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Year : 2021  |  Volume : 64  |  Issue : 4  |  Page : 767-770
Is immunohistochemistry always the panacea to morphologic mimics? Two, distinct soft tissue tumors exhibiting alveolar pattern and TFE3 immunoreactivity

Department of Surgical Pathology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India

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Date of Submission29-May-2020
Date of Decision26-Jun-2020
Date of Acceptance18-Feb-2021
Date of Web Publication20-Oct-2021


Alveolar soft part sarcoma (ASPS) and certain perivascular epithelioid cell neoplasms (PEComas) exhibit overlapping histopathological features, including immunohistochemical expression of TFE3, as well as TFE3 gene rearrangement. PEComas with an epithelioid morphology are known to exhibit variable immunoexpression of muscle markers. At the same time, aberrant immunoreactivity of HMB45 immunostain, which is invariably, used to substantiate a diagnosis of a PEComa, has been reported in various other tumors. Herein, we discuss two rare cases of soft tissue tumors with overlapping morphological and immunohistochemical features. Case1: A 34-year-old male underwent a biopsy for a recurrent, right-sided nasal polyp. Biopsy showed polygonal tumor cells, containing prominent nucleoli, arranged in a “nesting-type”/alveolar growth pattern. Immunohistochemically, tumor cells displayed TFE3 positivity and an aberrant positivity for HMB45. Special stain (PAS-diastase) highlighted intracytoplasmic granules and crystals. Diagnosis of ASPS was offered. Furthermore, the tumor cells displayed TFE3 gene rearrangement. Case 2: A 29-year-old female underwent an aural polypectomy. Microscopic examination revealed a tumor with a “nesting-type”/alveolar arrangement of tumor cells with vacuolated cytoplasm, arranged around thin-walled blood vessels. Immunohistochemically, tumor cells were diffusely positive for HMB45 and TFE3 and focally for SMA. A diagnosis of a PEComa was offered. This report constitutes the first documentation of aberrant HMB45 immunoreactivity in case of ASPS, and one of the first reported cases of a PEComa in the ear. It emphasizes the value of integrating clinicopathological features with immunohistochemical and molecular results in differentiating two rare, but distinct soft tissue tumors with overlapping features. An exact diagnosis of both these tumor entities has therapeutic implications.

Keywords: Alveolar soft part sarcoma, HMB45 aberrant cross-reactivity, PEComa, TFE3, TFE3 gene rearrangement

How to cite this article:
Shah A, Rekhi B, Patil A. Is immunohistochemistry always the panacea to morphologic mimics? Two, distinct soft tissue tumors exhibiting alveolar pattern and TFE3 immunoreactivity. Indian J Pathol Microbiol 2021;64:767-70

How to cite this URL:
Shah A, Rekhi B, Patil A. Is immunohistochemistry always the panacea to morphologic mimics? Two, distinct soft tissue tumors exhibiting alveolar pattern and TFE3 immunoreactivity. Indian J Pathol Microbiol [serial online] 2021 [cited 2023 Feb 2];64:767-70. Available from:

   Introduction Top

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma, mostly identified in young adolescents, characterized by typical histopathologic features, underlying ASPCR1-TFE3 fusion gene; is associated with an indolent biological behavior, but an overall poor prognosis.[1] Orbit and tongue are relatively common sites of this tumor.[2] Perivascular epithelioid cell neoplasms (PEComas) comprise perivascular myoid cells; are known to occur over a wide age range and are ubiquitous, but rarely reported in the head and neck region.[3]

Histopathologically, both ASPS and PEComa display polygonal-shaped tumor cells, containing eosinophilic, granular to vacuolated cytoplasm, arranged in an organoid/nesting or alveolar pattern. Invariably, PEComas display immunohistochemical co-expression of muscle and melanocytic markers, while ASPSs generally lack any lineage specific markers.[1],[2],[3] Most cases of ASPS and some PEComas display immunoexpression of a transcription factor TFE3, and TFE3 gene rearrangement.[1],[4]

We present two unusual cases of ASPS and PEComa at rare sites with overlapping morphological and immunohistochemical features.

   Case Histories Top

Case 1

A 34-year-old male, with a history of a recurrent right-sided nasal polyp for the last 7 years, was referred to us with a diagnosis of clear cell adenocarcinoma. Earlier, he underwent tumor resection on three different occasions.

