Indian Journal of Pathology and Microbiology

: 2020  |  Volume : 63  |  Issue : 2  |  Page : 177--187

Clear cell lesions in pathology: Histomorphologic approach to diagnosis

Asaranti Kar1, Kaumudee Pattnaik1, Tushar Kar2, Priyadarshini Biswal1, Chandraprava Mishra1, Lilabati Guru3,  
1 Department of Pathology, O&G, S.C.B. Medical College, Cuttack, Odisha, India
2 O&G, S.C.B. Medical College, Cuttack, Odisha, India
3 O and G, Consultant, Cuttack, Odisha, India

Correspondence Address:
Asaranti Kar
QTR.NO-JO-1, S.C.B.Medical College, Cuttack, Odisha


There has been remarkable progress in the field of surgical pathology; however, histomorphology has remained the most important and essential tool of the surgical pathologist in everyday practice till now. It is surprising that the hematoxylin–eosin (H and E) stain, introduced more than a century ago, has still remained the gold standard stain for histological examination and diagnosis of human diseases. Besides different findings or clues observed in histopathology sections like inclusions, granules, grooving, globules, halo, or clearing, which would enable the pathologist to provide a precise and accurate diagnosis; observation of clear cells is one of the important findings and clue for reporting. It may also sometimes lead to difficulties and delays in establishing the diagnosis. It can be focal or extensive and primary or rarely it may be secondary. Clear cell changes may be observed in many non-neoplastic, benign, or malignant tumors of diverse origin. Clear cell tumors contain a preponderance of clear cells. It can be seen in almost all the organs of human body and can be classified according to location or biological behavior. Commonly seen clear-cell tumors are usually malignant and common organs involved are female genital tract, urogenital tract, head and neck areas, central nervous system, skin, and rarely in bone and soft tissues. For approach to clear cell lesions, one has to decide if the change is artifactual, a mimic of clear cell tumors, or a clear cell tumor in reality. Once the mimics and artifactual/degenerative changes have been ruled out, a tumor either primarily of clear cell origin or showing secondary change has to be decided. The tumor next is to be diagnosed as benign/malignant and epithelial/mesenchymal based on morphology.

How to cite this article:
Kar A, Pattnaik K, Kar T, Biswal P, Mishra C, Guru L. Clear cell lesions in pathology: Histomorphologic approach to diagnosis.Indian J Pathol Microbiol 2020;63:177-187

How to cite this URL:
Kar A, Pattnaik K, Kar T, Biswal P, Mishra C, Guru L. Clear cell lesions in pathology: Histomorphologic approach to diagnosis. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 Jul 11 ];63:177-187
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Remarkable progress has been made in molecular medicine providing necessary information on tumors, clonality, gene expression profile, genetic alterations, prognosis, and predictive markers for response to target therapy. But till now, the microscope has remained the most important and essential tool of the surgical pathologist in everyday practice. For the selection of the relevant molecular/immunohistochemical investigations always, a precise or a presumptive histologic diagnosis is the starting point. It is surprising that the hematoxylin–eosin (H and E) stain, introduced more than a century ago, has stood the test of time as the gold standard stain for histological examination and diagnosis of human diseases.[1]

There can be different findings or clues observed in surgical pathology specimens, which can range among cellular features like inclusions, granules, grooving, globules, halo, or clearing. These are characteristic histomorphological features that would enable the pathologist to provide a precise and accurate diagnosis or lead to difficulties and delays in establishing the diagnosis. This can yield enormous amounts of information about the cells and their functions or aberrations. Observation of clear cells in surgical pathology is one of the important findings and clues for reporting. It can be focal or extensive. Frequently, clear cell changes are primary or rarely it may be secondary.

Not infrequently, surgical pathologists encounter malignant neoplasms composed of clear cells, the sources and nature of which are indeterminate on the basis of the conventional morphological study. Also, tumors of completely dissimilar lineage can show strikingly similar microscopic appearances; moreover, the anatomic location provides definitive clues to the final diagnosis in many cases.[2] The differential diagnosis of both benign and malignant clear-cell tumours must consider patterns of growth as well as accompanying cell populations when attempting to arrive at a definitive histological diagnosis.

Because of these factors, it is necessary to systematically pursue the approach to the pathological assessment of clear-cell tumors and lesions, routinely considering not only clinical and radiologic details but also the possible application of histomorphology, special stains, immunohistology, electron microscopy, and cytogenetics. This review describes various conditions associated with clear cells, causes for clearing, the potential drawbacks and limitations observed in clear-cell lesions with various techniques for their recognition, location-wise distribution of clear-cell tumors and an algorithmic approach towards arriving at an appropriate diagnosis of these tumors.

