Adrenal adenomatoid tumor in a patient with human immunodeficiency virus.

We present the clinical course of a patient with human immunodeficiency virus and an adrenal adenomatoid tumor (AAT). We describe the clinical course and laboratory, radiographic, and microscopic findings of a patient with human immunodeficiency virus (HIV) and an adenomatoid tumor of the right adrenal gland. A review of the literature was also done via electronic searches through PubMed for articles from 1965 to 2008 that contained the following search terms, adenomatoid tumor limited to the English language only. A 22 year-old African-American male with HIV was incidentally found to have a hypermetabolic right adrenal mass. The patient underwent laparoscopic adrenalectomy and the mass had morphological and immunohistochemical features that were consistent with an AAT. A review of the medical literature reveals that almost all cases of AAT were in male patients (96%) with a mean age of 41±11 years (range=22-64) with no significant difference in laterality (right side=46%, left side=50%, unknown=4%). AAT have an average size of 4.2±3.5 cm (range=0.5-14.3 cm). Pre-operative imaging studies do not appear to be able to reliably distinguish AAT from other types of adrenocortical tumors. For reasons that require further research, AAT typically occur in male patients and may be associated with immunosuppression. AAT can be safely removed laparoscopically with no evidence of long-term recurrence even with tumor extension beyond the adrenal capsule.

Introduction

Adenomatoid tumors most commonly occur in the genital tract including the epididymis, uterus, or fallopian tube.[1] Interestingly, these tumors have also been reported to occur in the adrenal gland.[1-6] Adrenal adenomatoid tumors are derived from mesothelial cells from mesothelial rests within the adrenal gland. These rests are likely present due to the close embryological relationship between the adrenal glands and the Mullerian tract.[6-7] This report represents the 29th case of an adrenal adenomatoid tumor in the literature, but is only the second case described in a patient with human immunodeficiency virus and the first case in which positron emission tomographic scanning was used as part of the diagnostic work-up.

Materials and Methods

We describe the clinical course, laboratory, radiographic, and microscopic findings of a patient with human immunodeficiency virus and an adenomatoid tumor of the right adrenal gland. A review of the literature was also done via electronic searches through PubMed for articles from 1965 to 2008 that contained the following search terms, adenomatoid tumor limited to the English language only. All articles that contained reported cases of adenomatoid tumor were analyzed. Pertinent references from these articles were reviewed and synthesized. This cycle continued until it was felt that a complete listing of all published cases of adenomatoid tumors in the English language was obtained. This study was approved by the Institutional Review Board at University Hospitals of Cleveland.

Results

Report of a case

AH is a 22 year-old African-American male with a past medical history of human immunodeficiency virus on HAART (Highly Active Anti-Retroviral Therapy) who was noted to have an incidental adrenal mass on computed tomography of the chest done as a follow-up study for mediastinal lymphadenopathy. No previous adrenal masses were noted on previous computed tomographic imaging.

The patient denied any symptoms of palpitations, diaphoresis, flushing, or uncontrolled high blood pressure. He subsequently had a magnetic resonance imaging scan to further characterize the adrenal mass. It was a right adrenal mass that measured 2.7 by 1.6 by 2.3 cm in size with atypical enhancement patterns with gadolinium contrast. The patient underwent a complete adrenal hormonal work-up. His 24-hour urine catecholamines, serum aldosterone, and plasma renin activity were all normal. Serum cortisol level was mildly elevated, but his urinary cortisol level was normal. Prior to surgical referral, the patient also underwent a follow-up positron emission tomographic scan which demonstrated increased uptake of 3.4 SUV. Based on the above findings, the differential diagnosis included a non-functioning adrenal adenoma or malignancy. The patient underwent a laparoscopic right adrenalectomy with no post-operative complications on follow-up examination seven months later.

