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Classic Kaposi sarcoma with sarcoid-like granulomas: A case report and literature review
Experimental and Molecular Pathology 87 (2009) 89–93
Contents lists available at ScienceDirect
Experimental and Molecular Pathology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y e x m p
Review
Classic Kaposi sarcoma with sarcoid-like granulomas: A case report and literature review☆ Nilufer Onak Kandemir a,⁎, Gamze Yurdakan a,1, Sibel Bektas a,1, Nilgun Solak Tekin b,1 a b
Department of Pathology, School of Medicine, Zonguldak Karaelmas University, 67600, Kozlu, Zonguldak, Turkey Department of Dermathology, School of Medicine, Zonguldak Karaelmas University, Zonguldak, Turkey
a r t i c l e
i n f o
Article history: Received 1 April 2009 and in revised form 30 July 2009 Available online 10 August 2009 Keywords: Granuloma Kaposi sarcoma Sarcoidosis
a b s t r a c t The occurrence of granulomatous reactions within lymph nodes that drain carcinomas is well known but uncommon. Even more rarely, granulomas may occur within the stroma of tumors. These lesions, called sarcoid-like reactions, commonly accompany carcinomas but are very rare in sarcomas. This study presents a case of classic Kaposi sarcoma that contained sarcoid-like granulomas, with a literature review. A soft tissue lesion of the foot was excised from a 74-year-old male. Histopathological examination showed that the tumor tissue consisted of spindle cells, areas of atypical vascular proliferation, and extravasated erythrocytes surrounded by non-caseating granulomas. The patient had no clinical or laboratory findings of sarcoidosis. The case was interpreted as “Kaposi sarcoma containing sarcoid-like granulomas”. The association of soft tissue sarcomas with a granulomatous reaction is very rare. A granulomatous reaction is reported to be a good prognostic indicator in several carcinoma types, although its importance in sarcomas is unclear. © 2009 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . Case report. . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . Clinical findings . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . Histology . . . . . . . . . . . . . . . . Histochemistry and immunohistochemistry Discussion . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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Introduction Kaposi's sarcoma (KS) is an uncommon, multifocal, low-grade vascular neoplasia. Disrupted immunological mechanisms contribute extensively to the development of this tumor (Ensoli et al., 2001; Pantanowitz et al., 2009). A granulomatous reaction is a specific, chronic tissue reaction accompanied by epithelioid histiocytes and
☆ This study was presented as a poster in XXVIIth Congress of the International Academy of Pathology held in 12–17 September 2007 in Athens, Greece. ⁎ Corresponding author. Fax: +90 372 261 01 55. E-mail addresses: [email protected] (N. Onak Kandemir), [email protected] (G. Yurdakan), [email protected] (S. Bektas), [email protected] (N.S. Tekin). 1 Fax: +90 372 261 01 55. 0014-4800/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yexmp.2009.07.010
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multinucleated giant cells (Agostini et al., 1998). The immune response mediated by T cells plays a role in the pathogenesis of granulomas and may have an infectious or non-infectious cause (Zumla and James, 1996). The occurrence of granulomatous reactions within lymph nodes that drain carcinomas is well known but uncommon (Brincker, 1992). Even more rarely, granulomas may occur within the stroma of malignancies (Llombart and Escudero, 1970). These lesions, also called sarcoid-like reactions, commonly accompany carcinomas but are very rare in sarcomas (Cohen and Kurzrock, 2007). These histological changes are believed to be a direct tissue response to tumor antigens or tumor tissues (Pavic et al., 2008). To our knowledge, no case of KS accompanied by a sarcoid-like reaction has been reported in the English-language literature. Here, we present a case of classical KS with sarcoid-like granulomas and review the relevant literature.
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N. Onak Kandemir et al. / Experimental and Molecular Pathology 87 (2009) 89–93
Case report Materials and methods Tissue specimens were fixed in 10% buffered formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin, periodic acid-Schiff (PAS), Gomori methenamine silver (GMS), and Erlich Ziehl Nielsen (EZN) stains. Immunohistochemical studies on paraffin-embedded materials were also performed (based on BSA methods using a DAB kit; Scy Tek Laboratories) using mouse
monoclonal antibodies against CD31, CD34, CD68, and Mac387 (Dako, Denmark) as well as a mouse monoclonal antibody against HHV8 (LNA1, Vector Laboratories, UK). Clinical findings A 74-year-old male presented with growing red-purple patches that had first occurred 3 months earlier. No pain was associated with the patches. The patient did not describe any previously experienced localized infection in the lesion region, trauma, or the use of any topical
Fig. 1. Nodular stage KS consisting of atypical spindle cells and extravasated erythrocytes under squamous epithelium. Granuloma structures are observed in the peritumoral stroma and within the tumor tissue (H&E; A, ×4; B, ×20). Epithelioid cell granulomas with Langhans-type giant cell in apposition to KS (C, ×10; D, ×40). Sarcoid-like granulomas are observed near the KS. They are circular, with no intensive inflammatory response around them and no necrosis in their centers (E, ×30). High-power view showing proliferation of spindle cells with erythrocyte extravasation (F, ×120).
