Adrenocortical tumor in a patient with familial adenomatous polyposis: A case associated with a complete inactivating mutation of the APC gene and unusual histological features

HUMAN PATHOLOGY

Volume 29, No. 3 (March 1998)

ADRENOCORTICAL TUMOR IN A PATIENT WITH FAMILIAL ADENOMATOUS POLYPOSIS: A CASE ASSOCIATED WITH A COMPLETE INACTIVATING MUTATION OF THE A P C GENE AND UNUSUAL HISTOLOGICAL FEATURES SHIGERUWAKATSUKI,MD, HIRONOBUSASANO,MD, PHD, TOMOKOMATSUI,MD, PHD, KAZUO NAGASHIMA,MD, PHD, TAKAYOSHITOYOTA,MD, PHI), AND AKIRAHORII, MD, PHD

Famih'al adenomatons polyposis (FAP) is an autosomal dominant hereditary disorder caused by a germline inactivating mutation of the adenomatons polyposis coli (APC) gene. Patients with FAP sometimes develop various exlracolonic manifestations including adrenocortical neoplasms. We present a 14-year-old boy with FAP who had an adrenocortical tumor with atypical histopathologic features, ie, sexcord-like differentiation. Immunohistochemical studies of adrenal 4 binding protein (Ad4BP) and steroidogenie enzymes showed the capacity of these tumor cells to produce steroids. Genetic analysis of the tumor disclosed a two-hit mutation in APC: a germline 5-base pair deletion accompanied by a loss of the normal allele. Because there were no reports of genetic alterations in adrenocortical tumors developed in FAP patients, we examined 10 sporadic adrenal tumors

(four carcinomas and six adenomas) for mutations in APC. However, no mutations were found in these 10 sporadic adrenal tumors. These results suggest that mutation of APC is also responsible for some fraction of the adrenocortical rumors: the tumor in this case is included. HUM PATnOL 29:302-306. Copyright © 1998 by W.B. Saunders Company Key words: adrenal tumor, familial adenomatons polyposis, the adenomatous polyposis coil gene. Abbreviations: FAP, familial adenomatous polyposis; APC, the adenomatons polyposis coli gene; Ad4BP, adrenal 4 binding protein; bp, base pair; PCR, polymerase chain reaction; PCR-SSCP, singiestrand conformation polymorphism analysis coupled with polymerase chain reaction; MCR, mutation cluster region.

Familial adenomatous polyposis (FAP) is a highly penetrant autosomal dominant disease characterized by development of hundreds of adenomatous polyps in the colorectnm in the second or third decade of life; the change is nearly 100% that one or more of the polyps will become malignant.l,2 The adenomatous polyposis coli (APC) gene was cloned as the gene responsible for FAP in 1991. 36 Patients with FAP have also been reported to develop various extracolonic manifestations that include desmoid tumors, 7-9 osteomas, tumors of the d u o d e n u m or periampulla, thyroid gland, 1° gastrointestinal tract, hepatobiliary system, n,12 and central nervous system. 13,14 FAP patients associated with osteomas or soft tissue lesions are referred to as having Gardner's syndrome, t°a5 However, genetic alterations of these extracolonic lesions have not been well characterized. Adrenocortical tumors have also been reported to occur in the patients with FAP. Our extensive literature search found 12 reported cases of FAP patients with adrenocortical tumors, 11 adenomas and 1 carcinoma. However, n o n e of them were analyzed for genetic alterations in APC. We recently experienced an adrenocortical tumor in a 14-year-old boy with FAP. We studied this adrenocorfical tumor immunohistochemically and genetically. Herein, we report results of our study of this tumor along with 10 additionally studied sporadic adrenocorfical neoplasms.

examination, the patient was diagnosed with FAP; adenomatons polyps of 5 m m or less in greater diameter were scattered throughout the colon. Abdominal computed tomagraphy scan and magnetic resonance imaging scan suggested the presence of a tumor of 6.5 cm in greater diameter in the right adrenal gland. Thorough clinical examinations revealed no other extracolonic manifestations. General laboratory and endocrinologic results were within normal ranges. The pat e n t underwent a right adrenectomy, and the postoperative course was uneventful. No recurrence of this adrenal tumor has been noted for 30 months after the surgery.

