Primary Adrenal Sarcomas: Diagnostic Challenges and Therapeutic Insights From a Case Series Including Leiomyosarcoma and Epithelioid Angiosarcoma

Abstract

Primary adrenal leiomyosarcoma and primary adrenal epithelioid angiosarcoma are exceptionally rare mesenchymal tumors of the adrenal gland. Both typically present as unilateral, nonfunctional adrenal masses and may closely resemble other adrenal or metastatic tumors, thus making diagnosis challenging. Immunohistochemical analysis is essential for accurate classification and clinical decision-making. We report two primary adrenal leiomyosarcomas and one primary adrenal epithelioid angiosarcoma, all occurring in elderly female patients without initial evidence of extra-adrenal disease. The leiomyosarcomas demonstrated spindle cell morphology with strong expression of smooth muscle markers and variable proliferative activity, including one patient that progressed to hepatic metastasis. The epithelioid adrenal angiosarcoma exhibited epithelioid features, extensive necrosis, diffuse CD31 and ERG positivity, and focal keratin expression. Complete surgical resection was achieved in all patients. These patients highlight the diagnostic complexity and prognostic variability of adrenal sarcomas. Documenting such rare tumors remains critical to improving diagnostic precision and guiding optimal management strategies.

Background

Primary adrenal leiomyosarcoma and primary adrenal epithelioid angiosarcoma are exceedingly uncommon malignant mesenchymal neoplasms of the adrenal gland, each constituting a rare but aggressive subset of nonepithelial adrenal tumors.^1–3 In contrast to adrenocortical carcinoma and pheochromocytoma, both adrenal leiomyosarcoma and angiosarcoma are hormonally inactive and are most often discovered incidentally during imaging performed for unrelated complaints or in the workup of nonspecific abdominal or flank pain.^2–4 Owing to their rarity, nonfunctionality, and overlapping radiologic features with more prevalent adrenal lesions such as adenomas, timely diagnosis remains challenging.^4,5

From a histopathological standpoint, primary adrenal leiomyosarcomas, similar to their counterparts in any organ system, are characterized by intersecting fascicles of spindle cells exhibiting smooth muscle differentiation, with varying degrees of atypia and mitotic activity.^2,3 Immunohistochemical (IHC) analysis is essential for definitive diagnosis, with positive staining for markers such as desmin, caldesmon, and smooth muscle actin, and negative expression of epithelial, neuroendocrine, or adrenocortical markers.^4,5 In contrast, again similar to angiosarcomas arising in any organ system, primary adrenal angiosarcoma demonstrates epithelioid cytomorphology and may exhibit variable immunoreactivity for endothelial markers including CD31, ERG, and FLI1, often accompanied by focal or aberrant expression of pankeratin, further complicating differential diagnosis.^6–8 Both tumors may show extensive hemorrhage and necrosis on gross examination, and proliferation indices such as Ki-67, or grading systems like the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC), may offer prognostic value.^2,3,6

The diagnosis of epithelioid angiosarcoma in the adrenal gland is particularly challenging due to its morphologic overlap with adrenocortical carcinoma, metastatic carcinoma, sarcomatoid melanoma, and other vascular tumors including epithelioid hemangioendothelioma. As a result, a comprehensive IHC workup and meticulous clinicoradiologic correlation are indispensable to exclude metastatic disease and confirm adrenal origin.^7–9 To date, fewer than 60 leiomyosarcomas and angiosarcomas arising from the adrenal gland have been reported in the English-language literature, largely as isolated case reports or small institutional series.^1–3,6–8

In this study, we present two adrenal leiomyosarcomas and one adrenal epithelioid angiosarcoma, each demonstrating unique clinicopathologic features. Through detailed clinicopathological correlation and comparison with the existing literature, we aim to broaden the current understanding of these rare entities and highlight the diagnostic complexities and therapeutic considerations associated with mesenchymal tumors of the adrenal gland.

Case Report

Patient 1

A woman with a known history of hypertension and type 2 diabetes mellitus presented with right-sided abdominal pain. Cross-sectional imaging revealed a large, heterogeneous solid mass measuring 78 mm in the right adrenal region, with close anatomical proximity to the superior pole of the right kidney, duodenum, liver, and inferior vena cava (Figure 1). The lesion exhibited features suspicious for malignancy, and the patient was referred to our center for surgical evaluation.

Figure 1.

(A) Axial T2-weighted image of the upper abdomen shows a solid lesion in the right surrenal gland (arrow). (B) Coronal T2-weighted image of the upper abdomen reveals a solid lesion in the right surrenal gland (arrow). (C) Axial fat-suppressed T1-weighted postcontrast magnetic resonance image shows an enhancing right adrenal mass (arrow). (D) Fused FDG positron emission tomography/computed tomography image shows increased FDG uptake of right adrenal lesion (arrow).

Surgical resection of the right adrenal gland was performed; however, negative margins could not be achieved due to extensive adherence of the tumor to surrounding structures. Grossly, the adrenal gland was replaced by a solid, tan-white mass measuring 90 mm in diameter, which was localized within the adrenal parenchyma and exhibited focal infiltration into adjacent soft tissue.

Microscopically, the tumor was composed of interlacing fascicles of spindle-shaped cells with mild-to-moderate nuclear pleomorphism. The cellularity was high, with alternating edematous and less cellular areas. No necrosis was observed. The mitotic activity was 12 per 10 high-power fields. According to the FNCLCC grading system, the tumor received a score of 4 (differentiation: 2, mitotic figures: 2, necrosis: 0), corresponding to grade 2.

