| Abstract|| |
Background: Gastrointestinal stromal tumors (GISTs) are biologically distinctive neoplasms harboring KIT and PDGFRA mutations. Cytokeratin expression in GISTs is an under-recognized diagnostic pitfall, especially in high grade GISTs with limited biopsy material and from metastatic sites. Materials and Methods: We evaluated the histomorphology and expression of four 'broad-spectrum' cytokeratin markers, AE1-AE3, CAM 5.2, MNF-116, and 34βE12 in 64 GISTs diagnosed over a 68-month period. Individual cytokeratins 5, 6, 7, 8, 14, 17, 18, 19, and 20 were investigated in the 'broad-spectrum' cytokeratin-positive GISTs. Results: Of 64 GISTs, 10 (15%) demonstrated cytokeratin immunopositivity. All 10, considered high risk by the National Institutes of Health consensus approach, were immunopositive for CAM 5.2 and MNF-116. Seven were AE1-AE3 immunopositive. Cytokeratins 8 and 18 were confirmed in 10 and 9 GISTs, respectively. One GIST demonstrated biphasic morphology with cytokeratin immunonegativity in low-grade spindle and immunopositivity in high-grade epithelioid foci. KIT and PDGFRA mutational analysis, undertaken in 5/10 cytokeratin-positive GISTs, harbored KIT exon 11 mutations. Conclusion: We hypothesize that cytokeratin expression exclusively in high risk GISTs is a consequence of tumor progression. Given the increasing number of commercially available broad-spectrum cytokeratin immunomarkers, including those reacting with cytokeratins 8 and 18, cytokeratin-positive GISTs must be differentiated from carcinomas, melanomas, and a range of cytokeratin-positive sarcomas to ensure optimal patient management and prognostication.
Keywords: Aberrant expression, cytokeratin, gastrointestinal stromal tumor, high risk, mimicry
|How to cite this article:|
Sing Y, Ramdial PK, Ramburan A, Sewram V. Cytokeratin expression in gastrointestinal stromal tumors: Morphology, meaning, and mimicry. Indian J Pathol Microbiol 2014;57:209-16
|How to cite this URL:|
Sing Y, Ramdial PK, Ramburan A, Sewram V. Cytokeratin expression in gastrointestinal stromal tumors: Morphology, meaning, and mimicry. Indian J Pathol Microbiol [serial online] 2014 [cited 2023 Sep 26];57:209-16. Available from: https://www.ijpmonline.org/text.asp?2014/57/2/209/134665
| Introductio|| |
Once a poorly understood enigmatic pathologic entity gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the digestive tract, is characterized by distinct histopathological, immunophenotypic, and molecular genetic features.  The cytokeratins (CKs) are a highly complex family of intermediate filaments that function as the supporting cytoskeleton in virtually all epithelial cells.  CK expression in tumors is generally regarded as evidence of epithelial differentiation, but CK expression is also documented in a range of nonepithelial neoplasms. ,, CK expression in GISTs is reported infrequently [Table 1], ,,,,,,,,, predominantly as case reports ,,,,, and isolated larger studies, ,,, the latter of which contain inconsistent CK immunohistochemistry , and varied molecular profiling. ,, The expression of CKs in GISTs with emerging 'dedifferentiated' and 'anaplastic' phenotypes may lead to potentially serious diagnostic pitfalls. ,
This descriptive clinicopathological study was therefore undertaken to assess and report on a South African experience with CK expression in GISTs, including correlation with risk for aggressive behavior and mutational status. Additionally, the expression and potential significance of the individual CK immunoprofiles as well as the pitfalls associated with histopathological diagnostic mimicry are discussed. Challenges associated with limited biopsy samples of GISTs with unusual clinical presentations and locations, high-grade morphology and atypical immunohistochemical features are highlighted.