His recent computed tomogram (CT) scan showed right-sided widening of the osteomeatal complex with mucosal thickening, extending into the nasal cavity and pushing the septum towards the opposite side. The anterior osteomeatal complex, including maxillary sinus ostia, infundibula, hiatus semilunaris, and the middle meatus of the right side were occluded.

Histopathologic examination of the excised specimen showed a tumor below the respiratory mucosa, comprising polygonal-shaped cells, arranged in “nests”/alveolar pattern and containing round nuclei, prominent nucleoli, granular eosinophilic to vacuolated cytoplasm [Figure 1]a, [Figure 1]b, [Figure 1]c. Immunohistochemically, tumor cells were diffusely positive for TFE3 (monoclonal, MRQ37, ready to use, Cell Marque, California, U.S.A) [Figure 1]d and showed aberrant granular, cytoplasmic immunoreactivity for HMB45 (monoclonal, HMB45, Dako, Glostrup, Denmark) [Figure 1]e, while these were negative for the various other markers, tested on UltraView Universal DAB Detection Kit, Ventana Medical systems, USA [Table 1].
Figure 1: Case 1. (a) Cellular tumor in a solid nesting pattern below respiratory mucosa. H and E, ×200. (b). Polygonal cells in a nesting-type pattern with intervening thin-walled blood vessels. H and E, ×200. (c). Tumor cells with moderate to abundant, granular to vacuolated cytoplasm (at places) and central nuclei with prominent nucleoli. H and E, ×400. (d and e). Immunohistochemistry. (d). Tumor cells displaying TFE3 positivity. Diaminobenzidine, ×200. (e). Tumor cells displaying aberrant granular cytoplasmic HMB45 reactivity. DAB, ×400

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Table 1: Immunohistochemical results in both the cases

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Special histochemical stain, Periodic acid Schiff (PAS) displayed characteristic intracytoplasmic globules and granules along with some crystals that were diastase resistant [Figure 2]a. A diagnosis of ASPS was finally offered. By FISH, tumor cells revealed TFE3 rearrangement in the form of split “red-green” signals [Figure 2]b.
Figure 2: Case 1. (a). Tumor cells displaying intracytoplasmic granules, bodies, and crystals. PAS stain with diastase, ×1000. (b). Tumor cells displaying TFE3 gene rearrangement in the form of red-green “split” signals (double white arrows), DAPI, ×1000

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Case 2

A 29-year-old female underwent an aural polypectomy, elsewhere.

CT scan revealed a minimally enhancing soft tissue lesion in the medial side of external auditory canal and towards the inferior side of her middle ear, along with erosion of the petrous bone and medial extension into the sigmoid sinus, posterior to the Eustachian tube.

Magnetic resonance imaging revealed a 10 mm x 9 mm x 11.5 mm sized well-defined, poorly enhancing soft tissue density in the inferior aspect of right-sided middle ear and hypotympanum, involving the bones of the internal ear. The radiologic impression was of glomus jugulare. She underwent a transmastoid excision.

Microscopic examination showed a tumor below the keratinized squamous epithelium composed of round to polygonal-shaped cells with, arranged in nests, containing vacuolated cytoplasm with focally discernible nucleoli and interspersed multinucleate giant cells [Figure 3]a and [Figure 3]b. Immunohistochemically, tumor cells were diffusely positive for TFE3 and HMB-45 [Figure 3c and d], while negative for the various other markers, listed in [Table 1]. Smooth muscle actin (SMA) immunostain distinctly highlighted perivascular polygonal cells, along with few interspersed tumor cells [Figure 3e]. Diagnosis of a PEComa was offered.
Figure 3: Case 2. (a). Cellular tumor below keratinized squamous epithelium. H and E, ×100. (b). Polygonal-shaped cells in a nesting/organoid pattern with interspersed multinucleate giant cells. H and E, ×200. Inset: Cells with vacuolated cytoplasm, around thin-walled blood vessels with interspersed multinucleate giant cells. (c-e). Immunohistochemistry. (c). TFE3 immunopositivity, including multinucleate tumor giant cells (arrow). DAB, ×400. (d). Diffuse HMB45 positivity. DAB, ×400. (e). Perivascular and focal SMA positivity. DAB, ×400

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By FISH, tumor cells did not reveal TFE3 gene rearrangement and lacked BRAFV600E mutation, on molecular testing.

