Malignant Perivascular Epithelioid Cell Tumor (PEComa) of the Adrenal Gland: Report of a Rare Case Posing Diagnostic Challenge with the Role of Immunohistochemistry in the Diagnosis
Leela Pant . Dipti Kalita . Ratna Chopra . Abhijit Das . Gaurav Jain
C Springer Science+Business Media New York 2015
Abstract Histological diagnosis of adrenal tumors is often challenging as diverse groups of tumors, both primaries and metastatic, may be seen in the adrenal gland with overlapping morphological features. Immunohistochemistry (IHC) plays the most important role in their diagnosis. Perivascular epithe- lioid cell tumor (PEComa), a rarely reported tumor in the adrenal gland, shares many features with another rare tumor sarcomatoid adrenocortical carcinoma (ACC). Extensive im- munohistochemical study is required to distinguish this tumor from adrenocortical carcinoma and from other morphological- ly similar tumors. The unique combination of immunoreactiv- ity for melanocytic markers, such as HMB-45 and Melan A, and myogenic markers, such as smooth muscle actin, is the hallmark of PEComas biological behavior, and prognosis of malignant PEComas is yet to be fully understood. Few cases of malignant PEComa have been reported in the adrenal gland. We report a case of malignant PEComa of the adrenal gland posing diagnostic challenge and compare its morpho- logical and immunohistochemical features with those of sarcomatoid ACC.
Keywords PEComa . Sarcomatoid adrenocortical . Carcinoma · Immunohistochemistry
L. Pant · D. Kalita . A. Das · G. Jain Department of Pathology, North DMC Medical College and Hindu Rao Hospital, Delhi 110007, India
e-mail: diptikalita@yahoo.co.in
R. Chopra Department of Surgery, North DMC Medical College and Hindu Rao Hospital, Delhi, India
Introduction
Histological diagnosis of adrenal tumors is often challenging as diverse groups of tumors, both primaries and metastatic, may be seen in adrenal gland with overlapping morphological features. Immunohistochemistry (IHC) plays the most impor- tant role in their diagnosis. Among primary tumors, adrenal cortical carcinoma (ACC) with sarcomatoid features and ma- lignant perivascular epithelioid cell tumor (PEComa) are rare, with few cases reported in literature. These tumors share histomorphological and immunohistological features with many other tumors. An extensive panel of IHC markers is required to distinguish them from each other. Here, we report a case of an adrenal gland tumor showing both epithelioid and spindle cell patterns posing diagnostic challenge, and our aim is to discuss the differential diagnosis based on morphology and immunohistochemical features.
Case Report
A 44-year-old lady was presented to surgical OPD with a history of anorexia, dyspepsia, and vomiting for a week. She was a known hypertensive under regular medications. There was no history of palpitation, sweating, weight loss, and other complaints. On examination, a firm to hard non-tender lump was felt in the subhepatic region on the right side, measuring approximately 10 cm×6 cm size. Computed tomography (CT) scan revealed a 14.5×14.5×14.1 cm well-defined solid tissue mass in the right adrenal gland without obvious infiltra- tion into adjacent liver tissue.
Routine hematological and biochemical investigations did not show any abnormality. Biochemical tests for adrenal tu- mors were carried out which revealed elevated plasma
| Test | Result | Range |
|---|---|---|
| Epinephrine (pg/ml) | 84.53 | <67 |
| Nor epinephrine (pg/ml) | 411.05 | 95-446 |
| Dopamine (pg/ml) | 79.13 | <87 |
| 24-h urine VMA (ug/g creatinine) | 5.41 | 1.5-4.2 |
| 24-h urine metanephrine (µg/g creatinine | 122.65 | 27-155 |
| 24-h urine normetanephrine (ug/g creatinine) | 336.24 | 46-256 |
epinephrine, 24-h urine normetanephrine, and 24-h urine vi- nyl mandelic acid (VMA) as shown in Table 1.
