An Immunophenotypic Comparison of Metanephric Metaplasia of ...

Anatomic Pathology / METANEPHRIC METAPLASIA OF BOWMAN CAPSULAR EPITHELIUM

An Immunophenotypic Comparison of Metanephric Metaplasia of Bowman Capsular Epithelium With Metanephric Adenoma, Wilms Tumor, and Renal Development A Case Report and Review of the Literature Edgar G. Fischer, MD, PhD,1* J. Aidan Carney, MD, PhD,1 Scott R. Anderson, MD,2* Edward C. Klatt, MD,3 and Donna J. Lager, MD1 Key Words: Metanephric metaplasia; Gastrointestinal stromal tumor; GIST; Carney triad; WT1; bcl-2; CD57 DOI: 10.1309/RCT9FVUMVN2UC2HB

Abstract Metanephric metaplasia of the parietal epithelium of the Bowman capsule is a rare pathologic finding of unknown pathogenesis that has occurred in patients with widespread malignant neoplasms of various types. We report this finding in a 25-year-old woman with partial expression of the Carney triad who died of a disseminated gastrointestinal stromal tumor, specifically a gastric stromal sarcoma. The metaplasia involved both kidneys diffusely. It originated in the parietal epithelium of the Bowman capsule, extended into the proximal tubules, and focally surrounded the glomeruli in a semicircular manner. Immunohistochemical analysis revealed that the cells of metanephric metaplasia expressed the Wilms tumor gene product, bcl-2 protein, and CD57 and cytokeratin 7 and keratin AE1/AE3 focally, but not CD56. This immunophenotype parallels that of metanephric adenoma, Wilms tumor, and nephrogenic rests and overlaps with antigen expression in certain periods of renal development.

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Am J Clin Pathol 2004;121:850-856 DOI: 10.1309/RCT9FVUMVN2UC2HB

Metaplasia of the parietal epithelium of the Bowman capsule is a rare finding. Initial descriptions of this lesion date from the late 19th century. 1,2 In 1882, Sharkey 2 described the case of a 28-year-old woman with ovarian carcinoma and liver metastases. At autopsy, the normally flat epithelium of the Bowman capsule was replaced by tall columnar cells that extended into the proximal tubules.2 Sharkey2 interpreted this finding as “growth of cancer cells from the epithelium of the malpighian tufts and tubules.” Subsequently, 13 additional cases with similar findings have been reported.1,3-14 Autopsy examination revealed that almost all patients had widespread malignant neoplasms involving the liver primarily or secondarily ❚Table 1❚. Epithelial changes of the Bowman capsule also have been reported in patients with end-stage renal disease who were undergoing long-term dialysis. Hughson et al15 reported 40 such cases and referred to the glomerular changes as “embryonal hyperplasia.” Epithelial clusters surrounded obsolescent glomeruli and compressed adjacent tubules, and the process had superficial resemblance to crescentic glomerulonephritis.15 de Silva et al16 described a patient with embryonal hyperplasia of the parietal glomerular epithelium and a metanephric adenoma in the same kidney and suggested a possible pathogenetic relationship between these uncommon lesions. The Carney triad is a rare syndrome characterized by gastric stromal sarcoma, pulmonary chondroma, and extraadrenal paraganglioma.17 Only 80 cases have been reported. In the majority of patients, only 2 of the 3 lesions develop, ie, partial expression of the syndrome. Renal morphologic abnormalities have not been described in the Carney triad. We describe a case of metanephric metaplasia of the parietal epithelium of the Bowman capsule in a 25-year-old © American Society for Clinical Pathology

Anatomic Pathology / CASE REPORT

❚Table 1❚ Survey of All Published Cases With Metanephric Metaplasia of the Parietal Glomerular Epithelium Sex/Age (y)*

