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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e318248bd97
Letters to the Editor

MUC1 Immunoexpression is a Virtually Constant Feature of Clear Cell Renal Cell Carcinoma Metastatic to the Pancreas

Pająk, Jacek MD, PhD*; Liszka, Łukasz MD*; Mrowiec, Sławomir MD, PhD; Gołka, Dariusz MD, PhD*,‡; Lampe, Paweł MD, PhD

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*Departments of Histopathology

Gastrointestinal Surgery, Medical University of Silesia, Katowice, Poland

Department of Pathology, Blackpool Teaching Hospitals, Blackpool, UK

The authors have no funding or conflicts of interest to disclose.

To the Editor:

We read with great interest a review paper of Dr Sangoi and coauthors on the usefulness of immunohistochemical stains in the diagnosis of metastatic clear cell renal cell carcinoma (CC-RCC) published in one of the recent issues of Advances in Anatomic Pathology.1 We really appreciate this paper and previous works of the authors2–4 regarding the issue of CC-RCC. We find these contributions very useful in our diagnostic practice as they contain well-balanced and evidence-based practical recommendations.

However, we would like to draw attention of the authors and the readers to 1 selected aspect of diagnosis of metastatic CC-RCC described in the aforementioned review, namely the relevance of application of MUC1 immunostain in differential diagnostics of neoplasms of the pancreas composed of clear cells.

Authors of the review stated1 that MUC1 [along with carcinoembryonic antigen (CEA) and cytokeratin 7 (CK7)] may be used to distinguish between metastatic CC-RCC of the pancreas and primary pancreatic ductal adenocarcinoma (PDAC), as MUC1 is “not typically immunoreactive in CC-RCC,” in contrast to PDAC. We have found a similar statement on CEA and MUC1 (but not CK7) in CC-RCC in the AFIP reference book on pancreatic neoplasms (p. 328).5 Primary publications, which Dr Sangoi and coauthors and the authors of the AFIP book refer to (Adsay et al,6 Luttges et al,7 and Adsay et al,6 respectively), are devoted to PDAC with clear cells but not to CC-RCC metastatic to the pancreas itself.

As in our anecdotal experience metastatic CC-RCC of the pancreas may in fact be MUC1-positive, we reviewed the literature on that issue and performed an immunohistochemical study on a series of CC-RCC metastatic to the pancreas using 2 commercially available MUC1 antibodies.

Metastatic CC-RCC represents a complicated clinical issue with many questions yet unanswered.8,9 The diagnosis of CC-RCC metastatic to the pancreas versus PDAC in a biopsy or resection specimen is therefore clinically relevant, as it may affect the decision on the type and extent of surgical procedures and the postoperative treatment. MUC1 is a transmembrane glycoprotein involved in signal transduction.10 PDAC is well known for its MUC1 immunopositivity.11 In contrast, MUC1 expression in CC-RCC seems to be a more complex issue. Results of several studies on MUC1 profile in CC-RCC are difficult to compare and to generalize as they were based on different populations, primary antibodies, staining protocols, and interpretation criteria.12–17 However, available data indicate that the MUC1 profile in CC-RCC is not only pathogenetically related to VHL gene alterations, which are common findings in those cancers, but it may also be correlated with the tumor stage10,13,15 and even have a prognostic value in CC-RCC patients.13,15–17

Data on the MUC1 profile in metastatic CC-RCC are scarce, in comparison with primary renal tumors. Dr Leroy and coauthors showed that MUC1 immunopositivity was a very frequent finding in metastatic CC-RCC (19 of 22 studied cases were positive).18 Unfortunately, no case of CC-RCC metastatic to the pancreas was included in that study.

Ten cases of resected CC-RCC metastatic to the pancreas stored in our departmental archives and diagnosed between 1994 and 2008 were available for the present study. Basic clinicopathologic data on these patients are presented in Table 1. Four-micrometer-thick sections were cut from the representative paraffin blocks of the tumoral tissue (a single block per case). After deparafinization and rehydratation performed in a standard manner, the slides were subjected to immunohistochemical stains in an automated machine (Dako, Carpinteria) as described in Table 2. In addition to MUC1, CEA, and CK7 stains were performed. A mouse monoclonal CEA antibody that we implemented here was previously proven to be useful in differential diagnostics of CC-RCC and PDAC.19

Table 1
Table 1
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Table 2
Table 2
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Membranous circumferential and/or cytoplasmic but not apical MUC1 staining was considered positive, as it was proposed13 and applied by other investigators.13,17,18

Both MUC1 antibodies showed very similar results in the context of extent and intensity of staining. Membranous circumferential reactions were observed in all studied cases of metastatic CC-RCC (10/10). The extent of staining varied from 30% up to 100% of cells (Figs. 1A–C). In 2 cases, we noticed a dominant distribution of the strong staining in close proximity to vessels within the tumoral tissue (Figs. 1D–F), similar to the results of Dr Leroy and coauthors.18 In other cases, there was a prevailing diffuse strong staining throughout the tumoral tissue, with an exception of a single case that showed a heterogeneous intensity of stain but rather random in its distribution and not centralized in perivascular areas (not shown). Cytoplasmic staining was seen focally (up to 10% of cells) in 2 cases (Figs. 1A–C). All cases were CEA-negative (not shown). CK7 immunostain was positive only in a single (1/10) case, which showed weak membranous reaction in <5% of cells (not shown).