 Clear Cells and the Causes of Clear Cytoplasm

In histology, a clear cell shows clear cytoplasm when stained with H and E stain—an area in cytoplasm appears unstained [Figure 1]a. The plasma membrane of clear cells is highly folded, mostly on the apical and lateral surfaces. The cytoplasm of clear cells contains large amounts of glycogen and many mitochondria. Artifactually, clearing may occur during the histotechnical processing of specimens. Improper cellular preservation of cells, hydropic degeneration of organelles can also lead to cytoplasmic clearing.[3] They may involve various regions and may be of diverse etiology. Clear cell changes can be physiological or pathological.{Figure 1}

Physiological clear cells

Normally or physiologically, clear cells are seen in several sites of human body like remnants of dental lamina, rests of Malassez, myoepithelial cells, mucous acinar cells, secretory cells in the epithelium, and eccrine sweat glands.[4],[5],[6],[7] Melanocytes appear as clear cells in the stratum basale of the skin, and Langerhans cells appear as clear cells in the stratum spinosum.[8] The clearing in epidermal cells such as keratinocytes and melanocytes is due to cytoplasmic shrinkage around the nucleus. Dissolution of lipids by alcohol during routine histotechniques is the reason why adipose tissues appear clear.

Clear cells are seen in endometrial glandular epithelium either as large cells with voluminous clear cytoplasm or smaller cells with pyknotic nuclei surrounded by a clear halo. These cells can be observed using a light microscope only in proliferative, hyperplastic, and malignant endometrial glands. Sometimes, they are only the indicator of estrogenic activity in weakly proliferative endometrium.[9]

Clear cell changes often seen in both intrauterine and ectopic pregnancies are the Arias-Stella reaction. These changes occur between 4 and 8 weeks after implantation and are a physiological glandular response to the presence of trophoblastic tissue. The Arias-Stella phenomenon [Figure 1]b is a benign change in the endometrium associated with the presence of chorionic tissue characterized by nucleomegaly with abundant pale eosinophilic to vacuolated cytoplasm.[10] In addition to functional endometrium, it can also be seen in endometriosis, ovarian inclusion cyst, endocervical polyps, vaginal adenosis, and mucinous cystadenoma. It is a strong differential diagnosis for clear cell carcinoma from which it can mostly be distinguished by absence of mitosis. Balloon-shaped macrophages seen in late and degenerating corpus luteum of ovaries can be confused with clear cells but characteristic morphology and positivity for general macrophage marker PGM1 can help in differentiation [Figure 1]c. Degenerative changes seen in many organs with ageing may also be a mimic for clear cells, e.g., in prostate [Figure 1]d.

Pathological clear cells

In histopathological sections, there are many causes for clearing of cytoplasm starting from fixation artifact and improper cellular preservation, hydropic degeneration of organelle to intracellular accumulation of various substances like glycogen, mucin, lipids, glycogen with mucin, intracellular fluid/water, combined glycogen, mucin and organelles, phagocytosed materials, and mitochondria. Clear cell changes may be observed in many non-neoplastic, benign, or malignant tumors of epithelial, mesenchymal, adnexal, melanocytic, or hematopoietic origin.[3] Depending on the organ involved and histomorphologic features they carry their significance. Each entity has characteristic and distinguishing features and it is essential to give a correct diagnosis to each of these clear cell entities for better and proper management of patients.

 Clear Cell Tumors

Clear cell tumors contain a preponderance of clear cells. These are polyhedral cells with the presence of abundant clear or vacuolated cytoplasm and centrally placed small hyperchromatic nuclei.[11] Clear-cell tumors, both benign and malignant, derive from a diverse group of epithelial cell types including renal epithelium, keratinizing, odontogenic and glandular epithelium, cutaneous adnexa, salivary glands, melanocytes, and even mesenchymally derived cells of smooth muscle, adipose tissue, cartilage and tendon sheath.[12] They are attributable to various factors including artifactual changes, improper cellular preservation, and hydropic degeneration of organelles, or due to the accumulation of various substances in the cytoplasm of tumor cells.

Role of special stains and immunohistochemistry used for differential diagnosis of clear cell lesions

Periodic acid–Schiff (PAS) stain is positive with glycogen, some mucins, and mucopolysaccharides [Figure 1]e, which can be diastase sensitive or resistant. Glycogen is PAS with diastase predigestion (PASD) negative (also called diastase sensitive because diastase removes PAS staining). Neutral and acid-simple nonsulfated and acid-complex sulfated mucins and mucopolysaccharides are stained by PAS stain but acid-simple mesenchymal mucins and acid-complex connective tissue mucins are not stained. Alcian blue is used to demonstrate neutral and acidic mucopolysaccharides, sialomucin, and sulfomucin. Mucicarmine stains acidic mucin. Oil Red O and Sudan Black B stain neutral lipids in frozen sections and lipoproteins in paraffin sections and a combination of PAS with alcian blue is a pan-mucin marker.

The commonly used immunomarkers can differentiate and distinguish most of the clear-cell tumors. Clear cell carcinoma (CCC) of female genital tract (FGT) are CD15, Napsin A, and CA125 positive and estrogen receptor (ER), Wilms tumor 1 (WT1),carcinoembryonic antigen(CEA), inhibin, and alpha-fetoprotein (AFP) negative; clear cell renal cell carcinoma (CCRCC) are CD10, epithelial membrane antigen (EMA), vimentin, Pax 2, and CK20 negative; variable CK7 andmelanomas are HMB45 and Melan A positive; skin CCCs are CK and HMWK positive; sarcomas are positive with vimentin and variably positive for desmin, smooth muscle actin, S-100, and CD68. In the central nervous system (CNS), immunomarkers such as glial fibrillary acidic protein (GFAP), neuron-specific-enolase (NSE), S-100, vimentin, and EMA are used for differentiation of entities. By combining morphology with immunohistochemistry (IHC), a definite diagnosis can be made in most instances.