Underlying MaligLiver nant Neoplasm Metastases

F/28

Ovarian carcinoma

Yes

M/16

Malignant epithelial tumor Carcinoma, gallbladder

Yes

F/54

Yes

M/16

Adrenal tumor, most likely adrenal cortical carcinoma

Yes

M/66

Carcinoma, esophagus

Yes

F/6 mo

Primary carcinoma, liver; NR distant metastases

M/34

Hepatocellular carcinoma; cirrhosis; gynecomastia Carcinoma, breast; widely metastatic disease

NR

F/63

Cholangiocarcinoma, liver

NR

F/47

Gallbladder carcinoma

Yes

F/63

Squamous cell Yes carcinoma, esophagus

M/5 wk

Hepatoblastoma (single NR 7-cm tumor nodule, no metastases)

M/21

Adrenal cortical carcinoma; chemotherapy

Yes

F/17

Primitive neuroectodermal tumor, lung; chemotherapy

No

F/25

Gastric stromal sarcoma; Yes Carney triad; chemotherapy

F/74

No

Bowman Capsule Parietal Epithelium

Histologic Features and Immunophenotype

“Earliest steps in develop- Deeply stained columnar cells, ment of new growth” several layers; tubules also involved “Increased cellular mass Deeply stained columnar cells, indicated new formation” several layers; oval nuclei Adenomatoid Columnar cells, up to 3 layers; transformation oval hyperchromatic nuclei; almost all glomeruli involved; focal extension into tubules Adenomatoid changes Columnar cells, single layer; deeply stained nuclei; 50%75% of glomeruli involved; focal papillary formations; focal extension into tubules Metaplasia of capsule NR

Author Conclusion

Reference

Cancer cell growth from Sharkey,2 1882 epithelium of malpighian tufts and tubules Primary carcinoma of Abram,1 1899 kidney arising in glomeruli Seems to be diffuse Eisen,4 1946 neoplastic change; significance obscure Metaplasia, in unknown way indirectly brought about by cancer

Chapell and Phillips,3 1950

Due to chronic narcotic Kanisawa and intoxication Isono,7 1961 Metaplasia or adenoma- Columnar cells, up to 3 layers; May represent response Nachman,11 toid transformation ovoid nuclei; 75% of of parietal layer in variety 1962 glomeruli involved; often of diseases; possibly extension into tubules related to liver disease Metaplasia or Columnar cells, up to 3 layers; Possible relationship with Sugimoto et adenomatous almost all glomeruli involved; carcinoma or liver al,14 1962 hyperplasia focal extension into tubules disease Metaplasia Stratified columnar cells; Cause of metaplastic MacPherson,9 prominent basophilic nuclei; change remains unknown 1963 70% of glomeruli involved; focally involving tubules Adenomatoid change Cubical or cylindrical cells; oval Pathogenesis and Eulderink,5 1964 hyperchromatic nuclei; significance obscure; almost all glomeruli involved; diffuseness of lesion focally involving tubules suggests humoral effect Columnar metaplasia Columnar cells, up to 3 layers; Hormonal or metabolic Rios-Dalenz,13 ovoid nuclei; 40%-50% of derangement, associated 1966 glomeruli involved with advanced neoplasm with or without liver involvement Metaplasia Tightly packed columnar cells, Multiple metastases to Reidbord,12 up to 3 layers; oval nuclei; kidneys most probable 1968 20%-30% of glomeruli explanation; alternatively, involved; focally small humoral agent of glandular lumens and neoplastic origin papillary fronds Adenomatoid Primitive, mainly columnar May be manifestation of Knowlson and epithelium epithelium; 50% of glomeruli aberrant development Cameron,8 involved, involving tubules 1979 focally with double entrance at urinary pole Adenomatoid metaplasia Columnar cells; pseudoDifferent from changes Grignon and stratification; up to 90% of occurring in end-stage Eble,6 1993 glomeruli involved; focally kidney disease involving tubules Adenomatoid hyperplasia Immature columnar cells; focal Consequence of paraneo- Mikami and stratification; focally involving plastic humoral disorder Manabe,10 tubules; CAM 5.2+, CD99– or growth factor–type 2000 substance Metanephric metaplasia Columnar cells, commonly Immunophenotype Present case involving tubules; WT1+, parallels that of metaCD57+, and bcl-2+; focally nephric adenoma, Wilms CK7+ and AE1/AE3+; CD56– tumor, nephrogenic rests, and renal development

