other markers are and two were female. The histologic stages were as follows: three summarized in Table 3. All forty-nine vascular tumors were cases (18.8%) were at the patch stage, six cases (37.5%) were at positively stained for vimentin and vascular makers such as the plaque stage and seven cases (43.8%) were at the nodular CD31, CD34 and factor VIII, which supported their diagnosis. stage. Ten out of 16 patients had the predisposing factors of SMA, S-100 and EMA were totally negative in all cases, which immuno-compromised status including organ transplantation, meant that no other mensenchymal differentiation was mesent in the selected cases. All sixteen Kaposi sarcomas revealed positive Table 1. Clinical features of 16 Kaposi sarcoma cases cytoplasmic staining for D2-40, which is a selective lymphatic endothelial cell marker. The benign vascular lesions and angio- Predis- Proce- Case Site Age Sex HIV Stage posing sarcoma showed the positive staining for D2-40 in 30.4% and dure factor 1 Skin, foot 82 M Negative Plaque No Table 2. Antibodies used for immunohistochemical study 2 Lung 24 M Biopsy Negative Nodular TPL Retrieval- 3 Skin, ankle 49 M Biopsy Negative Patch RA Antibody Dilution Source 4 Tonsil 54 M Biopsy Negative Nodular TPL methods 5 Skin, hand 70 M Biopsy Negative Nodular No HHV-8 LNA-1 Decloaking 1:50 Advanced Biotechnologies 6 Skin, arm 41 M Biopsy Positive Plaque AIDS chamber Inc. (Maryland, USA) 7 Ileum 41 M Biopsy Positive Nodular AIDS Ki-67 Microwave 1:100 DAKO (Glostrup, Denmark) 8 Skin 49 M Biopsy Positive Plaque AIDS CD31 Microwave 1:40 DAKO (Glostrup, Denmark) 9 Skin, foot 58 M Biopsy Negative Nodular DM CD34 Microwave 1:400 IMMUNOTECH 10 Skin, foot 71 M Biopsy Negative Nodular No (Marseille, France) 11 Skin, foot 62 M Biopsy Negative Plaque TPL Factor VIII None 1:200 DAKO (Glostrup, Denmark) 12 Oral cavity 32 M Biopsy Positive Plaque AIDS D2-40 Microwave 1:100 DAKO (Glostrup, Denmark) 13 Skin, 72 F Biopsy Negative Nodular Steroid Vimentin Proteinase K 1:150 DAKO (Glostrup, Denmark) 14 Skin, foot 69 M biopsy Negative Patch No SMA Proteinase K 1:150 DAKO (Glostrup, Denmark) 15 Skin, hand 80 M Biopsy Negative Plaque No S-100 None 1:500 DAKO (Glostrup, Denmark) 16 Skin, foot 50 F Biopsy Negative Patch No EMA None 1:200 DAKO (Glostrup, Denmark) c-kit Microwave 1:250 DAKO (Glostrup, Denmark) TPL, organ transplantation; RA, rheumatic arthritis; DM, diabetes melli- Bcl-2 Microwave 1:100 DAKO (Glostrup, Denmark) tus; AIDS, acquired immune deficiency syndrome; Steroid, long-term p53 Microwave 1:100 DAKO (Glostrup, Denmark) steroid medication. 364 Kyoung Bun Lee Hye Seung Lee Hee Eun Lee, et al.

25.0% of the cases, respectively (p<0.001). Benign vascular lesions Immunohistochemistry for the proliferation and tumor showing positive activity included two acroangiodermatitis, one related proteins , one , two pyogenic gran- ulomas and one . The staining pattern The proliferation index (Ki-67) is listed in Table 4. The mean was diffuse and cytoplasmic (Fig. 1D-F). value of the proliferation index in benign lesions was 16.0±3.6% and it was higher than that in the low or high malignant lesions (respectively 9.5±2.4% and 12.4±4.8%). Low malignancies

A B C

D E F

G H I

J K L

Fig. 1. Immunohistochemistry of HHV8 LNA1 revealed diffuse nuclear staining in Kaposi sarcoma (A), but no positivity in angiosarcoma (B) and (C). Expression of D2-40 was found along the vascular channel in Kaposi sarcoma (D), but not found in angiosar- coma (E) and (F). Bcl-2 was not expressed in Kaposi sarcoma (G), but positively stained in angiosarcoma (H) and pyogenic granuloma (I). Immunohistochemistry of p53 showed focal weak nuclear staining in Kaposi sarcoma (J) but strong positivity in angiosarcoma (K), but negative staining in cavernous hemangioma (L). Immunohistochemical Characteristics of Kaposi Sarcoma Compared with Its Mimics 365