The patient underwent surgical resection of the right adre- nal gland tumor, and the whole specimen was received for histopathological examination. On gross examination, a par- tially encapsulated soft tissue mass measuring 18×18×11 cm and weighing 1.6 kg was found. External surface showed adherent fat with two solid gray, white irregular nodules and areas of capsular breach. Cut surface of the main tumor mass showed nodular, variegated appearance showing areas of ex- tensive necrosis, hemorrhage, yellowish discoloration, and myxoid change (Fig. 1a, b). After extensive grossing, residual normal adrenal tissue and adrenal tumor interface could be identified (Fig. 1c, d). Invasion into renal capsule was seen intraoperatively, but no renal tissue was identified on gross examination.
Hematoxylin and eosin (H&E)-stained microsections from the main tumor mass revealed a tumor comprising of polyhe- dral and spindle-shaped cells arranged in a diffuse solid pat- tern. Most of the tumor cells showed eosinophilic granular cytoplasm, and some showed vacuolations as well. Nuclear
pleomorphism and multinucleation were also seen. In some areas, cytoplasmic hyaline globules and focal calcification were noted. Extensive necrosis and hemorrhage were seen in most of the tumor area. The tumor cells were seen infiltrating into the capsule and into the surround- ing adipose tissue. Mitotic figures were noted focally up to 5 per 50 high-power fields. Microsections from the separate nodules present on the external surface showed a marked fascicular pattern, more of a spindling and ganglion cell type. Tumor cells were largely negative for glycogen on Periodic acid Schiff (PAS) stain.
On the basis of histomorphological examination and bio- chemical findings, initially, two differential diagnoses were pro- posed: (1) sarcomatoid ACC and (2) mixed corticomedullary tumor.
IHC examination showed strong diffuse positivity for vimentin and focal but strong positivity for HMB-45 and Melan A. Strong positivity for smooth muscle actin (SMA) was noted in cells showing spindle morphology, diffusely in areas showing fascicular pattern. Tumor cells were negative for pan-cytokeratin (CK), epithelial membrane antigen (EMA), synaptophysin (Syn), chromogranin A (CG), calretinin, inhibin, and desmin.
In view of the IHC findings, especially nonreactivity of tumor cells for CG, Syn, and S 100, presence of medullary component was ruled out. We could not confirm the morphological diagnosis of sarcomatoid ACC because the tumor cells were negative for calretinin and inhibin, although they were positive for Melan A. The other close differential diagnosis was PEComa as the tumor cells were positive for HMB-45, Melan A, and SMA. Thereafter, we reviewed H&E slides and could appreciate the radial
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arrangement of tumor cells around blood vessels, which is a characteristic of PEComa.
After considering the overall gross (Fig. 1) and histomorphological (Fig. 2) and immunohistochemical (Fig. 3) findings, final diagnosis was given as malignant PEComa of the adrenal gland. We compared the histomorphological and IHC features of sarcomatoid ACC and PEComa (according to published literature) with the pres- ent case in Tables 2 and 3.
The patient was kept under close follow-up. After 5 months of surgery, the patient was found to be free of disease on positron emission tomography (PET) scan.
Discussion
Malignant adrenal tumor with both epithelioid and spindled appearance has a large number of differential diagnoses on morphology. Immunohistochemical analysis using an exten- sive panel of markers may be required to arrive at the diagno- sis. Sarcomatoid ACC, pheochromocytoma, epithelioid sarco- ma, renal cell carcinoma with sarcomatoid pattern, and meta- static tumors are some tumors which come under differential diagnosis on histomorphology alone.
In our case, radiological evaluation was done and it was found that the tumor was limited to the right adrenal gland, and there was no evidence of any tumor in any other location in the body. So, it was considered as a primary adrenal tumor.
Biochemical evidences pointed towards the presence of a medullary component by showing a mild increase in plasma epinephrine, 24-h urinary VMA, and metanephrine levels. However, several factors like sampling conditions, patient preparation, and intake of interfering medicines largely influ- ence their levels. False negativity and false positivity both have been issues in the diagnosis of pheochromocytoma [1]. Differentiation between adrenocortical and adrenomedullary tumors is not always possible on morphology alone. Morpho- logical features like cytoplasmic hyaline globules, ganglion cell-like appearance, and fascicular pattern found in our case are more frequently seen in medullary tumors. Pure pheochro- mocytoma was not our differential diagnosis because nesting pattern was not seen. Mixed corticomedullary tumors are rare. These refer to the association within the same mass (or possi- bly within the same cell) of features indicative of adrenocor- tical and adrenomedullary differentiation [2-4]. Lack of im- munoreactivity for neural markers such as S 100, CG, and Syn ruled out this diagnosis in our case.