CAM, cellular adhesion molecule; CK, cytokeratin; NR, not reported; WT1, Wilms tumor gene product; +, positive; –negative. * Unless otherwise indicated.

woman. The patient had manifested partial expression of the Carney triad and died of a metastatic gastrointestinal stromal tumor, specifically a gastric stromal sarcoma, with massive hepatic metastases. The metaplastic process is identical morphologically to the previously described cases of

adenomatoid metaplasia (Table 1).1-14 Immunohistochemical characterization of the metaplastic cells revealed expression of the Wilms tumor gene product (WT1), bcl-2 protein, and CD57 and focal expression of cytokeratin 7 (CK7) and keratin AE1/AE3, but no staining for CD56. This Am J Clin Pathol 2004;121:850-856

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DOI: 10.1309/RCT9FVUMVN2UC2HB

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Fischer et al / METANEPHRIC METAPLASIA OF BOWMAN CAPSULAR EPITHELIUM

immunoprofile is identical to that of metanephric adenoma, Wilms tumor, and nephrogenic rests.18

Case Report The patient was a 25-year-old woman who at age 20 years complained of urinary urgency, frequency, and dysuria. A paraganglioma of the urinary bladder was removed cystoscopically. At the age of 22 years, she had complaints of epigastric fullness. Abdominal ultrasound and computed tomography revealed a 9-cm midline mass and multiple liver metastases. The mass, which was attached to the stomach by a stalk, was resected. Pathologically, it proved to be a gastric stromal sarcoma. Subsequently, the patient underwent 5 cycles of chemotherapy with mesna, doxorubicin, ifosfamide, and dacarbazine. She received granulocyte colonystimulating factor for neutropenia and was given thalidomide orally for 1 year. There was some stabilization of disease progression during chemotherapy but no decrease in disease extent. At age 25 years, she had massive hematemesis originating from ulcerations of the gastric mucosa caused by recurrent tumor. Attempts to control bleeding failed, and the patient died 4 days after admission. An autopsy was performed with family consent.

Materials and Methods Immunohistochemical stains were performed as previously described.18 Pathologic Findings The paraganglioma of the urinary bladder was less than 1 cm in greatest diameter. It had the “Zellballen” architecture characteristic of paraganglioma and was diffusely positive for chromogranin (data not shown). The gastric stromal sarcoma had spindle cell morphologic features and was immunoreactive for c-kit (CD117; data not shown). At autopsy, multiple sarcoma nodules involved the stomach, liver, peritoneum, diaphragm, pericardium, periaortic lymph nodes, and ovaries. Microscopic metastasis was present in 1 kidney. The liver weighed 6,030 g and was replaced by tumor masses that distended the abdomen and caused compression of the lungs. Microscopically, kidney sections showed bilateral diffuse metanephric metaplasia of the parietal epithelium of the Bowman capsule, involving more than 99% of the glomeruli ❚Image 1A❚. The normally flat epithelium was replaced by small cuboidal to low columnar epithelial cells. These cells had little cytoplasm and oval nuclei with fine chromatin ❚Image 1B❚, ❚Image 1C❚, and ❚Image 1D❚. In some 852 852