Immunohistochemistry (IHC) showed that the tumor cells were diffusely positive for caldesmon and strongly positive in focal areas for desmin and actin. The Ki67 proliferation index was approximately 30%. No pleomorphic features or multinucleated giant cells were identified, consistent with the conventional histologic subtype of leiomyosarcoma.

Due to the presence of residual tumor risk and inability to achieve negative surgical margins, the patient underwent postoperative intensity-modulated radiotherapy. Adjuvant chemotherapy was administered, consisting of 4 cycles of doxorubicin and ifosfamide. At 14-month follow-up, the patient remained alive and was under active oncologic surveillance.

Patient 2

A postmenopausal woman with a medical history of hypertension, type 2 diabetes mellitus, hyperlipidemia, hypothyroidism, and a prior thyroidectomy for multinodular goiter presented with a long-standing, nonfunctioning left adrenal mass. This lesion was initially discovered during evaluation for flank pain several years ago. Ultrasonographic imaging at that time revealed a 57-mm hypoechoic solid lesion in the left adrenal gland, which was interpreted as an adenoma and monitored radiologically.

The patient subsequently underwent total abdominal hysterectomy for abnormal uterine bleeding, revealing an endometrial polyp along with a single 5-mm intramural uterine leiomyoma, unrelated to the adrenal lesion. However, interval follow-up imaging revealed significant growth of the adrenal lesion more than 2 years after its initial detection. Magnetic resonance imaging (MRI) demonstrated a 75-mm mildly lobulated solid mass located in both the lateral and medial crura of the left adrenal gland. The lesion was mildly hyperintense on T1-weighted and hypointense on T2-weighted sequences, with radiologic features suggestive of malignancy. No extra-adrenal lesions were identified. Gross examination of left adrenalectomy showed a 75-mm solid intra-adrenal tumor, showing focal areas of nodular pushing-type infiltration into adjacent soft tissue. Microscopically, a high-grade spindle cell neoplasm composed of intersecting fascicles of moderately pleomorphic spindle cells with cigar-shaped nuclei and prominent nucleoli was present (Figure 2). Foci of coagulative necrosis were observed, and the mitotic figures were 22 per 10 high-power fields. Based on FNCLCC grading system, the tumor received a score of 6 (differentiation: 2, mitotic figures: 3, necrosis: 1), corresponding to grade 3.

Figure 2.

(A) A spindle cell neoplasm with expansive growth demonstrated a transition to the adjacent normal adrenal cortex (H&E, 40×). (B) Higher magnification of the same tumor showed intersecting fascicles of eosinophilic spindle cells with mild nuclear pleomorphism (H&E, 100×). (C) Tumor cells showed diffuse cytoplasmic positivity for h-caldesmon (100×). (D) Strong and diffuse cytoplasmic desmin expression was observed in tumor cells (100×).

Immunohistochemically, the tumor cells exhibited diffuse strong positivity for desmin, caldesmon, and actin. The Ki67 proliferation index was approximately 80%. No pleomorphic features were identified, and the tumor was classified as conventional leiomyosarcoma. The patient received adjuvant chemotherapy with doxorubicin and ifosfamide. During clinical follow-up for 4 years, multiple T2-hyperintense, contrast-enhancing lesions were observed in the liver, the largest measuring 22 mm, consistent with metastasis. A second-line chemotherapy regimen including gemcitabine, docetaxel, and dexamethasone was initiated. The patient remained alive and under active oncologic management.

Patient 3

An 85-year-old female patient presented to her general practitioner with nonspecific abdominal complaints and was referred to a regional hospital for further evaluation. Her medical history was unremarkable for any chronic medical or oncologic conditions. Cross-sectional abdominal computed tomography revealed a 60-mm retroperitoneal mass in the right adrenal region. No lesions were detected in other organs, and a supplementary thoracic CT scan argued against pulmonary or mediastinal involvement. Hormonal evaluation, including serum cortisol, aldosterone, and ACTH levels, was within normal limits. Urinary catecholamine metabolite levels were also unremarkable, suggesting a nonfunctional adrenal mass.

The patient underwent surgical excision of the adrenal mass. Gross pathological examination of the 70 × 70 × 50 mm specimen revealed a well-circumscribed 60 × 50 × 30 mm hemorrhagic and necrotic mass. The adrenal gland was not discernible within the specimen. Histologically, the majority of the tumor exhibited geographic necrosis. The viable areas were composed of large, anaplastic epithelioid cells with abundant eosinophilic cytoplasm, prominent nucleoli, and scattered mitotic figures (Figure 3). The architecture was predominantly solid, though focal vascular-like lumina were observed interspersed among tumor cells. Periadrenal soft tissue infiltration was present.

Figure 3.

(A, B) Epitheloid high-grade malignant neoplasm with numerous mitotic figures, pleomorphism, and increased vasculature is seen in the adrenal gland (H&E, 200×). (C) Tumor cells diffusely express CD31 (100×) and (D) ERG (100×), confirming the diagnosis of epithelioid angiosarcoma.

Immunohistochemically, the tumor cells exhibited diffuse nuclear expression of ERG and strong membranous positivity for CD31, confirming endothelial lineage. Focal cytoplasmic reactivity for keratin AE1/AE3 was observed, whereas CD34 was negative. INI1 expression was retained. Notably, MYC showed diffuse nuclear positivity; however, fluorescence in situ hybridization analysis demonstrated no MYC gene amplification. Compressed adrenal cortical tissue was noted at the periphery of the mass, confirming the adrenal origin of the tumor.

