CMI 2017;11(1)7-16.html Fine-needle aspiration accuracy in the diagnosis of primary epithelioid angiosarcoma of the adrenal gland: a case report and review of the literature Tullio Torelli 1, Stefano Radaelli 2, Maurizio Colecchia 3, Biagio Paolini 3, Mario Achille Catanzaro 1, Nicola Nicolai 1, Davide Biasoni 1, Luigi Piva 1, Silvia Stagni 1, Roberto Salvioni 1 1 Department of Urology, IRCCS Istituto Nazionale dei Tumori, Milan, Italy 2 Department of Surgery, Melanoma and Sarcoma, IRCSS Istituto Nazionale dei Tumori, Milan, Italy 3 Department of Pathology, IRCCS Istituto Nazionale dei Tumori, Milan, Italy Abstract Primary epithelioid angiosarcoma of the adrenal gland is extremely rare. Only 37 cases have been reported in the scientific literature. Here we describe the case of a 55-year-old woman affected by metastatic angiosarcoma in the right adrenal gland, who died few days after the histological diagnosis made by fine-needle aspiration (FNA). This is the second case of primary epithelioid angiosarcoma diagnosed by FNA among scientific articles published in English in PubMed. Microscopically, the tumor showed a predominant epithelioid differentiation, thus making the diagnostic process more difficult than usual. Immunohistochemical examination revealed positive reactivity for cytokeratin, CD31, and CD34. The literature shows that epithelioid adrenal angiosarcoma has poor clinical outcome, especially when metastatic at presentation. Keywords: Adrenal glands; Hemangiosarcoma; Biopsy, Fine-Needle; Primary Epithelioid Angiosarcoma; Fine-Needle Aspiration Accuratezza diagnostica dell’agobiopsia nell’angiosarcoma epitelioide primario della ghiandola surrenale: caso clinico e review della letteratura CMI 2017; 11(1): 7-16 http://dx.doi.org/10.7175/cmi.v11i1.1256 Case report Corresponding author Tullio Torelli tullio.torelli@istitutotumori.mi.it Disclosure The authors declare they have no competing financial interests concerning the topics of this article Why we describe this case Epithelioid angiosarcoma of the adrenal gland is a very rare and aggressive tumor, with no specific clinical or radiological patterns. Diagnosis requires detailed pathologic examination accompanied by immunohistochemical studies using endothelial markers. When FNA is used for diagnosis, this process becomes much challenging due to the minimal amount of tissue available for examination Introduction Angiosarcomas are malignant tumors arising from the endothelial lining of blood vessels and accounting for less than 1% of all soft tissue sarcomas, which represent 1% of all solid tumors in adults. That means that the incidence of angiosarcoma is 0.1-0.2/100,000 per year. Adrenal gland is an uncommon site for angiosarcoma. Usually, it occurs in skin, soft tissue, breast, bone, liver, and spleen and has poor long-term prognosis [1]. No predisposing factors for primary adrenal angiosarcoma have been identified yet. Case report A 55-year-old woman was admitted to our Urology Unit on January 2014 to undergo a biopsy of right adrenal mass. Clinically, the patient suffered from continuous pain in the right lumbar region, a significant weight loss in the past two months (about 15 kg), and severe asthenia. Before hospitalization, ultrasonography showed a nonspecific mass located around the upper pole of the right kidney and abdominal computed tomography revealed a right adrenal neoplasm measuring 45 × 29 mm in diameter and bulging out toward the liver (Figures 1 and 2). Figure 1. Ultrasonography showing right adrenal mass (red arrow) infiltrating the upper pole of kidney and liver (one month before hospital admission) Figure 2. Abdominal computed tomography revealing the same adrenal mass (red arrow) in trasversal plan (one month before hospital admission) Physical examination revealed a tender palpable right upper quadrant mass. Laboratory studies were significant for anemia (6.2 g/dl) and leukocytosis (1.19 × 103/µl). Hormone panel including serum and urinary metanephrines, serum and urinary cortisol, plasma aldosterone, and serum adrenocorticotropic hormone was normal. Ten days after hospitalization, follow up chest-abdomen and pelvis CT scan revealed enlargement of the adrenal mass from 45 × 29 mm to 65 × 45 mm. New bilateral lung nodules were also noted (Figures 3 and 4). Figure 3. CT scan revealing growing adrenal mass (red arrow) with extensive infiltration of liver and upper pole of kidney (longitudinal plan, ten days after hospital admission) Figure 4. CT scan showing evidence of lung metastasis (red arrow) in right pulmonary lobe (ten days after hospital