| Materials and methods|| |
All biopsies coded as 'gastrointestinal/intestinal stromal tumor' from January 1, 2003 to August 31, 2008 were accessed using the SNOMED word and code search engines. The inclusion criteria were spindle cell and/or epithelioid mesenchymal tumors with unequivocal membranous and/or cytoplasmic CD117 and CD34 immunopositivity in the tumor cells. Care was taken to exclude other CD117-positive neoplasms. Sections were cut from archival wax blocks at 3 μm thickness and stained with hematoxylin and eosin (H and E). All tumors were reappraised to assess cell morphology (spindle, epithelioid and mixed spindle and epithelioid), cellularity, mitotic index per 50 high power fields (HPFs), and the presence of pleomorphism and necrosis. Clinical information including sex, age at diagnosis, tumor location, and tumor size were obtained from departmental records. The tumors were classified into risk groups using the National Institutes of Health (NIH) consensus approach, based on tumor size and mitotic count. 
Representative sections from all tumors were initially screened with four 'broad-spectrum' CK antibodies: AE1-AE3, CAM 5.2, MNF-116, and 34βE12 [Table 2]. While CAM 5.2 is not strictly a 'broad spectrum' CK antibody, it is included as such because it is a successful screening marker for epithelial differentiation.  Appropriate positive and negative control slides were stained in parallel [Table 2]. Tumors demonstrating positivity with any CK cocktail were subjected to an additional immunohistochemical panel of individual CKs [Table 2]. Sections were cut at 2 μm thickness for immunohistochemical analysis. Heat-assisted microwave antigen retrieval and the Novolink polymer detection system [Vision Biosystems (Europe) Ltd, Newcastle-Upon-Tyne, United Kingdom], with diaminobenzidine chromogen for antibody visualization were employed. The results of immunostaining were semi-quantitatively evaluated as follows: Negative (no immunostaining), rare positivity (immunostaining in <5% of tumor cells), focal positivity (immunostaining in 5-50% of tumor cells), and diffuse positivity (immunostaining in >50% of tumor cells).
Molecular analysis was performed in CK-positive GISTs with sufficient archival tissue. Tumor DNA was extracted from representative paraffin wax-embedded blocks using the QIAamp FFPE DNA extraction kit (QIAGEN, Valencia, California, USA) according to the manufacturer's instructions.  A total of 15 mg of genomic DNA was used in each 25 μl reaction. The FastStart Taq DNA polymerase PCR kit (Roche Bioscience, Palo Alto, California, USA) was used according to manufacturer's instructions  and PCR was performed on a CFX-96 thermal cycler (Bio-Rad Laboratories, Hercules, California, USA). c-KIT exons and PDGFRA exons 12, 14, and 18 were amplified [Table 3]. Nucleotide sequencing of the PCR products using the forward primer was performed by Inqaba Biotechnical Industries (Inqaba Biotechnical Industries, Pretoria, South Africa) and sequence analysis was performed using Sequencing Analysis 5.1.1 software (Life Technologies, Carlsbad, California, USA).
| Results|| |
A total of 64 GISTs met the criteria for inclusion in this study. All were composed of spindle and/or epithelioid cells with variable cellularity, atypia, and necrosis. The mitotic index ranged from <1 to 204 per 50 HPFs. Risk for aggressive behavior in accordance with the NIH consensus approach stratified the 64 GISTs as follows: [1/64 (1.6%) very low risk, 18/64 (28.1%) low risk, 8/64 (12.5%) intermediate risk, and 37/64 (57.8%) high risk]. 'Broad-spectrum' CK immunopositivity was identified in 10/64 (15%) GISTs from 10 patients [Table 2] and formed the study cohort (CK-positive GISTs).
Clinical features [Table 4]
The patient cohort consisted of five males and five females, with an age range at diagnosis of 44-67 (mean = 56) years. The most frequent primary anatomic tumor location was the stomach (six), followed by the omentum (two), rectum (one), and retroperitoneum (one). Metastatic disease was identified in six patients in the liver, lung, spleen, anterior abdominal wall, iliac fossa, omentum, and peritoneum [Table 4]. Biopsy material was obtained from metastatic sites of four patients, including the liver (two), anterior abdominal wall (one), and left iliac fossa (one). None of the patients had received imatinib mesylate prior to biopsy or excision of their tumors.