The tumor was diagnosed as malignant on the basis of its size, presence of invasion, extensive necrosis, and nuclear
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pleomorphism. Histological scoring systems, evaluating mul- tiple parameters, especially the criteria of Weiss, have been shown to be reliable in differentiating adenoma and carcinoma [5]. There are nine histological criteria according to Weiss system of grading, which are as follows: (1) high nuclear grade, (2) mitotic rate six or more per 50 high-power fields, (3) atypical mitosis, (4) clear cells less than 25 %, (5) a diffuse architecture pattern in more than one third of the tumor, (6) confluent necrosis, (7) venous invasion, (8) sinusoidal inva- sion, and (9) capsular invasion. A tumor is labeled malignant when it meets three or more of these histological criteria. Spindling of tumor cells is also an indicator of malignancy. Microscopically mitotic activity (especially if accompanied by atypical forms) and venous invasion correlate best with recurrence or metastasis. Our case met other criteria, but the mitotic activity was not very high and proliferative index on Ki 67 immunostaining was also low (<5 %).
| Features | Sarcomatoid ACC | PEComa | Present case |
|---|---|---|---|
| Epitheloid and spindle cell | Present | Present | Present |
| Fascicular pattern | Present | Present | Present |
| Perivascular arrangement | Not mentioned in literature | Present at least focally | Present |
| Cytoplasmic hyaline globule | May be present | Not mentioned in literature | Present |
| Clear to granular cytoplasm | Present | Present | Present |
| Round to oval, centrally located nucleus | Present | Present | Present |
Immunohistochemistry plays the most important role in the diagnosis of adrenal tumors. But as none of available markers is specific for adrenal tumors of cortical origin, a large panel of markers is required to arrive at the diagnosis [6, 7]. Calretinin, Melan A, and inhibin are reported to be highly sensitive and specific in differentiating adrenal cortical tumors from medul- lary tumors, but none is absolutely specific for adrenal cortical tumors. Calretinin may be positive in ganglioneuromatous areas of a composite pheochromocytoma. Adrenocortical cells normally express Melan A but not HMB-45, a pattern which is followed by ACC. SMA positivity may be seen in the sarcomatoid area of the ACC. We kept ACC in the differential diagnosis as tumor cells were negative for more sensitive
| IHC markers | Sarcomatoid ACC | PEComa | Present case |
|---|---|---|---|
| Pan-cytokeratin | May be positive | Negative | Negative |
| Vimentin | Positive | Positive | Positive |
| Synaptophysin | May be positive | Negative | Negative |
| HMB-45 | Negative | Positive | Focally positive |
| Calretinin | Positive | Negative | Negative |
| Inhibin | Positive | Negative | Negative |
| Melan A | positive | Positive | Positive |
| S 100 | May be positive | Negative | Negative |
| Chromogranin (CG) | Negative | Negative | Negative |
| Smooth muscle actin (SMA) | Positive in spindle cells | Positive | Positive |
| Desmin | Positive in spindle cells | May be positive | Negative |
markers calretinin and inhibin. Melanoma could be consid- ered as another differential diagnosis due to positivity for melanocytic markers HMB-45 and Melan A, but in our case, S 100 negativity and SMA positivity ruled out this diagnosis.
Adrenocortical carcinoma is a rare but highly aggressive malignancy with an estimated annual incidence of 1.5 to 2 per million population [8]. Adrenocortical carcinoma containing a component of sarcoma or sarcoma-like (spindle cell) differen- tiation is extremely rare, with only 15 cases described [9-12]. The diagnosis of adrenocortical carcinosarcoma on histologic examination is often challenging as well. It requires thorough sampling of the specimen to confirm the biphasic pattern and identify a well-differentiated carcinomatous component allowing to prove the adrenal origin as well as to rule out retroperitoneal sarcoma or poorly differentiated carcinoma. This is an aggressive variant of adrenocortical carcinoma char- acterized by short survival.