Figure 1
Figure 1
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We conclude that MUC1 does not seem to be an adequate marker for differential diagnostics of CC-RCC metastatic to the pancreas and PDAC. CEA and CK7 stains seem to be considerably better, although not ideal alternatives (the issue of CK7-positivity in CC-RCC was beyond the scope of our study and it has been recently discussed elsewhere20,21). However, studies on new markers that would be positive in CC-RCC but negative in PDAC are needed. Moreover, MUC1 immunostain may be potentially useful in prognostication of patients with metastatic CC-RCC or for selection of patients with CC-RCC for treatment protocols with a novel MUC1-based cancer vaccine.22

Jacek Pająk, MD, PhD*, Łukasz Liszka, MD*, Sławomir Mrowiec, MD, PhD†, Dariusz Gołka, MD, PhD*‡, Paweł Lampe, MD, PhD†

*Departments of Histopathology

†Gastrointestinal Surgery, Medical University of Silesia, Katowice, Poland

‡Department of Pathology, Blackpool Teaching Hospitals, Blackpool, UK

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REFERENCES

1. Sangoi AR, Karamchandani J, Kim J, et al. The use of immunohistochemistry in the diagnosis of metastatic clear cell renal cell carcinoma. A review of PAX-8, PAX-2, hKIM-1, RCCma, and CD10. Adv Anat Pathol. 2010;17:377–393

2. Sangoi AR, Fujiwara M, West RB, et al. Immunohsitochemical distinction of primary adrenal cortical lesions from metastatic clear cell renal cell carcinoma: a study of 248 cases. Am J Surg Pathol. 2011;35:678–686

3. Gokden N, Gokden M, Phan DC, et al. The utility of PAX-2 in distinguishing metastatic clear cell renal cell carcinoma from its morphologic mimics: an immunohistochemical study with comparison to renal cell carcinoma marker. Am J Surg Pathol. 2008;32:1462–1467

4. Sangoi AR, Karamchandani J, Lane B, et al. Specificity of brachyury in the distinction of chordoma from clear cell renal cell carcinoma and germ cell tumors: a study of 305 cases. Mod Pathol. 2011;24:425–429

5. Hruban RH, Pitman MB, Klimistra DS AFIP Atlas of Tumor Pathology Tumors of the Pancreas Fourth series, Fascicle 6. 2007 Washington American Registry of Pathology/American Forces Institute of Pathology

6. Adsay V, Logani S, Sarkar F, et al. Foamy gland pattern of pancreatic ductal adenocarcinoma: a deceptively benign-appearing variant. Am J Surg Pathol. 2000;24:493–504

7. Lüttges J, Vogel I, Menke M, et al. Clear cell carcinoma of the pancreas: an adenocarcinoma with ductal phenotype. Histopathology. 1998;32:444–448

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9. Konstantinidis IT, Dursun A, Zheng H, et al. Metastatic tumors in the pancreas in the modern era. J Am Coll Surg. 2010;211:749–753

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12. Cao YI, Karsten U, Zerban H, et al. Expression of MUC1, Thomsen-Friedenreich-related antigens, and cytokeratin 19 in human renal cell carcinomas and tubular clear cell lesions. Virchows Arch. 2000;436:119–126

13. Fujita K, Denda K, Yamamoto M, et al. Expression of MUC1 mucins inversely correlated with post-surgical survival of renal cell carcinoma patients. Br J Cancer. 1999;8:301–308

14. Leroy X, Copin MC, Devisme L, et al. Expression of human mucin genes in normal kidney and renal cell carcinoma. Histopathology. 2002;40:450–457

15. Kraus S, Abel PD, Nachtmann C, et al. MUC1 mucin and trefoil factor 1 protein expression in renal cell carcinoma: correlation with prognosis. Hum Pathol. 2002;33:60–67

16. Langner C, Ratschek M, Rehak P, et al. Expression of MUC1 (EMA) and E-cadherin in renal cell carcinoma: a systematic immunohistochemical analysis of 188 cases. Mod Pathol. 2004;17:180–188

17. Leroy X, Zerimech F, Zini L, et al. MUC1 expression in correlated with nuclear grade and tumor progression in pT1 renal clear cell carcinoma. Am J Clin Pathol. 2002;118:47–51

18. Leroy X, Aubert S, Ballereau C, et al. Diffuse expression of MUC1 in metastases of renal clear cell carcinoma as a possible therapeutic target for renal cancer. Histopathology. 2005;47:435–436

19. Kaufmann O, Deidesheimer T, Muehlenberg M, et al. Immunohistochemical differentiation of metastatic breast carcinomas from metastatic adenocarcinomas of other common primary sites. Histopathology. 1996;29:233–240

20. Truong LD, Shen SS. Immunohistochemical diagnosis of renal neoplasms. Arch Pathol Lab Med. 2011;135:92–109

21. Reuter VE, Tickoo SK. Differential diagnosis of renal tumours with clear cell histology. Pathology. 2010;42:374–383

22. Oudard S, Rixe O, Beuselinck B, et al. A phase II study of the cancer vaccine TG4010 alone and in combination with cytokines in patients with metastatic renal clear-cell carcinoma: clinical and immunological findings. Cancer Immunol Immunother. 2011;60:261–271

© 2012 Lippincott Williams & Wilkins, Inc.

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