glomeruli, the metaplastic cell layer extended along the basement membrane across the urinary pole into the proximal convoluted tubule (Image 1B). In other glomeruli, the process was more extensive and formed clusters of small tubular structures surrounding the glomeruli in a semicircular arrangement, supported by a basement membrane (Images 1C and 1D). Although involvement of the parietal epithelium was striking and diffuse, the visceral glomerular epithelium was spared completely. Immunohistochemical stains showed nuclear staining of the metaplastic cells for WT1 and strong staining of the podocyte cytoplasm ❚Image 2A❚. An antibody against bcl-2 protein strongly stained the metaplastic cell cytoplasm ❚Image 2B❚. There was strong expression of CD57 ❚Image 2C❚ and focal cytoplasmic expression of CK7 ❚Image 2D❚ and keratin AE1/AE3 (data not shown) by occasional single metaplastic cells. Stains for CD56, vimentin, and estrogen, progesterone, and androgen receptors were negative (data not shown).

Discussion We report the case of a 25-year-old woman with partial expression of the Carney triad, manifested by gastric stromal sarcoma and extra-adrenal paraganglioma of the urinary bladder, who died of disseminated stromal sarcoma. Autopsy revealed the unexpected finding of diffuse metanephric metaplasia of the parietal epithelium of the Bowman capsule. This finding is morphologically identical to the rare metaplasia that has been described in 14 cases during the past 120 years (Table 1).1-14 Our case is the first with the combination of this rare metaplasia and the Carney triad. It also is the first case with a disseminated sarcoma as the underlying malignant neoplasm. Of the previously reported cases, 13 had carcinomas and 1 had a primitive neuroectodermal tumor. We report the first comprehensive immunophenotypic characterization of the metaplastic cells; we found that the immunoprofile and the cytomorphologic features of metanephric metaplasia parallel those of metanephric adenoma, Wilms tumor, nephrogenic rests, and renal development. We therefore prefer the designation metanephric metaplasia over adenomatoid metaplasia or adenomatoid hyperplasia, the terms used in previous reports (Table 1). Review of the published cases and the present case revealed that 13 of 15 patients had an extensive primary liver tumor (hepatocellular carcinoma, cholangiocarcinoma, or hepatoblastoma) or a metastatic malignant neoplasm involving the liver. The male/female ratio was 1:1.5. More than half the patients (8 of 15) were younger than 30 years (Table 1), and almost all patients older than 30 years (6 of 7) had carcinomas of the hepatobiliary tract or esophagus. © American Society for Clinical Pathology


A

B

C

D

❚Image 1❚ A, Kidney sections show diffuse involvement of glomeruli by metanephric metaplasia (H&E, original magnification ×20). B, Higher magnification reveals glomeruli involved by metaplastic changes of various morphologic stages. Cuboidal to columnar cells with oval nuclei replace Bowman capsular epithelium and extend across the urinary pole into the proximal tubule (periodic acid–Schiff, original magnification ×400). C and D, Multiple tubular cross-sections are involved by metanephric metaplasia and surround the glomeruli in a semicircular arrangement (C and D, periodic acid–Schiff, original magnification ×400).

Although the metaplastic changes in the kidneys were diffuse and striking in all cases, there was no impairment of renal function. The remarkably rare occurrence of metanephric metaplasia suggests that some unknown factor operating in association with an advanced malignant neoplasm might be necessary for its development. An endocrine factor is suggested by the female predominance among the patients and the presence of liver cirrhosis with gynecomastia in 1 man.14 Other etiologic considerations include a metabolic abnormality or circulating humoral factor that causes a paraneoplastic process in patients with an advanced neoplasm and liver metastases.5,10,13

It is tempting to speculate that the liver, compromised by metastatic tumor, might be unable to correct this hypothetical metabolic abnormality or fail to clear a circulating humoral factor. The site and type of the primary tumor in the affected patients has been diverse.6 Grignon and Eble6 noted that the metaplasia has not been reported in association with common malignant neoplasms (eg, colorectal carcinoma) that have a propensity for liver metastasis and occur with a high prevalence in the general population. Another possible cause is exuberant repair after epithelial damage in the context of an advanced malignant neoplasm. Am J Clin Pathol 2004;121:850-856



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A

B

C

D

❚Image 2❚ A, Immunohistochemical staining of metanephric metaplasia of Bowman capsular epithelium demonstrates positivity of metaplastic cell nuclei for Wilms tumor gene product (WT1) in addition to strong cytoplasmic staining of podocytes (WT1, original magnification ×400). The metaplastic cells also express bcl-2 protein (B, original magnification ×400) and CD57 (C, original magnification ×400) and express cytokeratin 7 focally (D, original magnification ×400).