Based on these histologic and immunophenotypic findings, the lesion was diagnosed as primary adrenal epithelioid angiosarcoma. The tumor was staged as pT2 according to the American Joint Committee on Cancer classification. Surgical margins were negative. Given the absence of residual disease, the patient was managed with active surveillance. Comprehensive genomic profiling is being pursued due to the exceptional rarity of the diagnosis.

Discussion

Primary adrenal leiomyosarcoma and primary adrenal epithelioid angiosarcoma share similar clinical features and anatomic localization with more common primary adrenal lesions, however, leiomyosarcoma and epithelioid angiosarcoma arising from the adrenal gland exhibit distinct histopathologic and immunophenotypic profiles. Leiomyosarcoma is composed of spindle-shaped cells arranged in fascicular patterns, consistent with smooth muscle differentiation,^4–6 whereas epithelioid angiosarcoma demonstrates epithelioid morphology with vasoformative features, often accompanied by keratin expression that may mimic metastatic carcinoma.^2,3,8 Leiomyosarcoma consistently shows diffuse positivity for desmin, smooth muscle actin, and caldesmon, while lacking reactivity for epithelial and adrenocortical markers.^4–6 In contrast, epithelioid typically exhibits strong expression of endothelial markers such as CD31, ERG, and FLI1, with variable and often focal expression of pankeratin—a diagnostic pitfall that can lead to misclassification.^2,3,8 Interestingly, MYC expression and chromosome 8 polysomy have been reported in a subset of primary epithelioid angiosarcoma patients, though their prognostic or therapeutic implications remain uncertain.^2,3 In our series, both leiomyosarcomas demonstrated diffuse staining for smooth muscle markers, while the angiosarcoma displayed diffuse CD31 and ERG positivity, focal AE1/AE3 expression, and retained INI1 expression—findings consistent with previously reported epithelioid angiosarcoma profiles.^2,3,8

In the most extensive registry-based analysis to date, Aryal et al reviewed 332 primary adrenal sarcomas from the National Cancer Database, identifying leiomyosarcoma (37%) and angiosarcoma (27%) as the predominant histologic subtypes. ¹ While informative in terms of epidemiologic patterns, the utility of this dataset is constrained by its lack of centralized histologic review and absence of granular clinicopathologic data. Critical diagnostic parameters—such as mitotic figures, necrosis, IHC profile, and margin status—were not captured. To better contextualize our findings, we conducted a comprehensive review of previously published adrenal gland leiomyosarcoma and epithelioid angiosarcoma patients, summarized in Tables 1 and 2, respectively. These tables synthesize clinicopathologic and IHC data from the largest collection of individual case reports and small series currently available in the English-language literature. Notably, the leiomyosarcoma patients demonstrated considerable variability in tumor grade, mitotic index, presence of necrosis, and Ki67 proliferation rates, all of which may influence biological behavior and prognosis. Similarly, epithelioid angiosarcoma patients exhibited wide-ranging histologic patterns, including classic vasoformative architecture as well as solid epithelioid growth, and showed diverse immunophenotypic features—particularly in regard to keratin expression and MYC status. By incorporating our three patients into this collective dataset, we aimed to provide an updated comparative resource for pathologists and clinicians managing these diagnostically complex tumors.

Table 1.

Clinicopathologic Features of Primary Adrenal Leiomyosarcomas.