Pathologic findings

On gross examination, the adrenal gland was 5.5 by 3.0 by 1.0 cm in size with a well-circumscribed, firm, tan-gray cortical mass that measured 2.5 by 2.5 by 1.0 cm. No areas of necrosis or hemorrhage were identified in the mass. On light microscopy examination, the adrenal mass was composed of epithelioid cells forming nests, cords, and tubules. There were no areas of necrosis, mitotic activity, or significant atypia. On immmunohistochemical examination, the cells in the adrenal mass were positive for calretinin and cytokeratins (AE1/3 and CAM 5.2) and negative for CD31, CD34, and Factor VIII. These morphological and immunohistochemical features were consistent with an adenomatoid tumor (Figures 1–3).

Figure 1

The tissue at far right in this image is normal adrenal cortical tissue. The native adrenal tissue is replaced or extensively infiltrated by tumor cells forming small solid nests as well as anastomosing channels and tubules of variable size and shape.

Figure 3

Immunostain for calretinin highlights the tumor cells, in keeping with their mesothelial derivation.

Lesional cells range from plump epithelioid cells to flattened cells resembling endothelial cells, and many exhibit prominent vacuolization, to an extent that may mimic a signet-ring appearance with apparent intracytoplasmic lumina. They do not exhibit nuclear pleomorphism, necrosis or mitotic activity.

Literature review

As illustrated in Table 1 and Table 2, there have been 29 reported cases of adenomatoid tumors of the adrenal gland in the recent English-language medical literature.[1-19] Almost all of these cases were in male patients (97%) with a mean age of 40Literature Review10 years (range=22–64). The laterality of these tumors is approximately 14 (48%) tumors on the right side and 14 (48%) tumors on the left side (laterality was unknown in one patient) with an average size of 4.6±4.0 cm (range=0.5–16.7 cm). Many of these tumors were either discovered as part of an autopsy or incidentally found as part of a diagnostic work-up for various symptoms including: painless hematuria, hypertension, abdominal pain, and Cushing's syndrome. Various imaging modalities were used including computed tomography (n=18), magnetic resonance imaging (n=6), ultrasound (n=3), and positron emission tomography (n=1). Interestingly, eight (31%) patients had adenomatoid tumors that extended into the periadrenal adipose tissue or the adrenal gland capsule. However, no recurrences have been reported with a median follow-up time of 33 months (range=3 to 177 months).