Our patient had the Carney triad as a genetic syndrome, which is associated with the development of gastric stromal sarcoma. Therefore, this is the first reported case with metanephric metaplasia arising in the context of a genetic cancer syndrome. One pediatric patient had a congenital hepatoblastoma and adenomatoid metaplasia.8 Interestingly, more than half (8 of 15) of the patients were younger than 30 years, which raises the question whether they might have in common a genetic susceptibility to the development of malignant neoplasms, particularly of pediatric tumors, or to the development of “adult” tumors at an unusually young age. 854 854


Immunohistochemical analysis revealed that the metaplastic parietal epithelium of the Bowman capsule expressed WT1, bcl-2 protein, and CD57 and focally expressed CK7 and keratin AE1/AE3, but not CD56. In a recent series of metanephric adenomas, Wilms tumors, and nephrogenic rests, expression of WT1, CD57, and CK7 but lack of CD56 in these lesions was found, and the authors concluded that these findings establish a relationship between metanephric adenoma and Wilms tumor.18 WT1 expression has been shown to activate the bcl-2 gene, and sporadic Wilms tumors coexpress WT1 and bcl-2 protein.19 Nephrogenic rests also express bcl-2 protein.20 Our results are remarkable in that the © American Society for Clinical Pathology


immunoprofile for 5 antigens (WT1, bcl-2, CD57, CK7, CD56) and the immature cytomorphologic features of metanephric metaplasia parallel those of metanephric adenoma, Wilms tumor, and nephrogenic rests. It is tempting to speculate that these similarities might indicate a biologic connection between the metaplastic process and the neoplasms, rather than being purely coincidental. One possible connection could be that metanephric metaplasia and these renal tumors arise from nephrogenic precursor cells that have matured beyond the stage at which Wilms tumor would develop.18 Furthermore, the WT1, bcl-2, CD57, and CK7 antigens are expressed in the developing human kidney in a temporally well-characterized manner. The WT1 tumor suppressor gene is essential for early renal development and is expressed in the condensed mesenchyme, the renal vesicle, and the early glomerulus.21 The bcl-2 protein is detectable in the Bowman capsule and proximal tubular epithelial cells of the embryonal kidney.22 CD57 is found during the 10th to 28th gestational week in the then columnar epithelium of the Bowman capsule and in the most proximal tubules.23 CK7 is expressed in the early fetal prospective renal pelvis, the renal papilla, and in the renal pelvis epithelium. 24 CD56 is detectable in immature blastema and in developing tubuloglomerular structures. It is absent in the adult kidney23 and in metanephric metaplasia and also is lacking in metanephric adenomas and Wilms tumors.18 Thus, the immunophenotype of metanephric metaplasia overlaps with that of certain periods of renal development. Hughson et al15 for the first time described morphologic glomerular changes in patients with end-stage kidney disease who were undergoing long-term dialysis. These lesions were designated “embryonal hyperplasia of Bowman’s capsule epithelium”15 and were composed of clusters of small cells with an undifferentiated appearance that surrounded obsolescent glomeruli. While the cytomorphologic features were similar to those of the cells in metanephric metaplasia described herein, several architectural features indicate that these lesions are distinct from metanephric metaplasia. These features include cell groups forming papillary structures and tubules surrounded by basement membrane–like material within the Bowman space. Furthermore, adjacent tubules were compressed but uninvolved by the hyperplastic process.15 By contrast, in our case, the metaplastic cells did not form larger cell groups within the Bowman space and extended into the proximal tubules (Image 1). Immunophenotyping performed on a single case of embryonal hyperplasia in end-stage kidney disease revealed positive staining for vimentin but not for cytokeratin or epithelial membrane antigen.25 Metanephric metaplasia is unlikely to be found in medical renal biopsies because it causes no apparent functional