Multiple incisional tissue cores were obtained from each of five patients. Five resected GISTs, 6-28 cm in maximum diameter, were variably firm, white or tan on cut section with hemorrhagic, necrotic and cystic foci. A gastric tumor (patient 9) demonstrated contiguous splenic spread [Figure 1].
Five GISTs each were composed either of spindle cells exclusively [Figure 2]a], or of an admixture of spindle and epithelioid cells [Figure 2]b]. By definition, all tumors contained CD34 and CD117 immunopositive components [Figure 2]c-f], and demonstrated cellular pleomorphism with variably hyperchromatic nuclei and prominent nucleoli [Figure 2]a and b]. The epithelioid cellular component (patient 8) was arranged in nests and cords and displayed nuclear atypia. The mitotic count ranged from 20 to 205 (mean = 67) per 50 HPF. Coagulative necrosis was present in seven tumors. All 10 GISTs were considered high risk for aggressive behavior by the NIH consensus approach.
The GIST from patient 9 displayed biphasic histomorphology with a low-grade sclerosing spindle primary growth pattern [Figure 1]g] with <1 mitosis per 50 HPF. Additionally, a high-grade pleomorphic growth pattern [Figure 2]h] was observed with nuclear anaplasia and 40 (including atypical) mitotic figures per 50 HPF.
CAM 5.2 [Figure 3]a and b] and MNF 116 [Figure 3]c and d] were expressed in all 10 CK-immunopositive GISTs, while AE1-AE3 [Figure 3]e and f] was immunopositive only in 7. The immunoreactivity was focal in one and diffuse in nine GISTs. Paranuclear AE1-AE3 or CAM 5.2 dot-like accentuation [Figure 3]a,b,e,f] was identified in 6/10 GISTs. CK8 [Figure 4]a and b] and CK18 [Figure 4]c and d] immunopositivity was confirmed in 10 and 9 GISTs, respectively. There was no expression of 34βE12 or CKs 5, 6, 7, 14, 17, 19, or 20. Only the GIST from patient 7 demonstrated focal α-smooth muscle actin (SMA) immunopositivity. Muscle specific actin (MSA), desmin, and S-100 protein were negative in all GISTs. The GIST from patient 9 demonstrated diffuse CK immunopositivity with three 'broad-spectrum' CK antibodies (AE1-AE3, CAM 5.2, and MNF116) in addition to diffuse CK8 and CK18 in the high grade, pleomorphic epithelioid foci [Figure 4]e]. CK expression was not identified in the low-grade spindle cell component [Figure 4]f].
|Figure 1: GIST from patient 9 with areas of hemorrhage (H) and necrosis (N) extending from the stomach into the spleen (S)|
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|Figure 2: Pleomorphic, spindle (a) and epithelioid (b) Cell components of GISTs from patients 4 and 10, respectively [480×, hematoxylin and eosin] demonstrating CD34 (c, e) and CD117 (d, f) immunopositivity. GIST from patient 9 demonstrating low grade spindle (g) and high grade epithelioid (h) Cell components [480×, hematoxylin and eosin]|
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|Figure 3: Pleomorphic spindle and epithelioid cell components of GIST from patients 4 and 10, respectively, demonstrating AE1-AE3 immunopositivity with paranuclear accentuation (a, b), MNF-116 (c, d) and CAM 5.2 immunopositivity with paranuclear accentuation (E, F)|
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|Figure 4: Pleomorphic spindle and epithelioid cell components of GIST from patients 4 and 10, respectively, demonstrating CK8 (a, b) and CK18 (c, d) Immunopositivity. GIST from patient 9 demonstrating AE1-AE3|
immunopositivity in high grade epithelioid cell component (e) and immunonegativity in low grade spindle cell component (f)
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Sufficient archival tissue for DNA isolation and adequately preserved DNA was available in five CK-positive GISTs. KIT mutations involving exon 11 were detected in all [Table 5]. Mutations were not detected in KIT exons 9, 13, 17 or PDGFRA exons 12, 14 or 18.