   Discussion Top

ASPS and certain PEComas share overlapping histomorphological features and immunohistochemical expression of TFE3, leading to a diagnostic conundrum, as noted in the present cases.[1],[4] Both the tumors presented as polyps, in the nasal and aural locations, respectively, which are rare sites for these tumors. PEComa has not been reported in the external ear.[5],[6],[7]

Diagnosis in both the cases was achieved on histopathological examination. Various tumors which constitute differential diagnoses for both tumors, as similarly considered in the present cases are clear cell sarcoma of soft tissue, malignant melanoma, Xp11.2 translocation positive renal cell carcinoma (RCC), paraganglioma, granular cell tumor, alveolar rhabdomyosarcoma (ARMS), and an adrenocortical carcinoma.[1] Various immunohistochemical markers can be tested to differentiate these tumors, as used in the present cases. A renal cell carcinoma shows immunoexpression of EMA, AMACR, and PAX8, while an adrenocortical carcinoma shows variable expression of epithelial markers, along with vimentin and calretinin. Paragangliomas display immunopositivity for synaptophysin and chromogranin and S100P, the latter in the sustentacular cells, whereas granular cell tumors are diffusely immunopositive for S100P and CD68. ARMS shows immunoexpression for desmin, myogenin, and MyoD1. A clear cell sarcoma of soft tissue and cutaneous melanoma share overlapping immunohistochemical co-expression of S100P and melanocytic markers (HMB45 and Melan A). PEComas are invariably immunopositive for myo melanocytic markers, as noted in the second case.[8] HMB45 immunopositivity and lack of desmin made diagnosis of a glomus tumor, less likely in the second case, which was considered on radioimaging.

TFE3 is a useful immunohistochemical marker for diagnosing ASPSs. However, it has a limited specificity as it is also expressed in a granular cell tumor, Xp11.2 translocation-positive RCC, neuroendocrine tumors, adrenocortical carcinoma and in 10% PEComas.[1],[4],[9] Recently, Sharain et al.[10] showed a limited specificity and sensitivity of TFE3 in cases of TFE3 rearranged neoplasms.

In both of our study cases, TFE3 and HMB45 were diffusely immunopositive. The questions were whether ASPS can express HMB45 and whether a PEComa can show a reduced or loss of expression of myogenic markers? HMB45 positivity in ASPS can be attributed to cross reactivity, leading to its false positive immunostaining, as previously reported in few tumors.[11],[12] PEComas with an epithelioid morphology can show weak immunoreactivity to absence of smooth muscle markers.[9],[13] Histomorphologically, a significant tumor component, composed of clear/vacuolated cells, noted in the second case, has also been previously reported in epithelioid PEComas.[9]

In such cases, testing for TFE3 gene rearrangement might not lead to a conclusive diagnosis, as PEComas with epithelioid morphology are known to display TFE3 gene alterations, in 17% cases; similar to most cases of ASPS.[1],[4] While the first case revealed TFE3 gene rearrangement, the second case was negative for the same. Earlier, Argani[4] et al. observed TFE3 gene alterations in 50% PEComas, displaying TFE3 immunopositivity, including 2 cases lacking TFE3 gene alteration, but intensely positive for TFE3, when they tested this in an automated stainer. Likewise, both of our study cases were tested for TFE3 immunostaining, using an automated stainer.

The diagnostic dilemma in the present cases was resolved with PAS and PAS-D stains, which showed cytoplasmic granules and crystals, pathognomic of ASPS, in the first case.[1] This was further aided by clinical history of multiple tumor recurrences. The second case showed absence of crystals and granules and based on its morphological features and immunohistochemical results, diagnosis of PEComa was finally offered.