First AuthorPMIDYear	Age Sex	Side (R/L)	Size (cm)	Mitotic rate (/10 HPF)	Necrosis	Immunohistochemistry and further workup (if any)	Histologic type	Treatment	Metastasis/recurrence	Outcome
Choi 7464153 1981	50 F	L	16	NA	+ (central cystic)	NA	Spindle cell LMS	Adrenalectomy + partial nephrectomy	None	Alive (12 mo f/u)
Lack 1951846 1991	49 M	R	11	15	+	Positive: SMA, Actin, Vimentin,	Conventional LMS	Adrenalectomy + nephrectomy	None	Alive (9 mo f/u)
Hayashi 7570568 1995	55 F	R	NA	NA	NA	NA	Conventional LMS	Adrenalectomy + IVC and right atrial resection + GORE-TEX graft	IVC, hepatic vein and right atrium metastasis	Alive (52 mo f/u)
Zetler 7503667 1995	30 M	L	11	NA	+	Positive: SMA	Conventional LMS	Adrenalectomy	None	Alive (20 mo f/u)
Boman 9278611 1997	29 M	L	0.8	NA	NA	Positive: SMA	Conventional LMS	None (mass detected by autopsy)	None	NA
Etten 18521310 2001	73 F	R	27	Up to 10	+ (coagulative)	Positive: SMA	Spindle cell LMS	Unresectable, biopsy only	None	Deceased (3 weeks postop)
Matsui 11972651 2002	61 F	R	NA	High (not quantified)	+ (central degeneration)	Positive: SMA	Poorly differentiated LMS	Adrenalectomy + nephrectomy + IVC thrombectomy + bypass	Lung, lymph node, hepatic vein	Deceased (1 mo)
Lujan 12562292 2002	63 M	R	25	High (not quantified)	+	Positive: Desmin Calponin, Vimentin, Negative: SMA, PanK, KIT, S100	Pleomorphic LMS	Adrenalectomy + hepatectomy + nephrectomy	Lung	Deceased (shortly postop)
Thamboo 12701684 2003	68 F	R	13	High (not quantified)	+	Positive: Desmin, Calponin, Actin, Vimentin	Conventional LMS	Adrenalectomy + nephrectomy + hepatic lobectomy + cholecystectomy and chemotherapy	None	Alive (12 mo f/u)
Linos 15523410 2004	14 F	Bilateral	3.5 (R), 4.0 (L)	NA	+	Positive: SMA, Vimentin, HHF Negative: Desmin, S100, CD34, ALK	Spindle cell LMS	Bilateral laparoscopic adrenalectomy	History of previous contralateral tumor	Alive (third postoperative day, uneventful)
Kato 15221604 2004	59 M	L	10	High (not quantified)	+	Positive: SMA, Desmin, Vimentin, Negative: NSE, S100, Chromogranin, Synaptophysin, CD34	Spindle cell LMS	Nephroadrenalectomy + IVC thrombectomy	Bone + Liver + IVC recurrence	Deceased (6 mo)
Candanedo -Gonzalez 16000850 2005	59 F	L	16	15	+	Positive: Actin, Desmin, Vimentin, p53; Negative: S100, CD34, HMB45, ER	Pleomorphic LMS with osteoclast-like giant cells	Adrenalectomy + Chemo + Radiotherapy + Metastasectomy	Liver + Local recurrence (at 12 months)	Alive (36 mo f/u)
Wong 16140856 2005	57 M	L	NA	NA	+	NA	High-grade LMS	Adrenalectomy + nephrectomy + IVC thrombectomy + pulmonary embolectomy + cardiac repair + radiotherapy	Widespread recurrence	Deceased (shortly after recurrence)
Lee 16177871 2006	49 M	L	3	NA	+	Positive: Desmin, Negative: PanK, S100, CD34, KIT, HMB45	Spindle cell LMS	Laparoscopic adrenalectomy	None	Alive (10 mo f/u)
Wang 17910774 2007	64 F	R	14.2	3–5	+	Positive: SMA, Desmin Negative: S100, HMB45, KIT	Spindle cell LMS (adrenal vein origin)	Adrenalectomy + IVC tumor resection + DHCA	None at 10 months	Alive (10 mo f/u)
Mohant 17905130 2007	47 F	L	7	12–14	+	Positive: Desmin, Calponin, Actin Negative: PanK, RCC, CD10 (MME), S100, MelanA, Inhibin	Pleomorphic LMS	Adrenalectomy + Nephrectomy + Radiotherapy + Chemotherapy	Liver, lung, lymph nodes	Alive (18 mo f/u)
Mencoboni 21892297 2008	75 F	R	8	16/50 HPF	–	Positive: SMA, Desmin, HHF35 Negative: CD34, KIT	Spindle cell LMS	Adrenalectomy	None	Alive (12 mo f/u)
Goto 18250540 2008	73 F	R	8–10	2–5	+	Positive: SMA, NSE Negative: CD57, S100, KIT	Spindle cell LMS	Adrenalectomy + nephrectomy + IVC resection with graft replacement	None	Alive (10 mo)
Van Laarhoreu 19331188 2009	78 M	L	NA	NA	Not stated	Positive: Vimentin, SMA, muscle-specific actin Negative: S100, PanK	Spindle cell LMS (confirmed via adrenal biopsy)	None (ineligible for systemic treatment)	Bone, pancreas, brain	Deceased (shortly after diagnosis)
Hamada 19705248 2009	62 F	Bil	8 (R), 4 (L)	NA	+	Positive: SMA, Negative: PanK, CD34, KIT	Spindle cell LMS	Bilateral adrenalectomy + CYVADIC + RFA + RT	Pleura, bone, liver, kidney, pancreas	Deceased (16 mo)
Karaosmanoglu 20733196 2010	63 M	R	10	NA	+	Positive: Actin, Vimentin, Desmin (patchy), PanK (patchy)	High-grade LMS	None (unresectable) + Chemotherapy	None stated, rapid progression	Deceased (3 mo)
Kanthan 22540324 2012	28 F	L	16	Moderately (not quantified)	+	Positive: SMA, Vimentin	Conventional LMS	Adrenalectomy + nephrectomy	Kidney	NA
Shao 23127348 2012	66 M	L	9.5	Not stated	Not stated	Positive: SMA, Desmin Negative: KIT, HMB45, CD34	LMS from adrenal vein	Adrenalectomy (en bloc excision)	None	Alive (18 mo)
Liu 23196986 2012	79 F	L	6.3	NA	-	NA	Spindle cell LMS	Adrenalectomy	NA	Alive (12 mo f/u)
Deshmukh 23575089 2013	60 F	L	5.2	10–12	–	Positive: SMA, Desmin, Vimentin Negative: PanK, S100, KIT, HMB45, CD3	Conventional low-grade LMS	Adrenalectomy	None	Alive (21 mo f/u)