|Table 5: Cytokeratin – positive gastrointestinal stromal tumor: Differential diagnosis|
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| Discussion|| |
Although traditionally associated with epithelial tumors, CK expression in a variety of other neoplasms, including those of mesenchymal lineage are currently well-recognized. These include leiomyosarcoma,  angiosarcoma,  Ewing sarcoma/primitive neuroectodermal tumor  and alveolar rhabdomyosarcoma.  GISTs may occasionally show CK immunoreactivity [Table 1]. While Sarlomo-Rikala et al. demonstrated AE1 (CKs 10, 14, 15, 16, and 19) immunonegativity in all of 15 GISTs studied,  and 2 reviews on GISTs reported AE1-AE3 immunonegativity. , Lopes and colleagues recently reported a series of 24 GISTs with anomalous expression of CK with variable qualitative pan-CK (AE1-AE3) expression.  The majority (14/24: 58%) exhibited weak staining and 3/24 (13%) showed strong immunopositivity. None of the tumors were positive for low molecular weight CK (CAM 5.2). All 10 CK-positive GISTs in the present study expressed low molecular weight CK (CAM 5.2 and MNF-116) with diffuse staining in 9. In addition, 7/10 GISTs showed AE1-AE3 immunoreactivity, with diffuse staining in 6. Hence, 7/10 tumors were AE1-AE3 and CAM 5.2 immunopositive. A similar finding has been documented in a gastric GIST. 
Only three prior studies have documented individual CK polypeptide expression in GISTs. ,, In an investigation on anorectal mesenchymal tumors, CK 18 immunopositivity was confirmed in 2 of 57 cases.  This study did not investigate broad-spectrum CK expression. In their study cohort of 15 CK-positive GISTs, Sarlomo-Rikala et al. identified CK8 and CK18 in 5 and 15 GISTs, respectively, without coexpression of CK7, 14, 19, or 20.  In contrast, Lopes and colleagues demonstrated consistent CK8 immunonegativity in all GISTs, but documented a single GIST with CK14 immunopositivity; to date, this remains the only GIST in the literature with expression of a high molecular weight CK.  CK7 and CK20 were also negative and CK18 was not evaluated. Our study revealed CK8 expression in all cases (nine diffuse, one focal) and diffuse CK18 expression in nine cases. All cases were negative for CKs5, 6, 7, 14, 17, 19, and 20.
The Dakopatts manufactured AE1-AE3 antibody (Glostrup, Denmark) utilized in the present study reacts with type 1 CKs10, 13, 14, 15, 16, 19 (AE1 clone) and type 2 CKs1, 2, 3, 4, 5, 6, 7, and 8 (AE3 clone). The presence of CK8 in the antibody cocktail is the favored explanation for reactivity with this antibody. A similar explanation may account for immunopositivity with antihuman CK MNF116 (Dakopatts, Glostrup Denmark) and CAM 5.2 (BD Biosciences, San Jose, California, USA) that reacts with intermediate and low molecular weight CKs5, 6, 8, 17, 19 and CKs7 and 8, respectively. Although the latter antibody produced by BD Biosciences (San Jose, California, USA) was initially considered to react with CK8 and 18, the revised data sheet indicates primary reactivity with CK8 and a weaker but distinct reactivity with CK7.  Although AE1-AE3 and CAM 5.2 antibodies recognize CK8, the differential expression in CK-positive GISTs is interpreted as a lower affinity for CK8 by the CK cocktail, AE1-AE3, as posited for hepatocellular carcinoma.  All tumors were negative for high molecular weight keratin antibody clone 34βE12 that recognizes CKs1, 5, 10, and 14.