admission) Therefore, fine-needle aspiration (FNA) was performed. Histological sections showed sheets of epithelioid cells in a fibrotic stroma and focal necrosis. Cells have eosinophilic cytoplasm, prominent nucleoli and frequent mitotic figures. These histologic features were consistent with malignant neoplasm. Further studies with pax8, cytokeratin 19, claudin, calretinin, synaptophysin, chromogranin A, glypican-3, human melanoma black 45 and MART-1, and cytokeratin (AE1/AE3) were performed. The tumor cells were positive for cytokeratin and negative for all the remaining markers. A second panel of immunostains including CD31, cytokeratin, and ERG-1 was performed. Tumor cells were strongly positive for all (Figure 5). Hence, the diagnosis of epithelioid angiosarcoma was made. Unfortunately, the patient died few days after the histological diagnosis. Figure 5. Hematoxylin-eosin (H.E.) staining and immunohistochemical studies Ck = cytokeratin What should the clinician ask him/herself or the patient Adrenal mass is rapidly growing? Are there general symptoms as asthenia, malaise, and mild fever? Hormonal activity is normal? Discussion Angiosarcomas are very rare malignant tumors, which derive from the vascular endothelium and can occur at any site in the body [2]. Epithelioid angiosarcoma (EA) of the adrenal gland has poor prognosis: 5-year overall survival ranges between 25% and 45% in primary tumors, while is shorter than 12 months in metastatic patients [3]. To our knowledge, just 37 case reports have been reported in literature. Nevertheless, among them, only 29 are available for full review in English, according to PubMed systemic research through MeSH terms (Table I) [4-33]. The etiology of EA remains unknown: apart from a case of exposure to arsenic [6] and a case of exposure to vynil chloride [29], the published case reports didn’t succeed in identifying a clear correlation with the patients’ exposure to carcinogens or with a significant incidence of other diseases, even though three patients had concomitant adrenal cortical adenoma [26,31,32] (Table I). Case Gender (age) Clinical findings CT scan findings Side Other disease Therapy Follow up Ref. 1 M (54) Abdominal pain 6 cm solid mass L None Adrenalectomy + chemotherapy Relapse after 7 months 4 2 F (54) Fatigue, weight loss, paraneoplastic syndrome 6 cm soft tissue upper pole right kidney R None Adrenalectomy NED 6 months 5 3 M (58) Abdominal pain 8 cm solid mass R Chronic arsenical intoxication Adrenalectomy Died after surgery 6 4 M (41) Epigastric pain 10 cm rounded mass R Mesenteric fibromatosis Adrenalectomy + radiotherapy NA 7 5 M (67) Abdominal pain Inhomogeneous mass (13 cm) L None Adrenalectomy Died 2 months for lung mts 8 6 M (85) Incidental findings (autopsy) NA R None None None 9 7 F (60) Abdominal pain NA R None Adrenalectomy NED 13 years 9 8 F (64) Weight loss 10 cm suprarenal mass L None Adrenalectomy Died 12 months 9 9 F (60) Left flank pain Adrenal mass L None Adrenalectomy Died 2 months 9 10 M (82) Incidental finding NA NA NA Adrenalectomy Died 24 months (lung mts) 9 11 F (45) Cushing’s syndrome Adrenal mass R None Adrenalectomy NED 11 years 9 12 M (56) Fever, weakness Adrenal mass R None Adrenalectomy Died 6 months (lung mts) 9 13 F (56) Flank pain Adrenal mass L None Adrenalectomy + chemotherapy NED 6 years 9 14 M (50) Nausea, diarrhoea 5.5 solid mass, peritoneal mts R None Adrenalectomy Died 9 months (ileus) 10 15 M (50) Fever, lumbar pain 6 cm solid mass bone, liver mts R None Adrenalectomy + partial hepatectomy Died after surgery 11 16 M (62) Anorexia Adrenal mass (10 cm) L None Adrenalectomy Died 7 weeks 12 17 M (63) Incidental finding 3 cm solid mass L None Laparoscopic adrenalectomy NA 13 18 M (70) Abdominal pain 8 cm solid mass R None Adrenalectomy Died 3 weeks 14 19 M (34) Cushing’s syndrome 4 cm irregular mass L Pituitary adenoma Adrenalectomy NED 2 years 15 20 F (70) Abdominal pain 5 cm solid mass R Cistobiliary adenoma Adrenalectomy NED 18 months 16 21 M (61) Abdominal pain 12 cm irregular mass R None Adrenalectomy + nephrectomy NED 3 years 17 22 M (71) NA NA NA NA Adrenalectomy NA 18 23 M (60) Abdominal pain 11 cm solid and cystic mass L Colon polyposis Adrenalectomy + radiotherapy + chemotherapy Died 6 months (lung mts) 19 24 M (60) NA NA NA NA Adrenalectomy + chemotherapy NED 3 years 20 25 M (50) Renal colic 7 cm mass at the upper pole kidney L None Adrenalectomy + nephrectomy NED 12 years 21 26 M (69) Incidental NA NA Prostate carcinoma NA NA 22 27 M (49) Incidental Large and cystic mass R Blunt abdominal trauma Adrenalectomy NED 