We finally diagnosed the tumor as PEComa on the basis of characteristic histomorphological features and positivity for HMB-45, Melan A, and SMA. Weinreb et al. reported four cases of malignant PEComa where all cases showed actin positivity and multiple melanocytic markers which included Melan A, HMB-45, and micropthalmia transcription factor (MiTF) [13]. They suggested that tumor with diffuse melanocytic differentiation should be regarded as being relat- ed to PEComa family because sarcomas may also show focal or weak positivity for melanocytic marker [13]. In our case, we favored the diagnosis of PEComa over sarcoma because it showed strong positivity for melanocytic markers (HMB-45, Melan A), although it could not be appreciated diffusely throughout because of extensive hemorrhage and necrosis.
The World Health Organization defines perivascular epithe- lioid cell tumors (PEComa) as mesenchymal tumors composed of histologically and immunohistologically distinctive perivascular epithelioid cells (PECs) [14]. The PEComa family of tumors includes angiomyolipoma (AML); clear cell sugar tumor of the lung (CCST); lymphangioleiomyomatosis (LAM); clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres (CCMMT); and unusual clear cell tumors of the pancreas, rectum, abdominal serosa, uterus, vulva, thigh, and heart. PEComas have been reported in many organs as mentioned above; however, only two cases have been report- ed in the adrenal gland to the best of our knowledge [15, 16].
Histologically, PEComas are composed of epithelioid and spindle cells, with one or both cell types arranged in a fascic- ular or nested pattern. The cells are described to have clear to the granular eosinophilic cytoplasm and small, central, round to oval nuclei with small nucleoli. A prominent intrinsic vas- culature can be present, with tumor cells often arranged in a radial fashion around blood vessels. Multinucleated tumor giant cells are frequent finding. PEComas vary significantly in nuclear grade, mitotic activity (including atypical mitotic figures), tumor cell necrosis, and angiolymphatic invasion.
The unique combination of immunoreactivity for melanocytic markers, such as HMB-45 and Melan A, and myogenic markers, such as smooth muscle actin, is the hallmark of PEComas. Most PEComas are also positive for vimentin. It is thought that PEC can modulate its morphology and immunophenotype. It can show muscular features with a spin- dle shape and a stronger positivity for actin than for HMB-45, or it can have an epithelioid feature with a strong positivity for HMB-45 and a mild, if any, reaction for actin [17]. In our case, also such pattern is noted.
Clear criteria for malignancy in PEComas have yet to be elaborated, owing to their rarity. Development of such criteria has also been complicated by the relatively frequent presence of pseudomalignant changes [14]. It appears that PEComas displaying any combination of infiltrative growth, marked hypercellularity, nuclear enlargement and hyperchromasia, high mitotic activity, atypical mitotic figures, and coagulative necrosis should be regarded as malignant. Folpe et al. used a few criteria (tumor size, infiltrative growth pattern, high nu- clear grade, necrosis, and mitotic activity greater than 1 per 50 hpf) to categorized PEComas into three groups: benign, with no worrisome features; uncertain malignant potential (ei- ther nuclear pleomorphism/multinucleated giant cells or size greater than 5 cm alone), and malignant (two or more param- eters including size greater than 5 cm, infiltrative pattern, high nuclear grade and cellularity, mitotic rate greater than one mitosis per 50 high-power fields, necrosis, and vascular inva- sion) [18]. Malignant PEComas are aggressive sarcomas that frequently result in the death of affected patients, but it is also stated that clinically aggressive behavior may not be seen in all histologically malignant neoplasms.
Conclusion
Both the tumors sarcomatoid ACC and malignant PEComa are rare tumors with an aggressive clinical course and almost similar criteria for malignancy. Their histological diagnosis needs extensive sampling, careful histological examination, and extensive immunohistochemical studies. PEComa in the adrenal gland is rarely reported may be because of its mimickers from which it must be distinguished by a large panel of IHC markers, a task possible only in research labo- ratories. Biological behavior and prognosis of malignant PEComas are yet to be fully understood. A further study of more cases with longer follow-up periods is needed for better understanding about these tumors.
Acknowledgments The authors thank Dept. of Pathology, All India Institute of Medical Science, New Delhi, India, and Core Diagnostics for providing consultation.
Conflict of Interests The authors declare no conflict of interest.
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