Table 3. The results of immunohistochemical stainings in vas- Table 4. Ki-67 labeling index in vascular tumors cular tumors Mean of positive rate (%) p-value Kaposi Angiosar- p Antibody Benign 16.0±3.6 0.310 sarcoma coma value Low malignanya 9.5±2.4 HHV-8 LNA-1 0/23 (0.0%) 16/16 (100.0%) 0/8 (0.0%) <0.001 High malignancyb 12.4±4.8 D2-40 7/23 (30.4%) 16/16 (100.0%) 2/8 (25.0%) <0.001 Kaposi sarcoma 10.0±2.6 0.696 CD31 23/23 (100.0%) 16/16 (100.0%) 8/8 (100.0%) Angiosarcoma 12.0±4.8 CD34 23/23 (100.0%) 16/16 (100.0%) 8/8 (100.0%) factor VIII 23/23 (100.0%) 16/16 (100.0%) 8/8 (100.0%) a, Kaposi sarcoma and hemangioendothelioma were included; b, Angio- Vimentin 23/23 (100.0%) 16/16 (100.0%) 8/8 (100.0%) sarcoma was included. SMA 0/23 (0.0%) 0/16 (0.0%) 0/8 (0.0%) S-100 0/23 (0.0%) 0/16 (0.0%) 0/8 (0.0%) nostic accuracy, this detection method for HHV-8 LNA-1 by EMA 0/23 (0.0%) 0/16 (0.0%) 0/8 (0.0%) immunohistochemical staining on a formalin fixed paraffin block c-kit 0/23 (0.0%) 0/16 (0.0%) 1/8 (12.5%) 0.164 bcl-2 5/23 (21.7%) 0/16 (0.0%) 5/8 (62.5%) 0.005 was easy to do and it was easy to interpret the result. The posi- p53 0/23 (0.0%) 1/16 (6.3%) 1/8 (12.5%) 0.295 tive cases for HHV-8 LNA-1 showed diffuse and strong nucle- ar staining which was independent of the stage and immune sta- included Kaposi sarcoma and hemangioendothelioma and high tus of patients. These features increase the value of immunohis- malignancies included angiosarcoma. There was no difference tochemical staining for HHV-8 LNA-1 in the differential diag- of the Ki-67 labeling index between Kaposi sarcoma and angio- nosis between Kaposi sarcoma and those lesions that mimic it. sarcoma (10.0±2.6% and 12.0±4.8%, respectively, p=0.696). D2-40 is a monoclonal antibody to Mr 40,000 O-linked sialo- Any differences of the proliferation index according to the tumor glycoprotein, which is expressed in normal lymphatic endothe- stages and HIV status were not found among the Kaposi sarco- lium and vascular tumors such as , Kaposi sarcoma ma (data not shown). and angiosarcoma. In this study, all the Kaposi sarcoma showed The expression of bcl-2 was frequently found in benign vascu- strong positivity to both D2-40 and blood vessel endothelium lar lesions and angiosarcoma (21.7% and 62.5%, respectively), markers as CD31 and Factor VIII, which suggested that Kaposi but not in the Kaposi sarcoma. This expression pattern had sig- sarcoma may originate from pluripotent cells that have the abili- nificant difference (p=0.005) (Fig. 1G-I). The expression of p53 ty to undergo both lymphatic and blood vessel differentiation. revealed no significant difference between the groups. The stain- In addition to Kaposi sarcoma, positive staining for D2-40 was ing of p53 showed diffuse nuclear staining in one case of angio- found in two out of eight angiosarcomas in this study. This result sarcoma and focal weak staining in one case of Kaposi sarcoma, is similar to that of other studies,16,25 and it has been suggested which was at the plaque stage (Fig. 1J-L). Only one case of an- that angiosarcoma with lymphatic differentiation could be sep- giosarcoma was positively stained for c-kit, but all the Kaposi arated as a substantial subtype from classical angiosarcoma.14 In sarcomas and benign vascular lesions were negatively stained. our study, a portion of the benign vascular lesions showed positive staining for D2-40 as in Previous studies.16 It may be explained by that neoplastic conditions can induce the aberrant expression DISCUSSION of lymphatic markers in the vascular endothelium or that lym- phangioma can be misdiagnosed as hemangioma. Although a Kaposi sarcoma displays a broad spectrum of clinical and his- portion of the benign vascular lesions and angiosarcoma revealed topathological features and the differential diagnosis can include a positive reaction to D2-40, the constant expression of D2-40 in numerous diseases from benign vascular tumors and inflamma- Kaposi sarcoma, irrespective of the clinical stages, is quite help- tory condition to malignant tumors such as angiosarcoma. So ful for making the differential diagnosis of Kaposi sarcoma. precise diagnostic decision making is needed to manage these In general, the proliferation index (Ki-67) has been supposed patients. to be higher in malignant neoplasms than in benign neoplasms. We could detect KSHV/HHV-8 by immunohistochemical In the previous reports, angiosarcoma in the deep soft tissue with staining of HHV-8 LNA-1 in the formalin fixed paraffin sec- a high Ki-67 index had the poor prognosis, and Kaposi sarcoma tions of sixteen Kaposi sarcoma cases. The exclusive expression was revealed to have a high proliferation index irrespective of of HHV-8 LNA-1 in Kaposi sarcoma resulted in perfect sensi- the clinicopathological stages.21 However, all the cases included tivity (100%) and specificity (100%). In addition to the diag- in this study showed a low to moderate proliferation index around 366 Kyoung Bun Lee Hye Seung Lee Hee Eun Lee, et al.