N. Onak Kandemir et al. / Experimental and Molecular Pathology 87 (2009) 89–93
medicine. He had a history of cerebrovascular disease dating back 2 years and used anti-hypertensive drugs to treat systemic hypertension. His family history was unremarkable. Physical examination revealed a red-purple lesion that was elevated above the surface and located on the dorsal aspect of his right foot. Laboratory results were as follows: hemoglobin, 14.4 g/dl; leukocytes, 6000/mm3; and erythrocyte sedimentation rate, 20 mm/h. The leukocyte differential revealed 66.9% polymorphonuclear leukocytes, 19.5% lymphocytes, 7.7% monocytes, and 5.5% eosinophils. Serum biochemistry values were within normal ranges. Although anti-hepatitis C virus (HCV) and anti-human immunodeficiency virus (HIV) serum antibodies were negative, hepatitis B surface antibody (anti-HBs) was positive. The patient's angiotensinconverting enzyme (ACE) level was 5.82 μg/L (normal, b40 μg/L). The lesion was excised based on tentative diagnoses of KS and angiosarcoma. Pathology The specimen consisted of cutaneous and subcutaneous redpurple tissue that was elevated above the surface and measured 1 × 1.5 cm. It also contained nodular lesions. A section of the lesion included solid hemorrhagic areas. Histology Microscopic examination revealed spindle cells, extravasated erythrocytes, and a tumor, consisting of vascular cleavages below a hyperkeratotic epidermis. Many non-caseating granuloma structures, composed of epithelioid and giant cells, were observed within the tumor tissue and in the stroma surrounding the tumor. The granulomas were more common in the periphery of the tumor tissue.
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The granulomas were of annular configuration and similar in size. Necrosis was not found at the center of the granulomas, although focal fibrinoid material was occasionally observed. Around the granuloma structures, there were few mononuclear inflammatory cell infiltrations consisting of mature lymphocytes and plasma cells (Figs. 1A–F). A few macrophages containing hemosiderin were present in the tumor tissue. The distribution of hemosiderin was not related to the granuloma structures. Histochemistry and immunohistochemistry The epithelioid cells forming the granulomas were positive for CD68 (Figs. 2A and B) and Mac387 (Fig. 2C). EZN staining for acid-fast bacilli was negative, and no polarizable material was present in the granulomas. Fungal stains (PAS and GMS) were negative. PCR for Mycobacterium tuberculosis was negative in the tissue specimens. Immunohistochemical analyses showed positive reactions for CD31, CD34, and HHV8 (Fig. 2D) in the tumor cells. Based on the histopathological and immunohistochemical results, the case was diagnosed as “nodular stage Kaposi's sarcoma and noncaseating granulomatous reaction.” There were no finding related to tuberculosis or sarcoidosis. The granulomas observed in the tumor stroma were considered to be a sarcoid-like reaction against the tumor tissue or antigens. When new lesions were observed on the fourth and fifth toes of the right foot at the 6-month follow-up, the patient was referred for radiation oncology. Discussion KS is a multifocal angioproliferative disease. It has been investigated thoroughly because it is the most common malignancy observed
Fig. 2. Strong Mac387 immunoreactivity is observed in the histiocytes that form the granulomas and infiltrate the tumor tissue (DAB; A. ×4; B, ×40). Immunoreactivity in epithelioid cell granulomas with Langhans-type giant cell for CD68 (C; DAB, ×80). Nuclear HHV8 (LNA-1) immunoreactivity in neoplastic spindle cells adjacent to granulomas (D, ×100).