abnormality. However, if encountered in such circumstances, it should prompt a clinical search for a malignant neoplasm. We report a case of bilateral diffuse metanephric metaplasia of the parietal epithelium of the Bowman capsule in a young woman with partial expression of the Carney triad and a widely metastatic gastric stromal sarcoma. The immunophenotype and cytomorphologic features of the metaplasia parallel that of metanephric adenoma and Wilms tumor and overlap with events during nephrogenesis. We propose that development of this metanephric metaplasia is related in some way to the presence of liver metastases. From the Departments of 1Laboratory Medicine and Pathology, Mayo Foundation, Rochester, MN; 2Pathology, University of Utah Health Sciences Center, Salt Lake City; and 3Biomedical Sciences, Florida State University, Tallahassee. Address reprint requests to Dr Lager: Dept of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. * Dr Fischer is currently with the Department of Pathology, University of New Mexico, Albuquerque; Dr Anderson is currently with the Hospital of the University of Pennsylvania, Philadelphia.

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13. Rios-Dalenz JL. “Columnar metaplasia” of renal glomerular capsular epithelium. J Indiana State Med Assoc. 1966;59:333337. 14. Sugimoto T, Ikeda T, Uchida E , et al. Adenomatous metaplasia of renal glomerular capsular epithelium associated with carcinoma of the liver. Jpn Heart J. 1962;3:617-620. 15. Hughson MD, McManus JF, Hennigar GR. Studies on “endstage” kidneys, II: embryonal hyperplasia of Bowman’s capsular epithelium. Am J Pathol. 1978;91:71-84. 16. de Silva K, Tobias V, Kainer G , et al. Metanephric adenoma with embryonal hyperplasia of Bowman’s capsular epithelium: previously unreported association. Pediatr Dev Pathol. 2000;3:472-478. 17. Carney JA. Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc. 1999;74:543-552. 18. Muir TE, Cheville JC, Lager DJ. Metanephric adenoma, nephrogenic rests, and Wilms’ tumor: a histologic and immunophenotypic comparison. Am J Surg Pathol. 2001;25:1290-1296. 19. Mayo MW, Wang CY, Drouin SS , et al. WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 protooncogene. EMBO J. 1999;18:3990-4003.

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20. Wunsch L, Flemming P, Gluer S. Expression of MIB and bcl-2 in patients with nephrogenic rests with and without associated Wilms’ tumors. Eur J Pediatr Surg. 2001;11:105109. 21. Pritchard-Jones K, Fleming S, Davidson D, et al. The candidate Wilms’ tumour gene is involved in genitourinary development. Nature. 1990;346:194-197. 22. Lu QL, Poulsom R, Wong L, et al. bcl-2 expression in adult and embryonic non-haematopoietic tissues. J Pathol. 1993;169:431-437. 23. Satoh F, Tsutsumi Y, Yokoyama S , et al. Comparative immunohistochemical analysis of developing kidneys, nephroblastomas and related tumors: considerations on their histogenesis. Pathol Int. 2000;50:458-471. 24. Moll R, Hage C, Thoenes W. Expression of intermediate filament proteins in fetal and adult human kidney: modulations of intermediate filament patterns during development and in damaged tissue. Lab Invest. 1991;65:7486. 25. Ogata K, Hajikano H, Sakaguchi H. So-called embryonal hyperplasia of Bowman’s capsular epithelium: an immunohistochemical and ultrastructural study. Virchows Arch A Pathol Anat Histopathol. 1991;418:143-147.

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