 Classification of Clear Cell Lesions of the Human Body

According to location: Knowledge of the numerous non-neoplastic and neoplastic entities displaying clear cell change at each anatomic site can enable the surgical pathologists to approach the differential diagnosis of each condition in a more logical and rigorous manner.[13] Starting from head and neck, salivary glands, CNS, FGT, urogenital tract, skin, bone and soft tissues, the list of clear-cell tumors is very vast and is covered in this review with approach to each entity.

According to biological behavior: Non-neoplastic clear cell lesions can be in general cells in storage disorders, xanthomas, juvenile xanthogranuloma, viral infection cells such as koilocytes, cells in Hurler syndrome, Hand-schuller syndrome etc., In brain, the clear-cell tumors can be meningioma, oligodendroglioma, ependymoma, neurocytoma besides metastatic CCC. Head and neck tumors can be odontogenic tumors, salivary gland tumors, cutaneous adnexal tumors, mesenchymal tumors such as clear cell sarcomas, chondrosarcomas, alveolar soft part sarcoma, liposarcoma, paraganglioma etc. Most important clear cell lesions of urogenital tract are CCRCC, clear cell sarcoma (CCS), mesonephric blastoma, angiomyolipoma, clear cell adenocarcinoma of urethra and bladder, the classic type of seminoma, papillary cystadenoma of the epididymis, and well-differentiated adenocarcinoma of the prostate. CCC of endometrium, ovaries, cervix, clear cell hepatocellular carcinoma, cholangiocarcinoma, pulmonary blastoma, CCC of pancreas, gastrointestinal tract (GIT), follicular carcinoma of thyroid, clear cell carcinoid, and chordoma are some of the examples of the exhaustive list of clear cell neoplasms. CC variant of lymphoma, myeloma, melanoma, mesothelioma, thymoma, perivascular epithelioid cell neoplasms (PEComa), gastrointestinal stromal tumor (GIST), and yolk sac tumor are examples of rare clear-cell tumors.[14]

Head and neck

In the head and neck, clear-cell tumors represent a huge challenge to the pathologist because the classic morphological features of malignancy exemplified by cytological atypia are frequently absent in malignant clear cell variants. Salivary gland tumors frequently show clear cell change in their cytoplasm. According to National Cancer Institute (NCI), clear-cell tumors of the salivary glands comprise a diverse group of benign and malignant tumors with variable clinicopathological characteristics. The distinction between different tumors of this group and from metastatic tumors is essential especially distinguishing primary salivary tumors from metastatic tumors with clear cell features have important therapeutic, diagnostic, and decision-making considerations. This can be achieved and facilitated by a combination of thorough clinical evaluation, histomorphological examination, and histochemical as well as immunohistochemical staining features.

Clear-cell tumors of salivary glands constitute 1% of all primary salivary gland tumors. They are mostly malignant except two conditions: clear cell variant of oncocytoma and myoepithelioma. Also, most of the CCCs of salivary glands are low grade. Majority of salivary gland tumors showing features of clear cell change are contributed by the myoepithelial cells.[15] Based on this, primary salivary clear cell neoplasias can be divided into those that diagnostically require evidence of myoepithelial differentiation, i.e., clear cell myoepithelioma/myoepithelial carcinoma and epithelial-myoepithelial carcinoma and those that do not, i.e., CCC. Clear cell variants of salivary gland tumors such as acinic cell carcinoma, mucoepidermoid carcinoma [Figure 2], and oncocytoma also do not have myoepithelial differentiation. In this context, immunohistochemistry with calponin can be an important diagnostic tool.[16]{Figure 2}

Entities in these specific groups of tumors can be differentiated by histochemical stains like clear cell variant of mucoepidermoid carcinoma (positive stain for mucin), clear cell variant of acinic cell carcinoma (with zymogen granules and focal mucicarmine positivity), primary CCC not otherwise specified (no zymogen granules distinguishing from acinic cell carcinoma), epithelial-myoepithelial carcinoma (positive for glycogen), and clear cell myoepithelial tumors (positive for glycogen). Wang et al. analyzed the later three entities with myoepithelial cells differentiation and found that primary CCC present in intraoral sites have high glycogen contents and indolent course in contrast to the other two aggressive tumors.[17] Myoepithelioma, both benign and malignant types, may have clear cells but they are less in number and usually have mixed patterns of different types of myoepithelial cells. Another similar type of intraoral tumor containing hyaline stroma is differently named as, hyalinizing CCC of salivary gland. It was documented by Milchgrub S et al. where clusters of tumor cells are separated by broad bands of hyalinized stroma.[18]

The clear cell variant of acinic cell carcinoma is a very rare occurrence, characterised by presence of vacuolated cells and foci of parent tumor growth pattern in the tumor tissue. The vacuolated cells in acinic cell carcinoma lack glycogen. Clear cell mucoepidermoid carcinoma can be readily differentiated by the presence of clear squamous, mucous, and intermediate cells. The epithelial-myoepithelial carcinoma shows its typical growth pattern of bimodal ductal luminal cells and myoepithelial cells. Clear cell variant of oncocytoma shows encapsulation and organoid growth pattern separated by thin vascular septa. Tumor cells have small pyknotic nuclei with abundant eosinophilic granular cytoplasm of oncocytic cells. On histochemical staining, phosphotungstic acid haematoxylin (PTAH) is positive and PAS is positive with diastase sensitive (glycogen). When these clear cells lie haphazardly in the salivary gland, they are considered as features of oncocytosis usually seen in elderly but not oncocytoma.

