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).

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Figure 1. Ultrasonography showing right adrenal mass (red arrow) infiltrating the upper pole of kidney and liver (one month before hospital admission)

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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).

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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)

img_02_04.jpg

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.

img_02_05.jpg

Figure 5. Hematoxylin-eosin (H.E.) staining and immunohistochemical studies

Ck = cytokeratin

What should the clinician ask him/herself or the patient

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.

Key points

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