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in individuals infected with HIV type 1. There are four known epidemiological forms: classic, endemic, iatrogenic, and acquired immunodeficiency syndrome (AIDS)-associated KS (Horenstein et al., 2008). HHV8, which was first defined by Chang et al. (1994), is a virus that acts as an infectious cofactor in the development of this lesion; it is detected in all KS types. Classic KS is frequently encountered in elderly men in Mediterranean and European countries. In this form, the lesions are single or multiple and are commonly localized to a lower extremity. Surgical treatment may be inadequate for tumors that show slow progression due to multifocal lesions and frequent recurrences (Iscovich et al., 2000). The histological features of KS change depending on the stage of the disease. Although the atypical vascular structures that cause cleavages are more evident in early-stage lesions, spindle cell proliferation and extravasated erythrocytes are dominant features in developed lesions. The progression of lesions in KS is characterized by the development of patch, plaque, and nodular stages. Recently, many histological variants of KS have been defined. Grayson and Pantanowitz (2008) have divided these histological variants into four main groups: (a) KS lesions that encompass usual variants related to disease progression (i.e., patch, plaque, and nodular stages); (b) variants alluded to in the older literature, such as anaplastic and telangiectatic KS; (c) more recently described variants, such as hyperkeratotic, keloidal, micronodular, pyogenic granuloma-like, ecchymotic, and intravascular KS; and (d) KS lesions as a consequence of therapy (e.g., regressing KS). It is important to distinguish these histological subtypes during differential diagnosis (Ackerman, 1985; Pantanowitz and Dezube, 2008). KS is becoming increasingly common and thus is currently attracting considerable interest in terms of its epidemiology and biology. Here, we report the coexistence of sarcoid-like granulomas as an uncommon histological feature in a case of classic KS. To our knowledge, this is the first reported case of sarcoid-like granulomas, representing the immune response of the host to the tumor, in conjunction with KS. We present our results in light of the importance of sarcoid-like granulomas in terms of tumor immunology and tumor biology and provide data from the literature on the histopathological differential diagnostic criteria. In people who have no symptoms or findings of systemic sarcoidosis, non-caseating granulomatous structures formed by epithelioid cells may be observed in the primary tumor, the lymph nodes draining the tumor, and remote tissues and organs. These tumor-related histological alterations are called a sarcoid reaction and are also referred to by other names, such as sarcoid-like lesion, sarcoid lesion, sarcoid-like granuloma, sarcoid-like tissue reaction, and pseudotubercle (Brincker, 1992; Cohen and Kurzrock, 2007). A tumor-related sarcoid tissue reaction was first described by Herxheimer in 1917. In 1937, Nickerson defined local sarcoid reactions and systemic sarcoidosis as different entities (Neiman, 1977). Several studies have investigated the frequencies of sarcoid reactions in different tumor types and in different locations. Brincker (1986) reported sarcoid reactions in 4.4% of carcinomas, 13.8% of Hodgkin's disease, and 7.8% of non-Hodgkin's lymphomas. Llombart and Escudero (1970) detected sarcoid reactions in 5.6% of primary tumors and 2.4% of regional lymph nodes in their series of 1228 cases. Among solid tumors, sarcoid reactions generally accompany carcinomas and are rare in sarcomas. In 150 bone sarcomas, Llombart and Escudero (1970) identified only one patient with sarcoid-like granulomas, and of 100 soft tissue sarcomas examined, none showed a similar alteration. Nakamura et al. (1990) reported the presence of a sarcoid-like granuloma in a rectal leiomyosarcoma and the adjacent stroma. The granulomatous tissue response associated with malignant tumors may be a foreign body reaction that develops against the tumor tissue or necrotic material, or it may be a hypersensitivity reaction induced by antigenic factors originating from the tumor cells. Both tumor tissue and necrotic material can cause a granulomatous reaction by generating continuous stimulation that maintains macro-
phage colonization and activation. The occurrence of sarcoid-like reactions in non-metastatic lymph nodes and organs remote to the tumor, including skin, bone marrow, and spleen, indicate that sarcoid reactions occur primarily as a result of tumor antigens being transported through dendritic cells (Agostini et al., 1998; Pavic et al., 2008). The presence of a sarcoid reaction is an indicator of an immunological response to a tumor. It has also been reported to be an indicator of a good prognosis in Hodgkin's disease (Abrams et al., 1988; O'Connell et al., 1975) and gastric cancers (Nakamura et al., 2001), although Kamiyoshihara et al. (1998) found no influence on the prognosis of lung cancers. The histology of sarcoid reactions is similar to that of sarcoidosis granulomas. Lymphocytic cells surround the epithelioid cell clusters in the center (Kurata et al., 2005). Langhans and foreign body giant cells are frequently observed, whereas