Sebaceous neoplasms (positive stain for fat) can also infrequently be encountered as an entity amongst the salivary clear cell lesions.

Odontogenic tumors with extensive clear cell change is uncommon and can be cysts and tumors.[19] Clear cell odontogenic cysts are calcifying odontogenic cyst, gingival cyst of adults, and lateral periodontal cyst. Clear cell odontogenic tumors are calcifying epithelial odontogenic tumor (CCCEOT), clear cell odontogenic carcinoma (CCOCa), and clear cell odontogenic ghost cell tumor (CCOGCT).[19],[20] These odontogenic lesions show sheets, cords, or nests of clear cells but in addition to the characteristic features of the respective entity by which they can be differentiated from one another. But CCOCa has mostly islands of large clear cells separated by delicate fibrous connective stroma and interspersed with nests hyperchromatic basaloid cells with focal nuclear palisading. Tumor cells are immunoreactive for CK8 and CK19 and non-reactive for S-100 and vimentin.

Metastatic clear cell tumors are rare in oral cavity and comprise 1% of all oral neoplasms; these can be from kidney, liver, prostate, large intestine, and thyroid. However, the secondary tumors like any other site can be identified by the histomorphology and immunohistochemical findings of the primary entities. Rarely a metastatic balloon cell melanoma comes into the differential diagnosis when one finds clear to foamy cells, pleomorphic nuclei, prominent nucleoli, and intranuclear cytoplasmic inclusions. Melanoma immunomarkers (HMB45, Melan A) are needed to reach at diagnosis of this rare variant of malignant melanoma if the primary is occult.[21]

Central nervous system

Mass lesions of CNS, which may assume a clear cell appearance are diverse in nature and challenging to diagnose. Primary CNS clear cell tumors include oligodendroglioma (OG), neurocytoma [Figure 3]e, [Figure 3]f, [Figure 3]g, [Figure 3]h, [Figure 3]i, [Figure 3]j, clear cell [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d and chordoid meningioma, hemangioblastoma, clear cell ependymoma (CCE), germinoma, pleomorphic xanthoastrocytoma (PXA), and lipid-rich glioblastoma.[22] They can be correctly identified by giving attention to clinical presentation, location, radiographic findings, and histomorphological features with special stains, immunohistochemistry, and electron microscopic analysis wherever necessary. Recommended panel of antibodies used for differentiation of clear cell CNS tumors are GFAP, S-100, EMA, keratin, vimentin, and synaptophysin. Most commonly encountered clear cell neoplasms in CNS are oligodendroglioma (OG), central neurocytoma (CN), and clear cell ependymoma (CCE) can be differentiated by a panel of antibodies anti-NEUN, anti-VIM, and anti-EMA proved most useful for differential diagnosis. Prominent (>90%) anti-NEUN immunolabeling of tumor cells can distinguish CNs from OGs and CCEs. Anti-VIM immunolabeling and a characteristic cytoplasmic dot-like anti-EMA immunoreactivity pattern of tumor cells are detectable only in OGs and CCEs. But prominent anti-VIM immunoreactivity and anti-EMA cell membrane staining is characteristic for CCEs.[23]{Figure 3}

Differentiation of clear cell [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d and chordoid meningioma from other meningiomas is essential as these belong to WHO grade 2 with an aggressive biological behavior and eight-fold higher recurrence rate. Clear cell meningioma has predilection for young age and usually seen in cerebellopontine angle and cauda equine and consist of large clear cells in patternless arrangement with marked fibrosis and interstitial collagen. Positive immunostaining is seen with EMA, progesterone receptor (PR) and vimentin in majority cases. Chordoid meningioma comprise of cords and trabeculae of large cells with clear and eosinophilic cytoplasm (resembling physaliferous cells of chordoma) over myxoid stroma but should have foci of traditional meningiomas and positive for alcian blue and EMA. Positive immunomarkers for hemangioblastoma are neuron-specific enolase and inhibin and negative immunomarkers for germinoma are SALL, OCT4, PXA-. Immunomarkers such as CD10, HMB45, PanCK, and GFAP can be used to rule out metastatic tumors.[24],[25]

Female genital tract

Clear cell lesions of FGT can be non-neoplastic, benign or malignant, and epithelial or mesenchymal. Non-neoplastic clear cell changes are seen in lining epithelium of proliferative or hyperplastic endometrium indicating estrogenic activity, clear cell metaplasia, hobnail metaplasia of endometrial glands, Arias-Stella reaction, microglandular hyperplasia of cervix, mesonephric hyperplasia, and xanthogranulomatous inflammation of endometrium, ovary and fallopian tubes.