Alam 24858171 2014	35 F	L	8.5	NA	NA	NA	Spindle cell LMS	Adrenalectomy	NA	NA
Wei 24619012 2014	57 F	L	7.7	>10	+	Positive: SMA, Desmin, Vimentin, Negative: PanK, KIT, S100, HMB45, CD34, CD68, Myoglobin	High-grade LMS	Nephroadrenalectomy + reoperation + chemotherapy	Local recurrence at 17 mo	Alive (29 mo f/u)
Bhalla 25195305 2014	45 M	R	11	NA	+	Positive: SMA, Desmin	Spindle cell LMS	Chemotherapy	Liver metastasis	Alive (9 mo f/u)
Gulpinar 24716083 2014	48 M	R	9	NA	+	Positive: SMA, Caldesmon, Vimentin, Ki67 4%	Low-grade conventional LMS	Open adrenalectomy	None	Alive (8 mo f/u)
Lee 25588632 2014	28 M	R	15	25	+	Positive: SMA, Desmin, Ki67 60% Negative: PanK, S100, KIT	Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade 3 LMS	Open adrenalectomy	None	Alive (8 mo f/u)
Ozturk 25002946 2014	70 F	R	8	8–10	–	Positive: SMA, Desmin Negative: KRT–, Bcl-2–, Ki67 70%	Spindle cell LMS	Adrenalectomy + Cavatomy	Widespread metastasis	Alive (6 mo f/u)
Nagaraj 25685588 2015	61 M	L	16	High (not quantified)	+	Positive: Desmin, Vimentin Negative: PanK, S100	High-grade spindle cell LMS	Open adrenalectomy	No confirmed follow-up	NA
Zhou 26097622 2015	49 F	L	6	High (not quantified)	+	Positive: Desmin, SMA, Vimentin Ki67 > 60% Negative: CD34, KIT, S100, Bcl2, DOG1,	Spindle cell LMS	Laparoscopic adrenalectomy	None	Alive (6 mo f/u)
Quildrian 26215892 2015	44 F	R	12	12	+	Positive: Vimentin, H-caldesmon, SMA, Desmin, CD34, Ki67 20% Negative: S100, KIT, PanK	Spindle cell LMS, FNCLCC grade 2	Laparoscopic adrenalectomy	None	Alive (36 mo f/u)
Onishi 27368929 2016	34 M	R	5.2	NA	+	Positive: SMA, Ki67 ∼50% Negative: S100, CD34	Spindle cell LMS	Adrenalectomy lymphadenectomy IVC resection right renal vein reconstruction	Lymph node metastasis, no recurrence at 10 months	Alive (10 mo f/u)
Mulani 30402300 2018	50 M	L	8.1	NA	+	Positive: Desmin, Keratin MAK6, WT1, S100, Negative: CD34, chromogranin	Pleomorphic LMS	Chemotherapy Palliative radiation	Liver and lung metastasis	Alive (f/u N/A)
Doppalapudi 30936336 2019	70 M	R	12.2	Not stated	+	Positive: SMA, Desmin, Caldesmon, Vimentin Negative: S100	Spindle cell LMS, high-grade (grade 3)	Adrenalectomy Nephrectomy IVC thrombectomy	Pulmonary metastasis (at 1 year)	Deceased (14 mo)
Nerli 31950011 2019	27 M	L	9	8–9 per 50 HPF (∼1.6-1.8 per 10 HPF)	+	Positive: Desmin, H-Caldesmon Negative: KIT	Spindle cell LMS	Adrenalectomy	None reported	Alive (f/u N/A)
Sakellariou 32871746 2020	62 M	L	10.3	18	+	Positive: SMA, Desmin	Pleomorphic LMS	Adrenalectomy Chemotherapy Radiotherapy	Bone, liver, lung	Alive (31 mo f/u)
Jabarkhel 32537544 2020	72 M	L	10	10	+	Positive: SMA, Desmin, H-caldesmon	Pleomorphic LMS	Adrenalectomy Radiotherapy	Liver, bone, soft tissue (after 31 mo)	Alive (48 mo f/u)
	66 M	R	7.5	17	+	Positive: SMA, Desmin, H-caldesmon, CD163	Pleomorphic LMS	Adrenalectomy IVC resection	Multiple (lung, soft tissue)	Alive (23 mo f/u)
	58 F	L	6	NA	+	Positive: SMA, Desmin, H-caldesmon, Vimentin	Spindle cell LMS	Chemotherapy (Dacarbazine + Doxorubicin; then Gemcitabine + Docetaxel)	Liver metastasis	Alive (13 mo f/u)
Wang 32547099 2020	64 F	R	14	High	+	Positive: SMA, Desmin	Spindle cell LMS	Adrenalectomy Thrombectomy	IVC and right atrium involvement	Alive (10 mo)
Waack 36582750 2022	58 F	L	5.5	NA	+	Positive: SMA, Desmin, Calponin, Vimentin (focal)	Spindle cell LMS	Laparoscopic adrenalectomy	Hepatic metastasis (after 2.5 years)	Alive (30 mo f/u)
Oshidari34952313 2022	32 F	R	10.6	10	+	Positive: SMA, Desmin, Vimentin	Spindle cell LMS	Adrenalectomy	IVC invasion	Alive (2 mo f/u)
Wang 35953367 2023	29 F	R	3.4	Low	–	Positive: SMA, Desmin, Vimentin, H-caldesmon	Spindle cell LMS	Adrenalectomy	None	Alive (12 mo f/u)
Lin 36154829 2023	56 M	R	7.4	8	+	Positive: SMA, Desmin, H-caldesmon	Spindle cell LMS	Adrenalectomy Liver metastasectomy	Liver	Alive (6 mo f/u)
Suzuki 38110958 2023	71 F	R	11	NA	+	Positive: SMA, Desmin, Vimentin	Spindle cell LMS	Needle biopsy only, no treatment	Lung, lymph nodes, IVC thrombus	Deceased (8 mo)
	45 F	Left	7	NA	+	Positive: SMA, Desmin, Vimentin	Pleomorphic LMS	Planned chemo, discontinued	Para-aortic LN, IVC thrombus	Deceased (1 mo)
Mongardini 38930027 2024	52 F	Right	9	High (exact number NR)	+	Positive: SMA, Desmin, Calponin	Spindle cell LMS	Laparoscopic adrenalectomy chemo (Epirubicin + Dacarbazine)	Liver, bone, lung metastasis	Alive (12 mo f/u)
Present patients	60 F	Left	7.5	22	+	Positive: SMA, Desmin, Vimentin, H-caldesmon	Conventional LMS	Laparoscopic adrenalectomy chemo (Doxorubicin + Ifosfamide)	Liver metastasis (after 2.5 years)	Alive (13 mo f/u)
	60 F	Right	9	12	–	Positive: SMA, Desmin, Vimentin, H-caldesmon	Conventional LMS	Adrenalectomy + intensity-modulated radiotherapy + chemo (Doxorubicin + Ifosfamide)	None detected (ongoing follow-up)	Alive (7 mo f/u)