In the present study, all GISTs with CK expression were high risk for aggressive behavior.  In four patients, the initial diagnosis was made on specimens from metastatic sites, including the liver (two), anterior abdominal wall (one), and iliac fossa (one). Similarly, all case reports of CK-positive GISTs were also high risk for aggressive behavior characterized by metastases at varied locations including the liver (three), pleura (one), right iliac fossa (one), and lymph node (one). ,,,,, Sarlomo-Rikala et al. purported that malignant GISTs were more often positive for CK than their benign counterparts.  In their series, 8/12 CK-positive GISTs were classified as malignant at follow up.  These findings suggest that CK expression in GISTs may be a phenomenon related to tumor progression, similar to meningioma where CKs are preferentially expressed in high grade tumors  and malignant melanoma where CK positivity is seen more often in metastatic rather than primary melanoma.  The theory of tumor progression is further supported in this study by the GIST from patient 9 with a biphasic histopathological growth pattern that demonstrated CK immunonegativity in the low-grade spindle areas (primary growth pattern) and diffuse CK immunopositivity in the high-grade pleomorphic epithelioid sarcomatous areas (secondary growth pattern). The high grade secondary growth pattern in biphasic GIST is hypothesized to reflect histomorphological progression, which is associated with increasing chromosomal instability or sequential chromosomal alterations.  Antonescu et al. documented a similar phenomenon in their series of eight dedifferentiated GISTs where four demonstrated AE1-AE3 immunoreactivity in the anaplastic/pleomorphic dedifferentiated components, while the "conventional", low-grade spindle cell components were AE1-AE3 immunonegative. 
The exact pathogenesis of CK expression in mesenchymal tumors is unknown, but loose control of K8 and K18 genes is implicated.  In addition, transient expression of low molecular weight CKs8 and 18 has been observed in smooth and striated muscle cells during human embryogenesis  and transformed fibroblasts in cell culture.  Although speculative, it is possible that these low molecular weight CKs are aberrantly reexpressed in high grade GISTs in a similar fashion to other oncofetal antigens, as they are considered the most 'primitive' of the intermediate filament proteins and the first keratins to appear during embryogenesis.  The possibility that cross-reactivity with epitopes on non-CK protein/s that share partial homology with CKs may underpin CK expression in the present study is dismissed, as positive results were obtained with a range of different antibodies, including individual CKs8 and 18. Additionally, only one CK-positive GIST demonstrated patchy SMA positivity, nullifying the possibility that smooth muscle differentiation was responsible for CK expression in the remaining nine cases. Of six CK-positive GISTs with recorded mutational status, two demonstrated c-KIT mutations involving exon 11 with an insertional mutation at codon 558 and a hexanucleotide deletion spanning codons 558 to 560. , Five CK-positive GISTs that subjected to molecular profiling in the present study also contained c-KIT exon 11 mutations [Table 3], with deletions clustered between 1669_1704 (Lys550_Glu561), typical of exon 11 mutations and a substitution (Val559Asp) the most common missense mutation reported in c-KIT exon 11.  Hence, an altered molecular profile of the tested GISTs does not appear to drive anomalous CK expression, as the most commonly reported mutational "hot spots" and missense mutation in c-KIT exon 11 were identified.
The preeminence of CK expression in GISTs is the potential for misdiagnosis with other CK positive spindled and/or epithelioid cell neoplasms [Table 5]. The diagnostic complexity is multifold as endoscopic and trucut biopsies may yield limited material for histopathological evaluation of tumor architecture, while high grade pleomorphic tumor cells pose an additional difficulty, particularly when obtained from metastatic sites. GISTs demonstrating epithelioid morphology mimic carcinomas, typified and supported by CK expression, while spindle cell dominant GISTs mimic sarcomatoid/spindle cell carcinoma and sarcomas. The diagnostic difficulty is intensified in dedifferentiated GISTs that express CK with concomitant loss of CD117 and CD34 expression within their anaplastic/pleomorphic components.  Molecular profiling may also prove unhelpful as dedifferentiated GISTs may be wild type for both KIT and PDGFRA.  In this setting, identification of the 'conventional' well-differentiated spindle cell component is essential to avoid misdiagnosis.