Xanthogralumatous inflammation can be seen in uterus, tube, ovary, cervix, and vagina. It comprises of sheets of foamy histiocytes admixed with other chronic inflammatory cells and giant cells replacing the mother tissue. These cells when infiltrate myometrial muscle in uterus can be confused with CCC but nowhere the endometrial glands/hyperplasia or carcinoma features are seen. Foamy histiocytes are positive for CD68 and Mac-387.

Benign clear-cell tumors can be epithelial or mesenchymal. Leiomyoblastomas of uterus comprise of round, large epithelioid cells with vacuolated clear/eosinophilic cytoplasm with focal transition to typical smooth muscle cells. They exhibit immature smooth muscle cell differentiation like that of fetal uterus. These may be confused with CCC but they do not have nuclear atypia and tumor cell necrosis. These cells are positive for alfa smooth muscle actin, desmin, and myosin but restricted for caldesmon.[26]

Pregnancy luteoma is seen in reproductive females usually in second half of pregnancy, are incidental findings, and can be bilateral and multifocal. Histopathology reveals luteinized cells in sheets, trabeculae and follicle like structures and may be confused with clear cell lesions but can be differentiated due to characteristic features and absence of features of CCC.[27] Clear cell adenofibroma, both benign and borderline, are included under clear cell tumors of FGT. Histological examination reveals widely spaced simple glands embedded in a dense fibrous stroma. The glands are lined by one to two layers of cells with abundant clear cytoplasm and bland, uniform nuclei. In borderline tumors, mild to moderate cytologic atypia with glandular crowding may be seen but no stromal invasion.[28]

CCC of FGT is a rare type of tumor, in which the insides of the cells look clear when viewed under a microscope. These are adenocarcinomas that predominantly consist of clear cells with a solid boundary, abundant clear to pale eosinophilic cytoplasm with glycogen, central hyperchromatic nuclei, and prominent nucleoli. They pursue a bad prognosis with aggressive behavior. It is encountered in ovary, uterus, cervix, and vagina. CCC architecturally can be papillary, tubulecystic, or solid [Figure 4]a, [Figure 4]b, [Figure 4]c, [Figure 4]d, [Figure 4]e. Papillae are small and round with hyalinized core, lined by single layer of cuboidal epithelial cells. Tubulocystic pattern is lined by flat cells or cells often showing nuclear hobnailing. Solid pattern is characterized by sheets of large round to polygonal cells with pavement-like architecture containing abundant clear to pale eosinophilic cytoplasm and central uniform nuclei with pseudoinclusion and macronucleoli. Occasionally, pleomorphic nuclei, koilocyte like nuclei, plasmacytic infiltrate, eosinophilic hyaline globules, targetoid bodies, and psammoma bodies may be seen.[29]{Figure 4}

Morphologic features that suggest a diagnosis other than CCC are papillae lined by columnar cells, multilayering, severe nuclear atypia and hyperchromasia, squamous differentiation, and high mitotic index.[29] CCC of ovary may be associated with endometriosis, clear cell adenofibroma, and clear cell borderline tumors. CCCs can be confused with papillary serous and endometrioid carinoma and can be easily differentiated by applying above morphologic clues. They stain with CK7, 34βE12, CEA, Leu-M1, vimentin, p53, and CA-125 and are negative for CK20; can be variably positive with ER and Her-2/neu antibodies but are negative for PR.[30]

There are many common histopathologic features usually shared by CCC and yolk sac tumors (YSTs). Clinically, CCCs occur principally in older women, whereas YSTs, like most primitive germ cell tumors, arise in patients younger than 30 years. The papillae of CCC have hyalinized stromal cores and are often complex, whereas those of YST are usually single and simple, with the presence of loose stroma containing a central vessel (Schiller –Duval bodies). In contrast to CCC, YSTs are AFP postive and CK7, Leu-M1, and EMA negative.[31] Endometrioid adenocarcinoma with secretory change or squamous metaplasia with clear cytoplasm is separated from CCC by the absence of the typical architectural patterns and lack of hobnail cells with high-grade nuclei. Vimentin and CK7 are positive in endometrioid carcinoma. Serous adenocarcinoma is distinguished from CCC by the findings of irregular thick papillae, cellular stratification and budding, marked nuclear pleomorphism, and higher mitotic rates. In difficult cases, immunostains may aid in the diagnosis, as CCCs are typically ER and WT1 negative. Occasionally, CCC and endometrioid carcinoma may coexist. Juvenile granulosa cell tumor may come as a differential diagnosis but it occurs in younger women and morphologically is distinguished from CCC by the presence of large follicle-like cysts containing pale-staining material, positive immunostaining for inhibin, and lack of EMA expression. CCC should always be distinguished from metastatic carcinomas especially RCC and direct extension from colonic carcinoma. Metastatic CCRCC involving the ovary is uncommon, but may be initially misdiagnosed as an ovarian primary carcinoma. RCCs do not exhibit hobnail cells and are typically associated with a prominent sinusoidal vascular framework, not present in ovarian CCC. CCC of vagina is associated with diethyl stilbestrol therapy. Other rare malignant tumors of FGT with clear cell change include dysgerminoma, steroid cell tumors, hepatoid carcinoma, signet ring cell stromal tumors, and trophoblastic tumors.[32]