Table 2.

Clinicopathologic Features of Primary Adrenal Angiosarcomas.

First AuthorPMIDYear	Age Sex	Side (R/L)	Size (cm)	Mitotic rate (/10 HPF)	Necrosis	IHC Markers	Histologic Type	Treatment	Metastasis/recurrence	Outcome
Kareti 3178432 1988	58 M	L	17.5	NA	+	NA	Epithelioid AS	Adrenalectomy Left nephrectomy, splenectomy, partial gastrectomy, and distal pancreatectomy Adjuvant chemotherapy with paclitaxel	Extensive retroperitoneal metastatic disease, metastasis to the right adrenal gland and distal colon	Died 9 months postsurgery
Bosco 1895431 1991	65 F	R	15	NA	Present (gross necrosis)	NA	Epithelioid AS	Adrenalectomy + chemotherapy	Not specified	Died within 3 months
Livaditou 2068012 1991	59 M	R	7	Frequent mitotic figures, some atypical	Extensive necrosis and hemorrhage	Positive: Factor VIII, Vimentin, Ulex europaeus-I Negative: PanK	Epithelioid AS	En bloc right adrenalectomy + nephrectomy	Invaded liver capsule; no autopsy	Died on eighth postoperative day (hypovolemic shock)
Croitoru 11598858 2001	63 M	L	3	Rare mitotic figures	Present (hemorrhagic + necrotic)	Positive: CD34, Vimentin, factor VIII (weak) Negative: S100, chromogranin, HMB45, CAM5.2	Epithelioid AS	Laparoscopic adrenalectomy	None reported	Alive, disease-free postop
Krüger 11693805 2001	70 M	R	8	20–30	Extensive hemorrhage + necrosis	Positive: PanK, EMA, Vimentin, Factor VIII, CD31, CD34 Ulex europaeus-I	Epithelioid AS	Adrenalectomy + nephrectomy + liver resection	None at autopsy	Died 3 weeks postop (mesenteric infarction + ARF)
Gambino 18709789 2008	49 F	R	NA	NA	Widespread necrosis	NA	Epithelioid AS	Adrenalectomy + periadrenal fat & nodes	No recurrence at 1 year	Alive and disease-free at 1 year
Lepoutre-Lussey 22048963 2012	35 M	R	6	High (exact number NR)	+	Positive: CD31, CD34, and von Willebrand factor (factor VIII)	AS	Adrenalectomy, Adjuvant chemotherapy	None	Alive at 24 months postop
Schreiner 21472878 2012	69 F	R	14	Scattered mitotic figures	Extensive necrosis + hemorrhage	Positive: CD31, CD34, CAM5.2 Negative: AE1/AE3, KRT20, KRT7, EMA, S100, MelanA, synaptophysin, chromogranin, inhibin	Epithelioid AS	Right adrenalectomy + nephrectomy	Not specified	Not reported in the article
Hendry 24771258 2014	60 F	L	5.5	High (exact number NR)	+	Positive: CD31, Factor VIII, CD34 (focal/weak), AE1/AE3 (focal), Negative: EMA, CAM5.2	AS	Adrenalectomy	None	Alive at 9 months postop
Hayashi 25246132 2014	63 M	R	8.5	Up to 12	Present (with hemorrhage)	Positive: CD31, AE1/AE3, KRT7, CAM5.2, p53 (mutant), Galectin3 Negative: CD34, D2-40, SF1	AS	Adrenalectomy	Mediastinum	N/A
Cornejo 26223194 2015	53 F	L	15	20	Present	Positive: CD31, PanK, MYC Negative: CD34 FISH: No MYC amplification	Epithelioid AS	Adrenalectomy	Metastases to lung, brain, liver (postop chemo + RT)	Deceased at 3 months
	74 M	L	8.5	41	Present	Positive: CD31, PanK, MYC Negative: CD34 FISH: No MYC amplification	Epithelioid AS	Adrenalectomy	Deceased at 5 months	Deceased
	75 F	L	11	4	Present	Positive: CD31, PanK, MYC Negative: CD34 FISH: No MYC amplification	Epithelioid AS	Adrenalectomy	Metastases to lung and bone	Deceased at 16 months
	75 F	L	NA	15	Present	Positive: CD31, CD34, PanK, MYC (No FISH performed)	Epithelioid AS	Adrenalectomy	Brain metastasis at 18 months	Alive with disease at 19 months
Takizawa 28551383 2017	63 M	R	3.4	3 / 20 HPF (yaklaşık 1.5 / 10 HPF)	Fokal hemoraji	Positive: CD31, CD34, Factor VIII, AE1/AE3, ERG, FLI-1, CAM5.2 (focal), Vimentin (focal), D2-40, EMA, WT1	AS	Adrenalectomy, Adjuvant chemotherapy	Pleura	Deceased at 18 months postop
Li 29137070 2017	59 M	L	5.4	NA	Present (necrosis + hemorrhage)	Positive: CD31, Factor VIII, CD34, Ki-67: 25%–35% Negative: inhibin, chromogranin, synaptophysin, CD56, MelanA, S100	Epithelioid AS	Laparoscopic adrenalectomy	None reported	Alive, no recurrence at 6 months
Grajales-Cruz 2017	69 M	R	16.4	Not numerically stated; mitosis present	Present (extensive hemorrhage + necrosis)	Positive: CD31, Factor VIII Negative: CD34, S100, MelanA, Synaptophysin, Chromogranin, Desmin, EMA, KRT20, Inhibin	Epithelioid AS	Open adrenalectomy + 4 cycles of doxorubicin/ifosfamide + referred for RT	Suggestive recurrence (pleural effusion); no confirmed metastasis	Deceased (multiorgan failure post recurrence)
Yang 31938388 2018	60 M	L	6.5	5–40	Present (necrosis + hemorrhage)	Positive: CD31, CD34, ERG, FLI-1, KRT (focal), Vimentin, Negative: MelanA, HMB45, Calretinin	Epithelioid AS	Adrenalectomy	None	Alive, NED at 3 years
	60 M	L	8	5–40	Present (extensive)	Positive: CD31, CD34, ERG, Fli-1 PanK (focal) Negative: MelanA, HMB45, Calretinin	Epithelioid AS	Adrenalectomy, left nephrectomy and splenectomy	Adhesions to the capsule of the kidney and spleen	Died of disease at 1 month
Ishii 31149532 2018	57 M	L	7.4	Not specified numerically (mitotic activity implied)	Present (gross hemorrhagic features noted)	Positive: CD31, CD34, Factor VIII	Epithelioid AS	Adrenalectomy and splenectomy	Simultaneous occurrence of angiosarcoma in the spleen	Alive, NED at 18 months