10%. This result may be due to the location of tumor. Most of Engl J Med 1995; 332: 1181-5. the selected cases were superficially located in the skin except 5. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM, Kaposi’s for three cases in the lung, ileum and tonsil. Therefore, the pro- sarcoma-associated herpesvirus like DNA sequences in AIDS-related liferation index is probably not a useful marker for making the body-cavity-based lymphomas. N Engl J Med 1995; 332: 1186-91. differential diagnosis of cutaneous vascular tumors. 6. Soulier J, Grollet L, Oksenhendler E, et al. Kaposi’s sarcoma-associ- In this study, immunostaining for bcl-2 showed a different ated herpesvirus-like DNA sequences in multicentric Castleman’s expression status between Kaposi sarcoma and its mimicries with disease. Blood 1995; 86: 1276-80. statistical significance. The expression of bcl-2 was not found 7. Weeden D. Vascular tumor In Skin Pathology. 2nd ed. ChurchilLiv- in Kaposi sarcoma but noted in angiosarcoma and benign vas- ingstone, 2002; 1001-43. cular tumors. In the previous studies, the expression of bcl-2 in 8. Said JW, Shintaku IP, Asou H, et al. Herpesvirus 8 inclusions in pri- Kaposi sarcoma increased along with progression of stage.17-20 mary effusion lymphoma: report of a unique case with T-cell phe- This discordance may be due to the early stage of the selected notype. Arch Pathol Lab Med 1999; 123: 257-60. cases or the weak intensity of staining. 9. Wakely PE Jr, Menezes G, Nuovo GJ. Primary effusion lymphoma: An abnormal p53 expression was found in one of eight angio- cytopathologic diagnosis using in situ molecular genetic analysis for sarcoma cases and one of sixteen Kaposi sarcomas. According to human herpesvirus 8. Mod Pathol 2002; 15: 944-50. a previous study, p53 was immunopositive in the nodular stage 10. Friborg J Jr, Kong W, Hottiger MO, Nabel GJ. P53 inhibition by the and in the metastatic lesions of Kaposi sarcoma rather than in LANA protein of KSHV protects against cell death. Nature 1999; 402: the primary lesion.18 Yet in our study, the positive rate for p53 889-94. was too low to analyze the staining pattern according to the stage 11. Radkov SA, Kellam P, Boshoff C. The latent nuclear antigen of Kaposi or clinical history. The expression of c-kit was found in only one sarcoma-associated herpesvirus targets the retinoblastoma-E2F path- case of eight angiosarcomas. The expression of c-kit was reported way and with the oncogene Hras transforms primary rat cells. Nat in angiosarcoma and Kaposi sarcoma in another study, in which Med 2000; 6: 1121-7. the positive rate was 56% and 15% in angiosarcoma and Kaposi 12. Facchetti F, Lucini L, Gavazzoni R, Callea F. Immunomorphological sarcoma, respectively.26 In one in vitro study that studied dermal analysis of the role of blood vessel endothelium in the morphogen- microvascular endothelial cells, c-kit was an essential component esis of cutaneous Kaposi’s sarcoma: a study of 57 cases. Histopathol- of KSHV-mediated transformation of endothelial cells and tar- ogy 1988; 12: 581-93. geted therapy against PDGF receptor/c-kit led to a reduction of 13. Lymboussaki A, Partanen TA, Olofsson B, et al. Expression of the cutaneous Kaposi sarcoma lesions in AIDS-related patients.27-29 vascular endothelial growth factor C receptor VEGFR-3 in lymphatic In conclusion, immunohistochemical staining for HHV-8 endothelium of the skin and in vascular tumors. Am J Pathol 1998; LNA-1, D2-40 and bcl-2 on a formalin fixed paraffin block is a 153: 395-403. reliable and cost-effective method for detecting KSHV and dif- 14. Breiteneder-Geleff S, Soleiman A, Kowalski H, et al. 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