Urogenital tract

There can be a spectrum of lesions with cytoplasmic clearing in urinary tract and male reproductive system such as kidney, urinary bladder, testis, epididymis, and prostate. Non-neoplastic lesions include xanthogranulomatous cystitis and pyelonephritis where grossly enlargement of organ occurs with yellowish patches. Microscopic features are same as that of other regions with PAS positive granules seen in the cytoplasm of macrophages and positive immunostaining with CD68, which can differentiate this lesion from other clear cell entities. Renal replacement lipomatosis is another condition where renal parenchyma is replaced by fatty tissue and not xanthoma cells.[33] Microscopic examination reveals extensive fatty infiltration in the renal parenchyma with atrophied renal parenchyma at periphery and abrupt transition from normal tissue; the presence of sclerosed glomeruli, focal thyroidization of tubules, interstitial fibrosis, and thickened blood vessels. It should be differentiated from xanthogranulomatous inflammation, lipoma, and angiomyolipoma. The clinching point usually is the presence of atrophied renal parenchyma that is not seen in other conditions.

Nephrogenic metaplasia/adenoma is a rare benign condition of kidney where small hollow tubules are lined by cuboidal cells with clear to eosinophilic cytoplasm, small nuclei but absence of prominent nucleoli.[34] These cells are positive for AE1/AE3, PAX2, and luminal cytoplasmic mucin is PAS and mucicarmine positive.[34],[35] Benign clear cell tumors of urogenital tract include oncocytoma, epithelioid variant of angiomyoepithelioma (EAML), and papillary cystadenoma of epididymis.[13] Papillary cystadenoma of epididymis is characterized by cystic spaces with papillary infoldings projecting into lumen and lined by cuboidal to columnar cells with eosinophilic to clear cytoplasm.[36] They may resemble metastatic RCC but there is no pleomorphism, mitosis, and necrosis and are CK7 positive, CD10 negative ruling out RCC. Epithelioid angiomyolipoma (EAML) or oncocytoma-like angiomyolipoma is a rare benign tumor of kidney and also sometimes of cervix composed of admixture of blood vessels and adipose tissue with predominance of epithelioid cells and multinucleated giant cells. Oncocytoma comprising of large closely packed uniform round/polygonal cells with abundant dense eosinophilic and granular cytoplasm, should not be confused with clear cell tumors except when there is clear cytoplasm or in case of clear cell variants. The classic cytology and architecture with immunonegativity for CK7, CD10, and positivity for CK8 can establish its diagnosis easily.

Malignant neoplasms with clear cell change can be CCRCC, CC adenocarcinoma of bladder and urethra, adenocarcinoma of prostate, seminoma-classic type, clear cell sarcoma (CCS) and extension or metastasis from gynecologic clear cell malignancies in females. CCRCC [Figure 5]a, [Figure 5]b, [Figure 5]c is a heterogeneous group of renal carcinomas with clear or eosinophilic granular cytoplasm (divided by some authors into clear cell and granular cell types), and a common molecular signature of von Hippel-Lindau (VHL) inactivation. It is a clinically and radiologically detectable renal mass with microscopic features of intracytoplasmic lipid/glycogen, characteristic prominent sinusoid-like vasculature or chicken wire blood vessels, hemorrhage and hemosiderin-laden macrophages. Special stains used for detection of glycogen and lipid in the cytoplasm of RCC cells are PAS, Oil red O, and Sudan black B. Positive immunohistochemistry in RCC are CAIX, PAS8, PAX2, CD10, vimentin, AE1AE3, and EMA and negative immunostain with CK20 and CD117. The key immunohistochemical markers for making a diagnosis of primary RCC are currently PAX2, PAX8, CD10, and a combination of vimentin and CK. The characteristic immunoprofile for differentiating CCRCC from other types are: of CCRCC is negative for CK7 and AMACR, positive for CA IX and negative for TFE3, papillary RCC is positive CK7 and AMACR and negative for CAIX and TFE3, while for CC papillary RCC it is positive for CK7 and CAIX and negative for AMACR and TFE3. Lastly, Xp11translocation RCC is negative for CK7 and CAIX and positive for AMACRand TFE3.[37]{Figure 5}