Antao 31612098 2019	58 M	L	17.5	Brisk mitotic figures	Extensive necrosis + hemorrhage	Positive: CD31 (focal), CD34, Factor VIII, Vimentin, Synaptophysin, Negative: AE1/AE3, chromogranin, S100	Epithelioid AS	Left adrenalectomy + nephrectomy + splenectomy + gastrectomy + pancreatectomy + multiple lines of chemotherapy	Recurrence + metastases (right adrenal, abdominal soft tissue)	Deceased after fifth-line chemotherapy
Imran 32123554 2020	38 F	R	8.5	Brisk mitotic figures (not exact)	>50% necrosis + hemorrhage	Positive: CD31, CD34, Factor VIII, CAM5.2, Vimentin, Negative: Inhibin, Calretinin, Neuroendocrine markers	Epithelioid AS	Adrenalectomy, Chemotherapy for metastatic disease (paclitaxel)	Metastasis to ribs and right tibia	Alive, 6 months of postsurgery
Wei 34976833 2021	51 M	L	4	Not numerically specified;	Present (massive)	Positive: CD31, CD34, ERG (weak), FLI-1 (weak), PanK, KRT7, Ki67: 20% Negative: KRT20, MelanA, S100, synaptophysin	Epithelioid AS	Adrenalectomy, Chemotherapy for recurrence and metastasis, combination chemotherapy, consisting of six cycles of doxorubicin plus paclitaxel	Recurrence after 7 months after surgery, distant metastasis to mediastinal, inguinal, and retroperitoneal lymph nodes	Alive, 12 months postsurgery
Ladenheim 34029146 2022	44 F	L	11.7	NA	Present (extensive)	Positive: CD31 (+), ERG (+), AE1/AE3 (focal +), Ki67: 80%, CD34 in metastasis Negative: Inhibin, MelanA, chromogranin,	Epithelioid AS	Adrenalectomy, Chemotherapy (paclitaxel) for metastatic disease	Metastasis in the lungs	Alive on follow-up 14 months after resection
	65 M	L	11.2	Numerous atypical mitotic figures;	Present (cystic and hemorrhagic)	Positive: CD31, ERG, AE1/AE3 (focal), CAM5.2 (focal), Ki67: 50% Negative: CD34, Inhibin, Calretinin, synaptophysin, S100, GATA3, TTF1	Epithelioid AS	Adrenalectomy	Suspected recurrent angiosarcoma with bowel invasion after 4 months of adrenalectomy	Died 10 months postsurgery
Wannasai 37246360 2023	59 M	L	8.5	7	Present (with hemorrhage)	Positive: CD31, CD34, Factor VIII, panK (focal), FLI-1 Negative: MelanA, inhibin, calretinin, S-100, INI1 (retained)	Epithelioid AS	Adrenalectomy	No metastasis; lost to follow-up postoperatively	Discharged; follow-up data unavailable
Noman 37363587 2023	59 M	L	14	Not specified;	Present (extensive)	Positive: CD31, FLI-1, PanK, D2-40, Ki-67 > 50% Negative: chromogranin, synaptophysin, MelanA, inhibin, S100	Epithelioid AS	Adrenalectomy, Six cycles of adjuvant chemotherapy (doxorubicin and ifosfamide) For metastatic lesions: six cycles of (gemcitabine and docetaxel)	The primary tumor was adherent to adjacent organs but did not invade them. Recurrence in the local area and metastasis to both lungs	Alive, 11months postsurgery
Feng 37045632 2023	41 M	L	4.4	NA	Present (with hemorrhage)	Positive: CD31, CD34, ERG, FVIII, FLI-1, D2-40, Ki67: 30% Negative: SMA, S100, EMA, PanK	Epithelioid AS	Laparoscopic adrenalectomy + Paclitaxel	No recurrence/metastasis at 14 months	Alive, no evidence of disease
Naeem 37564399 2023	66 F	R	4.3	12	NA	Positive: CD31, ERG, FLI-1, Ki67: 10% Negative: AE1/AE3, SMA, Desmin, HHV8, STAT6, S100, Synaptophysin, Chromogranin	Epithelioid AS	Robotic-assisted adrenalectomy	No metastasis; under close follow-up	Alive and stable at reporting
Alsarraj 38098906 2023	54 F	R	5.7	Frequent mitotic figures (not quantified); pleomorphic cells	Central necrosis present	Positive: CD31, CD34, ERG	Epithelioid AS	Laparoscopic adrenalectomy	No metastasis	Alive; no recurrence noted
Babińska 38411042 2024	69 F	R	8.3	6	∼85% of tumor; hemorrhagic + necrotic	Positive: CD31, ERG, AE1/AE3; Negative: CD34, EMA, SOX10, MelanA, Syn, CgA, Inhibin	Epithelioid AS	Laparoscopic adrenalectomy	Local recurrence in right kidney at 6 weeks postop	Palliative care after recurrence
Zhou 37925290 2024	62 F	L	3.8	NA	Minor necrosis, hemorrhage	Positive: CD31 (+), CD34 (+), ERG (+), factor VIII (+), Ki67: 20%, Negative: KIT, HHV8, S100, SMA, D2-40	Well-differentiated AS	Laparoscopic adrenalectomy Docetaxel & Ifosfamide (4 cycles)	No recurrence at 7 months	Alive, disease-free at 7 months
Parisi 37461274 2024	41 F	R	14	∼25 / 50 HPF (∼5 / 10 HPF)	Extensive necrosis + hemorrhage	Positive: CD31, ERG, CD34 (patchy), Ki67: 70% Negative: AE1/AE3, CAM5.2, SF1, SOX10, MelanA, D2-40	Epithelioid AS	Adrenalectomy Pembrolizumab Doxorubicin/Ifosfamide/Irinotecan	Liver and lung metastases postop	Deceased within 6 months of diagnosis
Echeverría-Ortegón 40099058 2025	47 F	R	14	Not specified (high grade)	Present (gross + cystic)	Positive: CD31, FLI-1, PanK, D2-40; chromogranin, synaptophysin, Negative: MelanA, inhibin, S100	Epithelioid AS	Open adrenalectomy (curative intent)	No metastasis at diagnosis; no recurrence noted	Alive, no recurrence noted
Present patient	85 F	R	6	High (exact count not given)	Extensive necrosis	Positive: CD31, ERG, AE1/AE3 (focal), MYC Negative: CD34, INI1 (retained), FISH: No MYC amplification	Epithelioid AS	Adrenalectomy with negative margins	None (under surveillance)	Alive; under active follow-up