Surgery is the treatment mainstay for ASPS. In view of chemo and radioresistance observed in these tumors, targeted therapies (tyrosine kinase inhibitors) are being explored for treating this tumor, especially in advanced tumor stages.[14] On the other hand, mTOR1 inhibitors are being used for TSC2 gene re-arranged PEComas, whereas TFE3 gene re-arranged PEComas might not benefit from these but may benefit from therapeutic targets against MiT family of transcription factors.[15]

In conclusion, immunohistochemistry is not the only panacea for differentiating soft tissue tumors with overlapping histomorphological features. TFE3 positivity is seen in various tumors. Aberrant HMB45 cross immunoreactivity in the former case of ASPS, constitutes the first such documentation. Careful assessment of histopathological features and judicious application of ancillary techniques, including their correct interpretation is useful in resolving diagnostic conundrums and in identifying rare tumors. In view of newly available treatment options, it is imperative to differentiate ASPS from a PEComa.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


We are very grateful to Professor Andrew Folpe from Mayo Clinic, Rochester, USA for his invaluable opinion in the first case.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Ordonez NG, Ladanyi M. Alveolar soft part sarcoma. In: Fletcher CD, Bridge JA, Hogendoorn PCW, Mertens F, editors. World Health Organization (WHO) Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon: IARC Press; 2013. p. 218-20.  Back to cited text no. 1
Mullins BT, Hackman T. Adult alveolar soft part sarcoma of the head and neck: A report of two cases and literature review. Case Rep Oncol Med 2014;597291.  Back to cited text no. 2
Bandhlish A, Leon Barnes E, Rabban JT, McHugh JB. Perivascular epithelioid cell tumors (PEComas) of the head and neck: Report of three cases and review of the literature. Head Neck Pathol 2011;5:233-40.  Back to cited text no. 3
Argani P, Aulmann S, Illei PB, Netto GJ, Ro J, Cho HY, et al. A distinctive subset of PEComas harbors TFE3 gene fusions. Am J Surg Pathol 2010;34:1395-406.  Back to cited text no. 4
Barbareschi M, Ferrero S, Ottaviani F. Alveolar soft part sarcoma of the nasal cavity. Pathologica 1988;80:363-70.  Back to cited text no. 5
Afrogheh A, Schneider J, Bezuidenhout AF, Hille J. PEComa of the nose: Report of a case with immunohistochemical and ultrustructural studies and a review of the literature. Head Neck Pathol 2014;8:122-6.  Back to cited text no. 6
McGregor SM, Alikhan MB, John RA, Kotler H, Bridge JA, Mujacic I, et al. Melanotic PEComa of the sinonasal mucosa with NONO-TFE3 fusion: An elusive mimic of sinonasal melanoma. Am J Surg Pathol 2017;41:717-22.  Back to cited text no. 7
Dabbs Leona AD, Jason LH. Immunohistochemistry of neoplasms of soft tissue and bone. In: David JD, editors. Diagnostic Immunohistochemistry: Theranostic and Genomic Applications. 5th ed. U.S.A: Elsevier; 2019. p. 82-136.  Back to cited text no. 8
Schoolmeester JK, Dao LN, Sukov WR, Wang L, Park KJ, Murali R, et al. TFE3 translocation-associated perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: Morphology, immunophenotype, differential diagnosis. Am J Surg Pathol 2015;39:394-404.  Back to cited text no. 9
Bonetti F, Pea M, Martignoni G, Mombello A, Colombari R, Zamboni G, et al. False-positive immunostaining of normal epithelia and carcinomas with ascites fluid preparations of antimelanoma monoclonal antibody HMB45. Am J Clin Pathol 1991;95:454-9.  Back to cited text no. 10
Friedman HD, Tatum AH. HMB-45-positive malignant lymphoma. A case report with literature review of aberrant HMB-45 reactivity. Arch Pathol Lab Med 1991;115:826-30.  Back to cited text no. 11
Folpe AL, Kwiatkowski DJ. Perivascular epithelioid cell neoplasms: Pathology and pathogenesis. Hum Pathol 2010;41:1-15.  Back to cited text no. 12
Sharain RF, Gown AM, Greipp PT, Folpe AL. Immunohistochemistry for TFE3 lacks specificity and sensitivity in the diagnosis of TFE3-rearranged neoplasms: A comparative, 2-laboratory study. Hum Pathol 2019;87:65-74.  Back to cited text no. 13
Mitton B, Federman N. Alveolar soft part sarcomas: Molecular pathogenesis and implications for novel targeted therapies. Sarcoma 2012;2012:428789.  Back to cited text no. 14
Lin RJ, Melamed J, Wu J. PEComa with transcription factor E3 overexpression: A diagnostic and therapeutic challenge. Case Rep Oncol 2017;10:531-3.  Back to cited text no. 15

Correspondence Address:
Bharat Rekhi
Pathologist, Room 818, 8th Floor, Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai - 400 094, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_624_20

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