asteroid and Schaumann bodies are rarely present. No necrosis is generally observed in the center, although some cases may exhibit fibrinoid necrosis (Barbolini, 1988; Brincker, 1992.). Because of these histopathological similarities, comprehensive clinical and laboratory examinations may be required to differentiate sarcoid reactions from systemic sarcoidosis. Infectious, immunological, and neoplastic processes may play roles in the occurrence of KS. It has been reported that KS may develop in regions bruised after injuries, surgical intervention, pemphigus lesions, and herpes zoster infections (Chang et al., 1994; Pantanowitz and Dezube, 2008). Researchers have defined such post-traumatic KS lesions as Koebner-like phenomena (i.e., the appearance of a skin lesion as a result of trauma; Potouridou et al., 1997; Pantanowitz and Dezube, 2007). It has been proposed that these lesions occur as a result of the direct inoculation of the HHV8 virus in the bruised region; alternatively, cytokines and growth factors that are activated during inflammation or bruise healing may activate HHV8 that is already present in the patient and stimulate the development of KS. Furthermore, in some cases, KS develops in association with granulomatous infections in the same anatomic location (Glassman and Hale, 1995). A case in which sarcoidosis granulomas and KS were observed together has been reported. In this case, it was suggested that immune system changes emerging during systemic sarcoidosis led to the development of KS (Stavrianeas et al., 2007). In the present case, we observed granulomas, containing epithelioid cells and a few giant cells, in the tumor tissue and adjacent stroma (Fig. 1A). The granulomas were spherical with regular borders (Fig. 1E), and some had granular eosinophilic fibrinoid material in the center (Fig. 1B). The dominant giant cell type was the Langhans giant cells (Fig. 1D), and there were also a few foreign body-type giant cells. Histochemically, no specific reaction was observed with EZN, PAS, or GMS staining for tuberculosis or mycosis. Examinations under polarized light showed no findings related to foreign bodies. Schaumann and asteroid bodies were not present. The patient had no signs or symptoms of a local or systemic disease that could lead to infectious or non-infectious granuloma formation. Comprehensive clinical and laboratory examinations showed no sign of sarcoidosis or tuberculosis. In our case, there may have been a granulomatous disease growing synchronously with the neoplastic process in the pathogenesis of the sarcoid-like granulomas accompanying KS. Another possibility is that KS may occur secondary to the granulomatous inflammation that was previously present in the same location or in response to bruise healing. In the clinical and laboratory findings of the patient, no finding related to a specific granulomatous disease was determined. According to the patient, there had been no infection or trauma in the lesion region. In our case, the histological features and spreading pattern of the granulomas accompanying KS were deemed to be a reaction to the antigenic stimulus, in accordance with the development of sarcoid-like granulomas. All the data suggested that the granulomas observed in the tumor tissue and adjacent stroma were the products of a sarcoid tissue reaction that developed against the tumor cells or soluble tumor antigens.
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In conclusion, the association of soft tissue sarcomas with a granulomatous reaction is rare. A granulomatous reaction is reported to be a good prognostic indicator in several carcinoma types; however, its importance in KS cases is unclear. Further studies on more cases may provide information on the developmental mechanism and prognostic value of granulomas. References Abrams, J., et al., 1988. Epithelioid granulomas revisited: long-term follow-up in Hodgkin's disease. Am. J. Clin. Oncol. 11 (4), 456–460. Ackerman, A.B., 1985. Kaposi's sarcoma. In: Cerimele, D. (Ed.), Histologic Features of Kaposi's Sarcoma and Simulators of It. Spectrum Publications, New York, pp. 71–79. Agostini, C., Basso, U., Semenzato, G., 1998. Cells and molecules involved in the development of sarcoid granuloma. J. Clin. Immunol. 18 (3), 184–192. Barbolini, G., 1988. Morphology of sarcoid and sarcoid-like granulomas: diagnostic and prognostic-related problems. Sarcoidosis 5 (2), 160–161. Brincker, H., 1986. Sarcoid reactions in malignant tumours. Cancer Treat. Rev. 13 (3), 147–156. Brincker, H., 1992. Interpretation of granulomatous lesions in malignancy. Acta Oncol. 31 (1), 85–89. Chang, Y., et al., 1994. Identification of herpesvirus-like DNA sequences in AIDSassociated Kaposi's sarcoma. Science 16 (266), 1865–1869. Cohen, P.R., Kurzrock, R., 2007. Sarcoidosis and malignancy. Clin. Dermatol. 25 (3), 326–333. Ensoli, B., et al., 2001. Biology of Kaposi's sarcoma. Eur. J. Cancer 37, 1251–1269. Glassman, S.J., Hale, M.J., 1995. Cutaneous cryptococcosis and Kaposi's sarcoma occurring in the same lesions in a patient with the acquired immunodeficiency syndrome. Clin. Exp. Dermatol. 20 (6), 480–486. Grayson, W., Pantanowitz, L., 2008. Histological variants of cutaneous Kaposi sarcoma. Diagn. Pathol. 25 (3), 31. Herxheimer, G., 1917. Über Karzinom und Tuberkulose. Z. Tuberk. 27, 251–258.