Prognosis remains guarded for both adrenal leiomyosarcoma and epithelioid angiosarcoma, in part due to the rarity of these tumors and the consequent lack of standardized treatment protocols.^1,2,4 In leiomyosarcoma, adverse prognostic factors include high FNCLCC grade, elevated mitotic index, presence of coagulative necrosis, and incomplete surgical excision.^4–6 Similarly, epithelioid angiosarcoma demonstrates a propensity for aggressive clinical behavior when associated with large tumor size, high proliferative index, extensive necrosis, and high-grade epithelioid features.^2,3,8 Although complete surgical resection represents the cornerstone of management for both tumor types, the role of adjuvant therapies remains ill-defined. Limited reports have described the use of anthracycline- or taxane-based chemotherapy in epithelioid angiosarcoma, particularly in patients with recurrent or metastatic disease, albeit with variable responses.^2,3,8,9 In our cohort, the grade 3 leiomyosarcoma patient developed hepatic metastases during follow-up despite adjuvant chemotherapy, whereas the patient with the grade 2 tumor remained disease-free under surveillance. The epithelioid angiosarcoma patient, whose tumor was completely resected with negative margins, is currently under active follow-up, reflecting the broader uncertainty surrounding the benefit of adjuvant therapy in such patients.

Conclusion

Primary adrenal leiomyosarcoma and primary adrenal epithelioid angiosarcoma are exceptionally rare mesenchymal malignancies that present substantial diagnostic and therapeutic challenges due to their nonspecific clinical presentation, lack of hormonal activity, and morphologic overlap with other adrenal or metastatic neoplasms. In this study, we present two additional adrenal leiomyosarcomas and one adrenal epithelioid angiosarcoma, and integrated them into an updated review of the literature to emphasize key differences and shared features in their clinicopathologic profiles, IHC characteristics, and clinical outcomes. Accurate diagnosis relies on comprehensive histopathologic and immunophenotypic evaluation, particularly in tumors with atypical or overlapping features. While complete surgical resection remains the cornerstone of treatment, the role of adjuvant therapy is not yet well defined and requires individualized decision-making. As the cumulative number of reported patients continues to grow, each new contribution offers valuable insight into the biological behavior, prognostic variables, and evolving management approaches for these rare and aggressive adrenal sarcomas.