Differential diagnosis includes chromophobe RCC, oncocytoma, CC papillary RCC, EAML, and MiT family of tumors. Papillary RCC with focal clear cell like areas (which lack chicken wire vessels and diffuse positivity for AMACR) has unique clinical, immunohistochemical, and cytogenetic phenotype and associated with aggressive pathological characteristics and poorer prognosis. They express VEGF-2 and CK-7 with loss of chromosome 3p.[38] EAML are positive for HMB45, Melan A, cd63, cd117 and negative for CK, EMA, and S-100 and tend to display more aggressive behavior or malignant transformation.[39] MiT family of tumors harvor fusion genes involving transcription factors including TFE3 and TFEB. They have wide histologic spectrum and often have papillary, alveolar, and nested growth pattern with clear and eosinophilic cells and psammoma bodies; are more common in children/young adults. These tumors are positive for TFE3, TFEB, PAX5, AMACR, CD10, and also HMB45, MelanA, and variable negativity for CK and EMA.[40] Clear cell sarcoma of kidney (CCSK) is second common childhood renal malignancy, also known as bone-metastasizing renal tumor [Figure 5]d, [Figure 5]e, [Figure 5]f, [Figure 5]g, [Figure 5]h. The classic pattern consists of plump ovoid cells arranged in broad trabeculae or nests, separated by regularly spaced and arborizing fibrovascular septa. The distinctive alveolar and arborizing vasculature of CCSK over fibrovascular stroma with hyalinization and/or myxoid change is a helpful and distinctive diagnostic feature because it is not prominent in the other pediatric renal tumors. Clear cytoplasm is observed in only 20% of cases. Until recently, no particular immunohistochemical marker was known to be helpful in the diagnosis of CCSK. However, it shows moderate to strong cytoplasmic immunoreactivity to the nonspecific marker vimentin and is weakly positive for actin. There is negative staining for EMA, desmin, S100 protein, factor VIII-associated antigen, and MAC387.[41]

The most common cancers that metastasize to the kidney are melanomas and solid tumors, particularly lung, breast, stomach, gynecologic, intestinal, and pancreatic cancers and rarely leukemia and lymphoma. These can be considered if there is a possible clinical history of a nonrenal tumor, tissue-specific markers for metastasis from other sites such as TTF-1 from the lung, prostate-specific antigen (PSA) from the prostate, CDX2 from the colorectum, hepar-1 from the liver, inhibin from adrenal cortical carcinoma, and S100 and HMB-45 from melanoma.

Primary CCC (mesonephric, mesonephroid type) is a rare distinctive variant of urinary bladder adenocarcinoma, which also is encountered in urethra and is more common in females. This is considered the malignant counterpart of nephrogenic adenoma and differentiated by the absence of mitosis.[42] These tumors can exhibit a mixture of tubules, papillae, cysts, and solid growth patterns. [Figure 6]a, [Figure 6]b, [Figure 6]c, [Figure 6]d Two distinct characteristic features of this carcinoma are hobnail cells and abundant cytoplasmic glycogen positive for PAS stain with diastase resistance. This lesion must be differentiated from mesonephroid hyperplasia (nephrogenic adenoma), mixed transitional and CCC, CC variant of transitional cell carcinoma, and hepatoid adenocarcinoma. The classic histomorphologic features of CCC of bladder can help in ruling out these entities with the help of immunohistochemistry with b-catenin, p53, CK7, and MIB1. Clear cell lesions of prostate can also pose a diagnostic challenge. CCC of prostate include CCRCC, variants of prostatic adenocarcinoma, transitional cell carcinoma, and metastatic RCC which is very rare. Renal type CC adenocarcinoma in extrarenal site like prostate as a primary tumor is very rare.[43] The absence of mass in cystoscopy and high PSA level in serum can exclude clear cell type urothelial carcinoma. IHC shows positivity for low molecular weight cytokeratin, vimentin, EMA, and negativity for HMWK and PSA. Hypernephroid pattern of prostatic adenocarcinoma [Figure 5]h also is to be ruled out before giving a diagnosis of this rare type. Gleason grading system devised in 1960s–1970s has been significantly modified in 2005 and 2014 and has been incorporated into 2016 WHO classification where Grade group system has been adopted. According to this hypernephroid pattern [Figure 5]i with raggedly infiltrating tumor cells, solid sheets and fused glands with characteristic large pale cells having small hyperchromatic nuclei without intervening stroma is considered Gleason grade 4 and resembles RCC.{Figure 6}

CCC of penis is a recently described distinctive clinicopathological entity related to human papillomavirus (HPV).[44] Tumor cells are polygonal with well-defined borders, clear, slightly granular abundant cytoplasm, nuclear atypia with coarse chromatin, irregular nuclear membrane and prominent nucleoli and are arranged in nests with irregular jagged borders. These cells are PAS/dPAS positive and stain positively with GATA3 and p16. HPV can be detected in these tumors by in situ hybridization technique. CCC of penis can be confused with other carcinomas depicting clear cell features like SCC and verrucous carcinoma and rarely sebaceous carcinoma and CC urothelial carcinoma but these changes are focal and limited to superficial layers or central portions of an infiltrative nest.


Cutaneous clear cell lesions represent a heterogeneous group of several non-neoplastic, benign, primary malignant, and metastatic tumors with diverse histogenesis of epithelial, mesenchymal, and melanocytic origin.[45] In many cases, clearing of cytoplasm is idiopathic but different etiologies like intracytoplasmic accumulation of glycogen, lipid, mucin, artifact during tissue processing, and degenerative phenomenon are possible. Non-neoplastic clear cell entities of skin include xanthoma of various types like xanthoma, xanthelesma, juvenile xanthogranuloma, cerebrotendinous xanthomatosis, and sebaceous hyperplasia. Xanthoma cells are foamy macrophages with phagocytized lipid and stain positive for special stain Oil Red O. These patients have specific serological lipoprotein abnormalities.