1 year 23 28 M (55) Abdominal mass, weight loss 10 cm solid mass R None Adrenalectomy Died 12 months (lung mts) 24 29 F (69) Legs swellings 12.5 cm inhomogeneous mass R Chronic renal failure Adrenalectomy + nephrectomy NA 25 30 M (35) Hypertension 6 cm inhomogeneous mass R Adrenocortical adenoma Laparoscopic adrenalectomy NED 2 years 26 31 M (61) Fatigue, weight loss Hypo-dense space-occupying lesion (PET) R Epicardial mts Adrenalectomy NA 27 32 M (42) Flank pain Hypervascular solid mass (14 cm) R Cystic lesion of the adrenal gland Adrenalectomy and nephrectomy Died 3 months (liver mts) 28 33 M (68) Left sided chest pain Heterogeneous mass (7 cm) L Vynil chloride exposition Laparoscopic adrenalectomy Died 7 months (bone mts) 29 34 M (55) Abdominal mass, weight loss 14 cm solid mass L None Adrenalectomy NA 30 35 F (60) Hypertension 5 cm solid mass L Adrenal cortical adenoma Laparoscopic adrenalectomy NED 9 months 31 36 M (63) Weight loss 8 cm solid mass R Adrenal cortical adenoma Adrenalectomy NA 32 37 M (67) Hypertension 16 cm heterogeneous mass R Left renal cell carcinoma Adrenalectomy NED 12 months 33 Table I. Case reports on epithelioid angiosarcomas retrieved in PubMed L = left; mts = metastasis; NA = not available; NED = no evidence of disease; R = right The disease occurs more frequently in males (M/F= 28/9), ranges from 34 to 85 years of age, with a mean peak at 57 years. Patients can either be asymptomatic or suffer from weight loss, slight fever, anorexia, fatigue, weakness, and chronic pain in the upper abdominal quadrants, as in our patient. No increase in adrenal gland hormones production is noted in most of the reported cases, even though two patients had Cushing’s syndrome [9,15] and in three patients the disease was discovered for the sudden onset of hypertension, despite none of them had increased plasmatic aldosterone or metanephrines [26,31,33]. Actually, CT scan is the most used radiological tool for diagnostic purpose, even if F18 FDG PET/CT may be useful too [27]. Although adrenal angiosarcoma does not have a distinct gross pattern, a review of the literature showed that it tends to have a round, solid, and heterogeneous aspect. Frequently, it is a cystic mass and can range in size from 3 cm to 16 cm (Table I). Clinicians and pathologists should include primary adrenal angiosarcoma in the differential diagnoses list for large adrenal gland mass [34]. One can speculate that the rich adrenal vasculature may create a favorable milieu for hemorrhagic and necrotic changes, while the high mitotic index may explain both the solid pattern and the huge volume of the tumor that is often found. In this case, the differential diagnosis includes metastatic malignancy and other primary adrenal tumors. Epithelioid angiosarcomas can imitate carcinomas morphologically and immune-phenotypically. Metastatic or primary melanoma can also show both epithelioid and spindled morphology. Among benign and malignant neoplasms that may simulate epithelioid angiosarcoma, there are adrenal adenoma undergoing massive hemorrhage and epithelioid hemangioendothelioma. Moreover, the diagnosis of angiosarcoma can be a challenge due to pathohistologic features mimicking intravascular papillary endothelial hyperplasia (IPEH – Masson’s tumor). IPEH is a benign, reactive process that cannot be radiologically differentiated from other benign or malignant lesions [35]. Because of its rarity, in literature there is only one previous case of adrenal angiosarcoma diagnosed by fine-needle aspiration (FNA) [25]. In fact, owing to its epithelioid morphology, this tumor may be mistaken for other neoplasms. Sometimes, the difficult diagnosis may cause an insufficient surgical approach. If the tumor is confined to the adrenal gland, it is suggested to remove it, and also take the periadrenal fat tissue and pericaval or periaortic tissue out in order to eradicate any site of potential local tumor microinfiltration. Involved organs, such as liver, spleen, pancreas, kidney, or bowel must be removed [16]. Too often, patients undergo surgery before a proper diagnosis is made and the high incidence of local relapses may sometimes be explained by inadequate approaches. Laparoscopy may be used carefully in district surgeries: among the studied case reports, it was used in four patients with a follow up no longer than one year [13,26,29,31]. So far, diagnostic process is supported by histopathology and immunohistochemistry. Epithelioid angiosarcomas are morphological variants of angiosarcomas, in which polygonal endothelial cells with “epithelioid” appearance