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Horenstein, M.G., Moontasri, N.J., Cesarman, E., 2008. The pathobiology of Kaposi's sarcoma: advances since the onset of the AIDS epidemic. J. Cutan. Pathol. 35 (l2), 40–44. Iscovich, J., et al., 2000. Classic Kaposi sarcoma: epidemiology and risk factors. Cancer 88 (3), 500–517. Kamiyoshihara, M., et al., 1998. Sarcoid reactions in primary pulmonary carcinoma: report of seven cases. Oncol. Rep. 5 (1), 177–180. Kurata, A., et al., 2005. Inflammatory cells in the formation of tumor-related sarcoid reactions. Hum. Pathol. 36 (5), 546–554. Llombart, A., Escudero, J.M., 1970. The incidence and significance of epithelioid and sarcoid-like cellular reaction in the stromata of malignant tumours. A morphological and experimental study. Eur. J. Cancer 6 (6), 545–551. Nakamura, M., et al., 1990. Leiomyosarcoma of the rectum with sarcoid-like reaction—a case report. Kurume Med. J. 37 (3), 171–175. Nakamura, M., et al., 2001. Multiple early gastric cancer associated with sarcoid-like reaction in the regional lymph nodes. J. Gastroenterol. 36 (10), 710–717. Neiman, R.S., 1977. Boeck's sarkoid. Report of six cases in which autopsies were made. Arch. Pathol. Lab. Med. 101, 518–521. O'Connell, M., et al., 1975. Epithelioid granulomas in Hodgkin disease. A favorable prognostic sign? JAMA 233 (8), 886–889. Pantanowitz, L., Dezube, B.J., 2007. Kaposi's sarcoma and pemphigus. J. Eur. Acad. Dermatol. Venereol. 21 (4), 571–572. Pantanowitz, L., Dezube, B.J., 2008. Kaposi sarcoma in unusual locations. BMC Cancer. 7 (8), 190. Pantanowitz, L., Moses, A.V., Dezube, B.J., 2009. The inflammatory component of Kaposi sarcoma. Exp. Mol. Pathol. 7. Pavic, M., et al., 2008. Sarcoidosis and sarcoid reactions in cancer. Rev. Med. Interne 29 (1), 39–45. Potouridou, I., et al., 1997. Koebner phenomenon in classic Kaposi's sarcoma. Acta Derm. Venereol. 77 (6), 481. Stavrianeas, N.G., et al., 2007. Kaposi's sarcoma as a Köbner phenomenon in a patient with bullous pemphigoid and sarcoidosis. Clin. Exp. Dermatol. 32 (5), 579–581. Zumla, A., James, D.G., 1996. Granulomatous infections: etiology and classification. Clin. Infect. Dis. 23 (1), 146–158.
Contents lists available at ScienceDirect
Experimental and Molecular Pathology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y e x m p
Review
Classic Kaposi sarcoma with sarcoid-like granulomas: A case report and literature review☆ Nilufer Onak Kandemir a,⁎, Gamze Yurdakan a,1, Sibel Bektas a,1, Nilgun Solak Tekin b,1 a b
Department of Pathology, School of Medicine, Zonguldak Karaelmas University, 67600, Kozlu, Zonguldak, Turkey Department of Dermathology, School of Medicine, Zonguldak Karaelmas University, Zonguldak, Turkey
a r t i c l e
i n f o
Article history: Received 1 April 2009 and in revised form 30 July 2009 Available online 10 August 2009 Keywords: Granuloma Kaposi sarcoma Sarcoidosis
a b s t r a c t The occurrence of granulomatous reactions within lymph nodes that drain carcinomas is well known but uncommon. Even more rarely, granulomas may occur within the stroma of tumors. These lesions, called sarcoid-like reactions, commonly accompany carcinomas but are very rare in sarcomas. This study presents a case of classic Kaposi sarcoma that contained sarcoid-like granulomas, with a literature review. A soft tissue lesion of the foot was excised from a 74-year-old male. Histopathological examination showed that the tumor tissue consisted of spindle cells, areas of atypical vascular proliferation, and extravasated erythrocytes surrounded by non-caseating granulomas. The patient had no clinical or laboratory findings of sarcoidosis. The case was interpreted as “Kaposi sarcoma containing sarcoid-like granulomas”. The association of soft tissue sarcomas with a granulomatous reaction is very rare. A granulomatous reaction is reported to be a good prognostic indicator in several carcinoma types, although its importance in sarcomas is unclear. © 2009 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . Case report. . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . Clinical findings . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . Histology . . . . . . . . . . . . . . . . Histochemistry and immunohistochemistry Discussion . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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Introduction Kaposi's sarcoma (KS) is an uncommon, multifocal, low-grade vascular neoplasia. Disrupted immunological mechanisms contribute extensively to the development of this tumor (Ensoli et al., 2001; Pantanowitz et al., 2009). A granulomatous reaction is a specific, chronic tissue reaction accompanied by epithelioid histiocytes and