Benign tumors include lipoma, histiocytoma, atypical fibroxanthoma, CC dermatofibroma, PEComa, sebaceous adenoma, CC hydradenoma, CC syringoma, CC ecccrine carcinoma, eccrine fibroadenoma with clear cell change, CC poroma, CC porocarcinoma, CC myoepithelioma, and balloon cell nevus.

CC squamous cell carcinoma (CCSCC) is a rare variant of SCC related to ultraviolet radiation exposure and characterized by the presence of intracellular fluid; not glycogen, mucin or lipid.[46] It is otherwise (in its growth pattern and nuclear features) no different from conventional SCC. However, clear cell changes may be seen in many variants of SCC. There is no prognostic significance to the clear cell change. Recognition of clear cell features in SCC is important for the distinction from other clear cell tumors, such as CC sweat gland carcinoma, sebaceous carcinoma, trichilemmoma, balloon cell melanoma and nevus, epithelioid leiomyoma, leiomyosarcoma, pleomorphic liposarcoma, chordoma, parachordoma, and metastatic renal cell carcinoma. Correct diagnosis depends on careful analysis of histologic features using supporting special histochemical and immunohistochemical stains

Bone and soft tissues

CC lesions are rare in bone but in soft tissues include entities with varying morphological patterns and a range of clinical behavior and prognosis.[47] Benign clear cell tumors include perivascular epithelioid cell tumors, CC fibrous papule, CC mesenchymal tumor, CC variant of fibrous histiocytoma, myoepithelioma, leiomyoma, and atypical fibroxanthoma.

Malignant tumors comprise of CCS, liposarcoma, and rare perivascular malignant epithelioid cell tumors; CC variant of LMS and rhabdomyosarcoma; metastatic CCRCC and adrenal cortical carcinoma. CCS can also occur in soft tissues and known as melanoma of soft parts [Figure 7]a, [Figure 7]b, [Figure 7]c, [Figure 7]d, [Figure 7]e. It can affect any tendon, ligament, and aponeurosis and affects young females in the age group from 20-40 years. But a rare case was reported by Agarwal R et al. in a 5-year old boy in paraspinal ligament.[48] CCS must be distinguished from CC melanoma by identification of characteristic cytogenetic hallmark, i.e., translocation t(12,22)(q13;q12) resulting in a chimeric EWSRATF gene or less commonly a t(2;22)(q34;q12) translocation fusing EWSR1 and CREB1. Similar histological features and immunohistochemical positivity for HMB45 is observed in both cases. This condition should not be related to childhood CCSK.{Figure 7}

CC chondrosarcoma is a very rare low grade variant chondrosarcoma of young adults usually affecting epiphyseal ends of long bones. Histologically characterized by lobules of cells with abundant clear to pale eosinophilic cytoplasm over cartilaginous matrix and with bony trabeculae.[49] Foci of conventional chondrosarcoma and scattered giant cells may be present. Vacuolated clear cells are positive with PAS stain and strongly positive for S-100. Conventional osteosarcoma with clear cell change reveals clear cells scattered irregularly or in small groups or in large demarcated groups. Their cytoplasm is PAS positive but S-100 negative. Chondroblastic osteosarcoma, osteoblastoma-like clear cell lesions of any other part of body needs careful consideration of clinical history, imaging studies, special stains, and judicious use of immunohistochemistry for differentiation and a correct diagnosis.

 Algorithmic Approach to Diagnosis of Clear Cells

Clearing of cytoplasm or clear cell change can be seen in various entities of different locations due to diverse reasons. Whenever clear cells are encountered, one has to proceed according to the algorithmic approach described here. [Table 1] To start with, one has to decide if the change is artifactual, a mimic of clear cell tumors, or a clear cell tumor in reality. Once the mimics and artifactual/degenerative changes have been ruled out, a tumor either primarily of clear cell origin or showing secondary change has to be decided. Next step is to diagnose the tumor as of epithelial or mesenchymal origin and also benign or malignant in nature. Depending on findings like architectural pattern, pleomorphism, necrosis, and mitosis it can be easily distinguished. If malignancy is suspected, secondary or metastatic tumors like RCC, melanoma, CC adenocarcinoma from liver, prostate, lungs, GIT etc., must be ruled out. Before attempting to zero out on the particular type of clear cell tumor whether benign or malignant, it is mandatory to have a thorough knowledge of different CC tumors of different organs and their differential diagnoses. After morphologic evaluation, one can take help of special stains and immunohistochemistry to reach at a final diagnosis; the different special stains and immunomarkers necessary are different according to type and location of the tumor, which can easily give the clue to diagnosis.{Table 1}


Clear cell change can be a positive clue (associated with some malignancies) or a diagnostic pitfall. Demerits of clear cells: even though it can be a clue to histomorphologic distiction, help in diagnosis due to specific features of clear cell tumors; the presence of clear cell change can cause delay and challenge in diagnosis. Also it may lead to problems in immunohistochemical staining. With artifactual clear cell change, there might be problems in electron microscopy procedures also and may result in difficulty in correct diagnosis.

Hence it is justifiably said Beware Of Clear Cells-They Can Be Deceptive!!!!


To the technical staff of Dept. of Pathology, S.C.B. Medical College, Cuttack.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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