Table 1

clinical data from review of the medical literature

#	Author	Gender	Age	Side of mass	Size of mass (cm)	Clinical data	CT Sscan	MRI	U/S	Hormonal function	Resection	Follow-up
1	Evans et al.	MALE	36	LEFT	11	Painless hematuria	Y	N	N	All WNL	OPEN	8 months
2	Simpson et al.	MALE	44	LEFT	Not stated	HTN	Y	N	N	Elevated urinaryhomovanillic acid level	OPEN	177 months
3	Travis et al.	MALE	24	LEFT	1.1	Cushing syndrome	Not stated	Not stated	Not stated	Not stated	OPEN	Patient expired 6months later secondaryto massive pulmonarycarcinoid metastases
4	Raaf et al.	MALE	49	RIGHT	1.3	Incidental	Autopsy	Autopsy	Autopsy	Autopsy	Autopsy	Found at autopsy
5	Raaf et al.	MALE	57	LEFT	3.8	Incidental	Autopsy	Autopsy	Autopsy	Autopsy	Autopsy	Found at autopsy
6	Raaf et al.	FEMALE	50	RIGHT	0.5	Incidental	Autopsy	Autopsy	Autopsy	Autopsy	Autopsy	Found at autopsy
7	Raaf et al.	MALE	40	LEFT	6	Incidental	Y	N	N	Not stated	Not stated	Not stated
8	Angeles-Angeles et al.	MALE	34	RIGHT	3	AIDS	Autopsy	Autopsy	Autopsy	Autopsy	Autopsy	Found at autopsy
9	Gasque et al.	MALE	28	RIGHT	9	Abdominal pain	N	Y	Y	All WNL	Not stated	16 months
10	Glatz et al.	MALE	54	LEFT	6.5	Sudden epigastic pain	Y	N	N	Not stated	Not stated	Not stated
11	Chung-Park et al.	MALE	51	RIGHT	3	HTN	Y	N	N	Low plasma renninactivity and high aldosteroneto plasma renin ratio	LAP	Not stated
12	Isotalo et al.	MALE	37	LEFT	3.1	Incidental	Not stated	Not stated	Not stated	Not stated	Not stated	40 months
13	Isotalo et al.	MALE	31	RIGHT	3.2	Incidental	Not stated	Not stated	Not stated	Not stated	Not stated	Not stated
14	Isotalo et al.	MALE	31	Not stated	3.5	Syncope	Not stated	Not stated	Not stated	Not stated	Not stated	50 months
15	Isotalo et al.	MALE	64	LEFT	1.2	Incidental	Autopsy	Autopsy	Autopsy	Autopsy	Autopsy	Found at autopsy
16	Kim and Ro	MALE	33	LEFT	1.7	HTN	Y	N	N	Not stated	Not stated	Not stated
17	Denicol et al.	MALE	42	LEFT	14.3	HTN	Y	N	Y	All WNL	OPEN	3 years
18	Garg et al.	MALE	46	RIGHT	11	Right flank pain	Y	N	Y	Not done	OPEN	Not stated
19	Garg et al.	MALE	33	LEFT	1.7	HTN	Y	N	N	Not done	OPEN	Not stated
20	Garg et al.	MALE	33	RIGHT	4.2	Incidental	Y	Y	N	All WNL	OPEN	1 year
21	Varkarakis et al.	MALE	54	RIGHT	3.6	Incidental	Y	Y	N	Elevated urinary homovanillic acid level	LAP	1 year
22	Hamamatsu et al.	MALE	30	LEFT	3	Incidental	Autopsy	Autopsy	Autopsy	Autopsy	Autopsy	Found at autopsy
23	Timonera et al.	MALE	47	RIGHT	5.6	Incidental	Y	Y	N	All WNL	LAP	Not stated
24		MALE	52	RIGHT	2	HTN	Y	Y	N	All WNL	LAP
25	Fan et al.	MALE	42	LEFT	2.5	HTN	Y	N	N	All WNL	LAP	Not stated
26	Hoffman et al.	MALE	26	RIGHT	1.5	Incidental	Y	N	N	Not done	OPEN	Not stated
27	Bisceglia et al.	MALE	39	RIGHT	5.5	Incidental	Y	N	N	All WNL	OPEN	Not stated
28	Liu et al.	MALE	44	LEFT	16.7	Incidental	Y	N	N	All WNL	OPEN	3 months
29	Phitayakorn et al.	MALE	22	RIGHT	2.5	Incidental	Y	Y	N	Elevated serum cortisol	LAP	7 months

Table 2

Pathological data from review of the medical literature.