☆ This study was presented as a poster in XXVIIth Congress of the International Academy of Pathology held in 12–17 September 2007 in Athens, Greece. ⁎ Corresponding author. Fax: +90 372 261 01 55. E-mail addresses: [email protected] (N. Onak Kandemir), [email protected] (G. Yurdakan), [email protected] (S. Bektas), [email protected] (N.S. Tekin). 1 Fax: +90 372 261 01 55. 0014-4800/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yexmp.2009.07.010
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multinucleated giant cells (Agostini et al., 1998). The immune response mediated by T cells plays a role in the pathogenesis of granulomas and may have an infectious or non-infectious cause (Zumla and James, 1996). The occurrence of granulomatous reactions within lymph nodes that drain carcinomas is well known but uncommon (Brincker, 1992). Even more rarely, granulomas may occur within the stroma of malignancies (Llombart and Escudero, 1970). These lesions, also called sarcoid-like reactions, commonly accompany carcinomas but are very rare in sarcomas (Cohen and Kurzrock, 2007). These histological changes are believed to be a direct tissue response to tumor antigens or tumor tissues (Pavic et al., 2008). To our knowledge, no case of KS accompanied by a sarcoid-like reaction has been reported in the English-language literature. Here, we present a case of classical KS with sarcoid-like granulomas and review the relevant literature.
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N. Onak Kandemir et al. / Experimental and Molecular Pathology 87 (2009) 89–93
Case report Materials and methods Tissue specimens were fixed in 10% buffered formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin, periodic acid-Schiff (PAS), Gomori methenamine silver (GMS), and Erlich Ziehl Nielsen (EZN) stains. Immunohistochemical studies on paraffin-embedded materials were also performed (based on BSA methods using a DAB kit; Scy Tek Laboratories) using mouse
monoclonal antibodies against CD31, CD34, CD68, and Mac387 (Dako, Denmark) as well as a mouse monoclonal antibody against HHV8 (LNA1, Vector Laboratories, UK). Clinical findings A 74-year-old male presented with growing red-purple patches that had first occurred 3 months earlier. No pain was associated with the patches. The patient did not describe any previously experienced localized infection in the lesion region, trauma, or the use of any topical
Fig. 1. Nodular stage KS consisting of atypical spindle cells and extravasated erythrocytes under squamous epithelium. Granuloma structures are observed in the peritumoral stroma and within the tumor tissue (H&E; A, ×4; B, ×20). Epithelioid cell granulomas with Langhans-type giant cell in apposition to KS (C, ×10; D, ×40). Sarcoid-like granulomas are observed near the KS. They are circular, with no intensive inflammatory response around them and no necrosis in their centers (E, ×30). High-power view showing proliferation of spindle cells with erythrocyte extravasation (F, ×120).
N. Onak Kandemir et al. / Experimental and Molecular Pathology 87 (2009) 89–93
medicine. He had a history of cerebrovascular disease dating back 2 years and used anti-hypertensive drugs to treat systemic hypertension. His family history was unremarkable. Physical examination revealed a red-purple lesion that was elevated above the surface and located on the dorsal aspect of his right foot. Laboratory results were as follows: hemoglobin, 14.4 g/dl; leukocytes, 6000/mm3; and erythrocyte sedimentation rate, 20 mm/h. The leukocyte differential revealed 66.9% polymorphonuclear leukocytes, 19.5% lymphocytes, 7.7% monocytes, and 5.5% eosinophils. Serum biochemistry values were within normal ranges. Although anti-hepatitis C virus (HCV) and anti-human immunodeficiency virus (HIV) serum antibodies were negative, hepatitis B surface antibody (anti-HBs) was positive. The patient's angiotensinconverting enzyme (ACE) level was 5.82 μg/L (normal, b40 μg/L). The lesion was excised based on tentative diagnoses of KS and angiosarcoma. Pathology The specimen consisted of cutaneous and subcutaneous redpurple tissue that was elevated above the surface and measured 1 × 1.5 cm. It also contained nodular lesions. A section of the lesion included solid hemorrhagic areas. Histology Microscopic examination revealed spindle cells, extravasated erythrocytes, and a tumor, consisting of vascular cleavages below a hyperkeratotic epidermis. Many non-caseating granuloma structures, composed of epithelioid and giant cells, were observed within the tumor tissue and in the stroma surrounding the tumor. The granulomas were more common in the periphery of the tumor tissue.