predominate and are often arranged in solid nests and sheets, mimicking carcinoma. Although irregular, anastomosing vascular channels are commonly identified within the lesion, supporting the diagnosis. Malignant cells stain positively for endothelial markers CD31, factor VIII, and Fli-1. CD34 is reported to be less sensitive even though it is present in about 40% of cases (Table II). Case Gross finding Ck CD31 CD34 Factor VIII Ki-67 Ref. 1 Solid and hemorrhagic mass NA NA NA NA NA 4 2 Solid mass with a central hemorrhagic mass Pos NA NA Pos NA 5 3 NA NA NA NA NA NA 6 4 Hemorrhagic cyst Pos NA NA Pos NA 7 5 Necrotic mass with nodules NA NA NA Pos NA 8 6-13 Solid cystic mass Pos NA Pos Pos NA 9 14 NA NA NA NA NA NA 10 15 Hemorrhagic cystic lesion Pos Pos Pos Pos NA 11 16 Hemorrhagic mass Pos Pos Pos Pos NA 12 17 Hemorrhagic mass Neg NA Pos Pos NA 13 18 Solid mass replacing the adrenal gland Pos Pos Pos Pos NA 14 19 Multiple soft reddish nodules Neg Pos Pos Pos 30% 15 20 Hemorrhagic lesion NA Pos NA NA NA 16 21 Hemorrhagic cystic mass Pos Pos Neg Neg NA 17 22 NA NA NA NA NA NA 18 23 Cystic mass with hemorrhagic areas Neg Pos Pos Pos NA 19 24 Hemorrhagic cyst Pos Pos Pos NA NA 20 25 Bilocular cyst containing thick material Neg Pos NA Pos NA 21 26 NA NA NA NA NA NA 22 27 Hemorrhagic mass NA NA NA NA NA 23 28 Solid mass with hemorrhagic foci Weak pos Pos Pos Pos NA 24 29 Biopsy: epithelioid cell Pos Pos Pos NA NA 25 30 Lobulated mass with hemorrhagic foci Pos Pos Pos Pos NA 26 31 NA NA NA NA NA NA 27 32 Cystic changes with old hemorrhage Pos Pos Neg Neg 60% 28 33 Infiltrating hemorrhagic noduli Focal pos Pos Neg Pos NA 29 34 NA NA NA NA NA NA 30 35 Solid mass with hemorrhagic areas Pos Pos Weak pos Weak pos NA 31 36 Areas of hemorrhage and necrosis Pos Pos Neg NA NA 32 37 Hematoma NA Pos Pos Pos NA 33 Table II. Immunohistochemical and gross findings of reported cases Ck = cytokeratin; NA = not available Most epithelioid angiosarcomas co-express cytokeratin and diagnostic errors may be promoted by immunohistochemical reactivity for this marker. In fact, cytokeratin reactivity may also occur in non-epithelial tumors like mesenchymal ones and the literature shows a lot of studies documenting the presence of cytokeratin in these tumors. Therefore, cytokeratin immunoreactivity may be considered as “aberrant expression” or “cross-reactivity” of this marker [36]. Surgery, combined with chemotherapy, represents the mainstay of treatment. Chemotherapy is preferably used in neoadjuvant setting to shrink the tumor and eventually prevent local or distant spread. In these cases, histological diagnosis is mandatory, before therapy and FNA may play an important role, because this tumor has not specific clinical or radiological patterns. Most active agents are anthracycline, ifosfamide, gemcitabine, and taxanes. In advanced or metastatic disease, cytotoxic chemotherapy based on the same active drugs is the treatment of choice. Even if the response rate of angiosarcoma to these treatments is higher than other tumors, in most cases their dose-limiting toxic effects (mostly cardiac and neurological) do not allow to use these therapies longer than 6 months [3]. Thus, new and non-toxic drugs are strongly needed. Among new anti-angiogenetic therapies, activity of sorafenib, sunitinib, bevacizumab, and thalidomide has been recently described, obtaining response rates up to 15% [37,38]. Especially in palliative setting, where the goal is to increase survival and preserve the quality of life, the sequential use of taxanes and gemcitabine could be, probably in most cases, more advisable than their combination [39]. Conclusions Epithelioid adrenal angiosarcoma is a very rare tumor and only 37 cases are reported in scientific literature. It is very aggressive and has poor long term prognosis. Such data show that early diagnosis is mandatory. Nevertheless, early diagnosis is rarely made since the tumor may be asymptomatic or present with aspecific symptoms, like slight fever, anorexia, fatigue or general pain or discomfort in the upper parts of the abdomen. Actually, endocrine tests are not indicative and the radiology workup may suggest just an indistinct malignancy. Even if histomorphological and immunohistochemical studies are time-consuming, they are an essential part of the definitive diagnosis and FNA may be an helpful tool to obtain a preoperative and definitive diagnosis. Unfortunately, sometimes diagnosis is made when disease is advanced, with no therapeutic options, as happened in this case. 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