# Author	Tumor characteristics	Tumor extension	Histochemistry	Electron microscopy
1 Evans et al.	Tan, smooth with cystic spaces	No extension	Not stated	Numerous slender microvilli,desmoslome-like intracellular junctions,intracytoplasmic tonofilaments
2 Simpsonet al.	Fleshy, gray, solid, cystic	Extension into peri-adrenaladipose tissue	Positive for antihuman cytokeratin,but negative for carcinoembryonic antigen;No glycogen or mucin content	Not done
3 Travis et al.	Pale, white, and solid	Extension into cortex and periadrenaladipose tissue	Strongly positive for keratin (AE1/AE3)and vimentin; Weakly positive for epithelialmembrane antigen	Tortuous microvilli with a moderateamount of tonofilaments
4 Raaf et al.	White and solid	No extension	Reacted with MAK-6 and AE1/AE3;Positive staining for vimentin	Long, thin, bushy microvilli with well-developed desmosomes, basal laminae,and cytoplasmic tonofilaments
5 Raaf et al.	White, solid, firm, and smooth	No extension	Reacted with MAK-6 and AE1/AE3;Positive staining for vimentin	Not done
6 Raaf et al.	White, firm and smooth	No extension	Not stated	Not done
7 Raaf et al.	White, predominantly cystic	No extension	Reacted with MAK-6 and AE1/AE3;Positive staining for vimentinlaminae, and cytoplasmic tonofilaments	Long, thin, bushy microvilliwith well-developed desmosomes, basal
8 Angeles-Angeles et al.	Ill-defined, white-yellowish, and firm nodule	No extension	Stained positive for low molecular weightcytokeratin CKAE-3 and weakly for vimentin	Not done
9 Gasque et al.	Grayish with pseudocyst	No extension	Stains positive for cytokeratin (CAM 5.2)	Not done
10 Glatz et al.	Pale-yellow, spongy, cystic	No extension	Strongly positive for keratin (Cam 5.2, Lu-5)and calretinin; Weakly positivefor thrombomodulin.Negative staining for CEA, MOC-31, BerEP4,and CD34.	Long and slender microvilliLong and slender microvilliand abundant desmosomes alongluminal surface with bundlesof tonofibrils in the cytoplasm
11 Chung-Park et al.	Pale-yellow, solid, and firm	Extension into adrenal cortx	Positive for cytokeratin and calretinin,but negative for synaptophysin,chromogranin,factor VIII, CD34, and S-100.	Long, busy microvilli withintracytoplasmic tonofilaments,and intercellular desmosomes
12 Isotalo et al.	Solitary and poorlycircumscribed	Extension into peri-adrenaladipose tissue	Strongly positive for calretinin, cytokeratins(AE1/AE3, CAM 5.2, CK7) and vimentin.Weakly positive for CK5/CK6.Negative for CD15, CD31, CD34, CK20,MOC31, and p-CEA.	Not done
13 Isotalo et al.		Extension into adrenal gland capsule		Not done
14 Isotalo et al.		Extension into adrenal gland capsule		Not done
15 Isotalo et al.		Extension into peri-adrenal adipose tissue		Not done
16 Kim and Ro	Smooth, grayish, white and firmwith cystic spaces	No extension	Stained positive for cytokeratinand calretinin	Desmosomes. Cytomplasmic fibrillarnetworks, and numerous long, bushy,microvilli on luminal surfaces
17 Denicol et al.	Multicystic, yellow, opaque	No extension	Stains positive for AE1, AE3, and vimentin	Not done
18 Garg et al.	Fibrous wall with an intramuralwell-demarcated tumorcontaining adipose tissue andlymphoid	No extension	Stains positive for calretinin and focal weakstaining for cytokeratin 5/6	Numerouslong, bushy, and slender microvilli
19 Garg et al.	Aggregates, areas ofmucin production, cells witha signet ringlike appearance	No extension	Stains positive for calretininand strong staining for cytokeratin 5/6	Numerouslong, bushy, and slender microvilli
20 Garg et al.		No extension	Sains positive for calretinin	Not done
21 Varkarakis et al.	Tan nodular with sitesof heterotopic ossification	No extension	Stains positive for calretinin	Not done
22 Hamamatsu et al.	White, solid, well-circumscribed,and smooth	No extension	Stained positive for calretinin, D2–40,vimentin, and cytokeratins(AE1/AE3, OV-TL 12/30, CAM 5.2,and MNF116	Not done
23 Timonera et al.	Well-circumscribed, solid,	No extensionwith variegated yellowand tan cut surface	Strongly positive for D2–40 and calretinin	Not doneand weak reactivity for cytokeratin 5/6
24 Timonera et al.	Well circumscribed,heterogeneous cystic and solidmass with hemorrhagic areas
25 Fan et al.	Ill-defined edge, smooth,greyish-white, firm, withno hemorrhage or necrosis	Focal infiltration of adrenalcortex and medulla	Positive for cytokeratin 7,calretinin, vimentin,antimesothelial cell ab,and epithelial membrane antigen	Not done
26 Hoffman et al.	Grey-whitish pattern of small cysticnodules with trabeculae	No extension	Positive for cytokeratin and calretinin,but negative for CD31, CD34, and CD56	Not done
27 Bisceglia et al.	Cystic, gray to pale yellowish with slightmural thickening and short endoluminalpapillations	No extension	Positive to cytokeratins and calretinin,but negative to endothelial markers	Numerous small microvilli(coelomic or mesothelial type)
28 Liu et al.	Ill-circumscribed multilocular cystictumor with tan wall with no hemorrhageor necrosis, cyst fluid was clear-yellow	Enveloped around the ipsilateralrenal artery and vein	Positive for calretinin and epithelialmembrane antigen,but negative for endothelial markers	Not done
29 Phitayakorn et al.	Well circumscribed, tan-graycortical mass	No extension	Stained positive for calretinin and cytokeratins(AE1/AE3 and CAM 5.2), and stainednegative for CD31, CD34, and factor VIII.	Not done