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The granulomas were of annular configuration and similar in size. Necrosis was not found at the center of the granulomas, although focal fibrinoid material was occasionally observed. Around the granuloma structures, there were few mononuclear inflammatory cell infiltrations consisting of mature lymphocytes and plasma cells (Figs. 1A–F). A few macrophages containing hemosiderin were present in the tumor tissue. The distribution of hemosiderin was not related to the granuloma structures. Histochemistry and immunohistochemistry The epithelioid cells forming the granulomas were positive for CD68 (Figs. 2A and B) and Mac387 (Fig. 2C). EZN staining for acid-fast bacilli was negative, and no polarizable material was present in the granulomas. Fungal stains (PAS and GMS) were negative. PCR for Mycobacterium tuberculosis was negative in the tissue specimens. Immunohistochemical analyses showed positive reactions for CD31, CD34, and HHV8 (Fig. 2D) in the tumor cells. Based on the histopathological and immunohistochemical results, the case was diagnosed as “nodular stage Kaposi's sarcoma and noncaseating granulomatous reaction.” There were no finding related to tuberculosis or sarcoidosis. The granulomas observed in the tumor stroma were considered to be a sarcoid-like reaction against the tumor tissue or antigens. When new lesions were observed on the fourth and fifth toes of the right foot at the 6-month follow-up, the patient was referred for radiation oncology. Discussion KS is a multifocal angioproliferative disease. It has been investigated thoroughly because it is the most common malignancy observed
Fig. 2. Strong Mac387 immunoreactivity is observed in the histiocytes that form the granulomas and infiltrate the tumor tissue (DAB; A. ×4; B, ×40). Immunoreactivity in epithelioid cell granulomas with Langhans-type giant cell for CD68 (C; DAB, ×80). Nuclear HHV8 (LNA-1) immunoreactivity in neoplastic spindle cells adjacent to granulomas (D, ×100).
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in individuals infected with HIV type 1. There are four known epidemiological forms: classic, endemic, iatrogenic, and acquired immunodeficiency syndrome (AIDS)-associated KS (Horenstein et al., 2008). HHV8, which was first defined by Chang et al. (1994), is a virus that acts as an infectious cofactor in the development of this lesion; it is detected in all KS types. Classic KS is frequently encountered in elderly men in Mediterranean and European countries. In this form, the lesions are single or multiple and are commonly localized to a lower extremity. Surgical treatment may be inadequate for tumors that show slow progression due to multifocal lesions and frequent recurrences (Iscovich et al., 2000). The histological features of KS change depending on the stage of the disease. Although the atypical vascular structures that cause cleavages are more evident in early-stage lesions, spindle cell proliferation and extravasated erythrocytes are dominant features in developed lesions. The progression of lesions in KS is characterized by the development of patch, plaque, and nodular stages. Recently, many histological variants of KS have been defined. Grayson and Pantanowitz (2008) have divided these histological variants into four main groups: (a) KS lesions that encompass usual variants related to disease progression (i.e., patch, plaque, and nodular stages); (b) variants alluded to in the older literature, such as anaplastic and telangiectatic KS; (c) more recently described variants, such as hyperkeratotic, keloidal, micronodular, pyogenic granuloma-like, ecchymotic, and intravascular KS; and (d) KS lesions as a consequence of therapy (e.g., regressing KS). It is important to distinguish these histological subtypes during differential diagnosis (Ackerman, 1985; Pantanowitz and Dezube, 2008). KS is becoming increasingly common and thus is currently attracting considerable interest in terms of its epidemiology and biology. Here, we report the coexistence of sarcoid-like granulomas as an uncommon histological feature in a case of classic KS. To our knowledge, this is the first reported case of sarcoid-like granulomas, representing the immune response of the host to the tumor, in conjunction with KS. We present our results in light of the importance of sarcoid-like granulomas in terms of tumor immunology and tumor biology and provide data from the literature on the histopathological differential diagnostic criteria. In people who have no symptoms or findings of systemic sarcoidosis, non-caseating granulomatous structures formed by epithelioid cells may be observed in the primary tumor, the lymph nodes draining the tumor, and remote tissues and organs. These tumor-related histological alterations are called a sarcoid reaction and are also referred to by other names, such as sarcoid-like lesion, sarcoid lesion, sarcoid-like granuloma, sarcoid-like tissue reaction, and pseudotubercle (Brincker, 1992; Cohen and Kurzrock, 2007). A tumor-related sarcoid tissue reaction was first described by Herxheimer in 1917. In 1937, Nickerson defined local sarcoid reactions and systemic sarcoidosis as different entities (Neiman, 1977). Several studies have investigated the frequencies of sarcoid reactions in different tumor types and in different locations. Brincker (1986) reported sarcoid reactions in 4.4% of carcinomas, 