Careful microscopic appraisal and CDX2, CK7 and CK20 immunohistochemistry will facilitate the identification of rare admixed collision tumors,  encompassing adenocarcinoma and GISTs. Awareness of paranuclear 'dot-like' CK accentuation and CD 56 immunopositivity is pivotal to avoid misdiagnosis of a neuroendocrine carcinoma that may be CD117 positive. , Intraabdominal CK-positive inflammatory myofibroblastic tumors (IMFTs) may simulate GIST,  but IMFTs contain a heterogeneous myofibroblastic spindle cell population, a variable lymphoplasmacytic infiltrate, are CD117 and CD34 immunonegative and anaplastic lymphoma kinase-1 immunopositive.  Malignant melanoma may demonstrate a variable infiltrate of CD117 immunoreactive spindle and/or epithelioid cells with aberrant CK expression, particularly in metastatic deposits. S-100 protein, HMB45 and Melan A immunopositivity and CD 34 immunonegativity will facilitate distinction from CK-positive GISTs. A CK-positive GIST mimicking epithelioid angiosarcoma with a solid growth pattern and CD34, CD117, and CK expression has been reported.  Absence of subtle clefting, autolumenation, immunoreactivity for CD31 and molecular investigations underpin diagnosis of CK-positive GIST. The expression of smooth muscle markers in GISTs may mimic leiomyoma and leiomyosarcoma. Hence, negative CD117 and CD34 immunostains are mandatory prior to leiomyosarcoma diagnosis. CK expression in malignant peripheral nerve sheath tumors and gastrointestinal schwannomas is postulated to represent cross-reactivity with glial fibrillary acid protein.  CD 117 negativity in both nerve sheath tumors aids in their distinction from CK-positive GISTs. CK-positive metastatic pleural GIST may mimic malignant mesothelioma.  A high index of suspicion for GIST and an extended immunopanel, including mesothelial and classic GIST markers, are helpful in this setting.
| Conclusion|| |
We highlight the occurrence, clinicopathological features and potential histopathological diagnostic pitfalls of 10 CK-positive GISTs, particularly in tumors with limited biopsy material from metastatic sites, unusual clinical presentations and high-grade, dedifferentiated or anaplastic morphology. We postulate that the exclusive expression of CKs in high risk/grade GISTs in the present study is a consequence of tumor progression. This theory emanates from and is strengthened, not only by our finding that all CK-positive GISTs were high-grade/risk tumors, but also by the biphasic GIST that was negative for CK in low-grade areas and diffusely CK positive in high-grade/pleomorphic areas, a finding that was also confirmed in four dedifferentiated GISTs reported by Antonescu et al.  We also confirm that CKs 8 and 18, the primary keratin pair of simple epithelial cells, are responsible for this phenomenon. In view of the increasing number of commercially available immunomarkers that react with CK8 and CK18, CK-positive GISTs must be differentiated from carcinomas, melanomas and a range of CK-positive sarcomas. Ultimately the integration of clinical, histopathological, and molecular findings should form the basis for diagnosis, to ensure optimal patient management and prognostication, especially in GISTs with unusual phenotypic or immunophenotypic features.
| Acknowledgments|| |
Mrs Mali Moodley for manuscript typing and literature retrieval, Mr D Sookhdeo and Mr C Sydney for laboratory work, Drs N Pillay and S Subrayan for collegial support and the NHLS management for support of research initiatives. This project has been approved by the Biomedical Research Ethics Committee of the University of Kwa-Zulu Natal, protocol number PG019/09.
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Department of Anatomical Pathology, Level 3, Laboratory Building, Inkosi Albert Luthuli Central Hospital, 800 Bellair Road, Mayville, 4058, KwaZulu-Natal
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]