In terms of tumor color, these tumors have been described as being white, tan, fleshy, pale-yellow, opaque, and grayish. In terms of tumor consistency, however, these tumors have been described as being firm, smooth, cystic, solid, and well-circumscribed. Other histopathological characteristics have been noted in adenomatoid tumors including: heterotopic ossification, lymphoid aggregates, sites of mucin production, and cells with a signet ring-like appearance.

Adenomatoid tumors have been found to stain positive with a wide variety of agents including: vimentin, calretinin, cytokeratins (CAM 5.2, CKAE1, and CKAE3), MAK-6, D2–40, OV-TL 12/30, and MNF 116. A few studies have examined adenomatoid tumors using electron microscopy and found various features including: numerous long, thin, bushy microvilli with well developed desmosomes, basal laminae, and cytoplasmic fibrillar networks.

Discussion

Patients with human immunodeficiency virus (HIV) frequently present with a number of associated neoplasms, often as a result of their immunosuppression. It is very unusual for HIV-positive patients to present with adrenal gland neoplasms other than Kaposi's sarcoma or lymphoma. HIV-positive patients may also present with infectious etiologies that may present as an adrenal mass, including cytomegalovirus necrotizing adrenalitis, mycobacterium, cryptococcus, or other fungal infections.[20,21] This case represents only the second reported case of an adenomatoid tumor in a patient with HIV. However, it is unknown how many other patients with reported adrenal adenomatoid tumors were tested for HIV. It is possible that the incidence of adrenal adenomatoid tumors in patients with HIV may increase as a consequence of anti-retroviral therapies or chronic immunosuppression.

Although the first adenomatoid tumor was described in 1945, adrenal adenomatoid tumors were not well described until the late 1980's.[22] This result may be due to the increasing use of diagnostic computed tomographic imaging in detecting adrenal incidentalomas. This case also highlights an important caveat in that imaging techniques such as computed tomography cannot reliably distinguish adrenal adenomatoid tumors from other adrenocortical tumors.[5] Magnetic resonance imaging of the adrenal adenomatoid tumor in this patient was more consistent with a functional adrenal tumor. Another study that used MRI in a patient with an adrenal adenomatoid noted that the tumor was mainly solid with cystic peripheral portions, and that the solid areas were homogenously isointense to the spleen on all images.[5] In this particular case, the use of a positron-emission tomographic (PET) scan was also not helpful in pre-operatively diagnosing an adrenal adenomatoid tumor. In fact, the level of 18F-FDG uptake of 3.4 SUV was in the range of malignant adrenal lesions.[23]

Finally, this case emphasizes that although adrenal adenomatoid tumors have been described in the past as extending into the perirenal adipose tissue, the clinical behavior is definitely benign.[10] Adrenal adenomatoid tumors may be misclassified as lymphangiomas or adenocarcinomas because of infiltrative borders into the adrenal capsule or periadrenal adipose tissue.[24] These tumors can be reliably distinguished from adrenal adenocarcinoma as adenomatoid tumors stain positive for keratin and do not produce mucin. Based on Table 1, local resection limited to the adrenal gland itself without any specific post-operative surveillance protocol appears to be sufficient treatment of adrenal adenomatoid tumors. Laparoscopic adrenalectomy which is the current gold-standard for the surgical resection of adrenal tumors can be safely employed in the case of adrenal adenomatoid tumors.