13.8% of Hodgkin's disease, and 7.8% of non-Hodgkin's lymphomas. Llombart and Escudero (1970) detected sarcoid reactions in 5.6% of primary tumors and 2.4% of regional lymph nodes in their series of 1228 cases. Among solid tumors, sarcoid reactions generally accompany carcinomas and are rare in sarcomas. In 150 bone sarcomas, Llombart and Escudero (1970) identified only one patient with sarcoid-like granulomas, and of 100 soft tissue sarcomas examined, none showed a similar alteration. Nakamura et al. (1990) reported the presence of a sarcoid-like granuloma in a rectal leiomyosarcoma and the adjacent stroma. The granulomatous tissue response associated with malignant tumors may be a foreign body reaction that develops against the tumor tissue or necrotic material, or it may be a hypersensitivity reaction induced by antigenic factors originating from the tumor cells. Both tumor tissue and necrotic material can cause a granulomatous reaction by generating continuous stimulation that maintains macro-
phage colonization and activation. The occurrence of sarcoid-like reactions in non-metastatic lymph nodes and organs remote to the tumor, including skin, bone marrow, and spleen, indicate that sarcoid reactions occur primarily as a result of tumor antigens being transported through dendritic cells (Agostini et al., 1998; Pavic et al., 2008). The presence of a sarcoid reaction is an indicator of an immunological response to a tumor. It has also been reported to be an indicator of a good prognosis in Hodgkin's disease (Abrams et al., 1988; O'Connell et al., 1975) and gastric cancers (Nakamura et al., 2001), although Kamiyoshihara et al. (1998) found no influence on the prognosis of lung cancers. The histology of sarcoid reactions is similar to that of sarcoidosis granulomas. Lymphocytic cells surround the epithelioid cell clusters in the center (Kurata et al., 2005). Langhans and foreign body giant cells are frequently observed, whereas asteroid and Schaumann bodies are rarely present. No necrosis is generally observed in the center, although some cases may exhibit fibrinoid necrosis (Barbolini, 1988; Brincker, 1992.). Because of these histopathological similarities, comprehensive clinical and laboratory examinations may be required to differentiate sarcoid reactions from systemic sarcoidosis. Infectious, immunological, and neoplastic processes may play roles in the occurrence of KS. It has been reported that KS may develop in regions bruised after injuries, surgical intervention, pemphigus lesions, and herpes zoster infections (Chang et al., 1994; Pantanowitz and Dezube, 2008). Researchers have defined such post-traumatic KS lesions as Koebner-like phenomena (i.e., the appearance of a skin lesion as a result of trauma; Potouridou et al., 1997; Pantanowitz and Dezube, 2007). It has been proposed that these lesions occur as a result of the direct inoculation of the HHV8 virus in the bruised region; alternatively, cytokines and growth factors that are activated during inflammation or bruise healing may activate HHV8 that is already present in the patient and stimulate the development of KS. Furthermore, in some cases, KS develops in association with granulomatous infections in the same anatomic location (Glassman and Hale, 1995). A case in which sarcoidosis granulomas and KS were observed together has been reported. In this case, it was suggested that immune system changes emerging during systemic sarcoidosis led to the development of KS (Stavrianeas et al., 2007). In the present case, we observed granulomas, containing epithelioid cells and a few giant cells, in the tumor tissue and adjacent stroma (Fig. 1A). The granulomas were spherical with regular borders (Fig. 1E), and some had granular eosinophilic fibrinoid material in the center (Fig. 1B). The dominant giant cell type was the Langhans giant cells (Fig. 1D), and there were also a few foreign body-type giant cells. Histochemically, no specific reaction was observed with EZN, PAS, or GMS staining for tuberculosis or mycosis. Examinations under polarized light showed no findings related to foreign bodies. Schaumann and asteroid bodies were not present. The patient had no signs or symptoms of a local or systemic disease that could lead to infectious or non-infectious granuloma formation. Comprehensive clinical and laboratory examinations showed no sign of sarcoidosis or tuberculosis. In our case, there may have been a granulomatous disease growing synchronously with the neoplastic process in the pathogenesis of the sarcoid-like granulomas accompanying KS. Another possibility is that KS may occur secondary to the granulomatous inflammation that was previously present in the same location or in response to bruise healing. In the clinical and laboratory findings of the patient, no finding related to a specific granulomatous disease was determined. According to the patient, there had been no infection or trauma in the lesion region. In our case, the histological features and spreading pattern of the granulomas accompanying KS were deemed to be a reaction to the antigenic stimulus, in accordance with the development of sarcoid-like granulomas. All the data suggested that the granulomas observed in the tumor tissue and adjacent stroma were the products of a sarcoid tissue reaction that developed against the tumor cells or soluble tumor antigens.
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