CASE REPORT The patient was an asymptomatic 14-year-old Japanese boy who underwent gastrointestinal evaluation because of his family history of colon cancer (Fig 1). After endoscopic

From the Departments of Molecular Pathology, Histopathology, and Internal Medicine III, Tohoku University School of Medicine, Sendai, Japan, the Department of Internal Medicine, Asahikawa Medical College, Asahikawa,Japan, and Department of Pathology, Hokkaido UniversitySchool of Medicine, Sapporo,Japan. Supported in part by the Japanese Ministries of Education, Science, Sports and Culture, and Health and Welfare, and by the Vehicle Racing Commemorative Foundation. Address correspondence and reprint requests to Professor Akira Horii, Department of Molecular Pathology,Tohoku UniversitySchool of Medicine, Sendai, 980-77,Japan. Copyright © 1998by W.B. SaundersCompany 0046-8177/98/2903-001658.00/0

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HISTOPATHOLOGIC FINDINGS

GrossFindings The adrenal tumor was surgically removed. The resected adrenal tumor was well circumscribed and encapsulated. It weighed 80g and measured 5.5 × 5.0 X 3.0 cm. Nonneoplastic and nonatrophic adrenal tissue was detected at the periphery of the capsule. The tumor seemed light brown on the cut surface and contained no loci of hemorrhage or necrosis.

HistologicalFindings The tumor was encapsulated and adjacent nonneoplastic adrenal gland was unremarkable (Fig 2A). The tumor was composed of polygonal cells that formed trabeculae a n d / o r islands (Fig 2B). Some of the cells formed glands or folliclelike structures (Fig 2B, 2C). Foam cells were present in the stroma or inside of these glands or follicle-like structures (Fig 2B, 2C). At high power magnification, prominent nucleoli were present in the tumor cells (Fig 2D). Nuclear grooves were not observed in the great majority of the tumor cells. No loci of necrosis, atypical mitosis, hemorrhage, capsular, or vascular invasion were detected. Among the nine histological criteria of adrenocortical malignancy proposed by Weiss et al, 16'17 only the architecture and cytoplasm were positive. Scattered loci of tumor ceils with eosinophilic or clear cytoplasm were also present.

Immunohistochemical Findings Immunohistochemistry of the steroidogenic enzymesls,19 and adrenal 4 binding protein (Ad4BP) ~° was performed in tissue sections of the specimens fixed in 10% formalin and

CASE STUDIES

Screening of Germline Mutation of APC in Patient and his Family Germline mutation of APC was screened by polymerase chain reaction (PCR) according to methods described previously. 1When we used the primer set for system 2 by Ando et aP (5'-ATGGGC&AGACCCAAACAC-3' and 5'-GTACTTTGATTCCTTGATTGTC-3'), an extra band was observed, a 5-basepair (bp) deletion at codon 1061 that would cause a truncation of the APC protein was suggested. We confirmed the 5-bp deletion by sequencing, as shown in Fig 3A. This mutation was also observed in the constitutional DNA of his mother, but not of his sister (data not shown). Thus, the patient and his mothel, but not his sister, were affected by FAR

colon cancer?

Screening of Somatic Mutation of APC in Tumors

4U

colon cancer?

14

16

FIGURE 1. A pedigree chart of the patient's family. The proband is indicated by an arrow. His mother, uncle, and grandfather all died from colon cancer (or suspected), suggesting that these three individuals were patients with FAP.Ages at death are also indicated.

We used this gerrnline 5-bp deletion for analysis of the second hit in specimens of patient's adrenal tumor as well as his mother's tumors. PCR amplifications with a primer set of system 2 were performed. Then the PCR products were r u n on 20% polyacrylamide gels and visualized by ethidium bromide staining. Typical examples of screening of the second hit are shown in Fig 3B. As shown in lane 3, two bands corresponding to the normal and mutated alleles were clearly seen in patient's constitutional DNA. However, in lane 4, the intensity of the upper band corresponding to the normal sequence of APC was very faint. These results indicated that the normal allele was lost in the tumor cells. No allelic loss was observed in his mother's tumors (data not shown). We further screened the second hit in his mother's tumors by singlestrand conformation polymorphism analysis coupled with polymerase chain reaction (PCR-SSCP) 23 in the mutation cluster region (MCR) 24 with primer sets described by Aoki et al, 25 but no mutation was detected.

Screening of Mutation of APC in Sporadic Adrenal Tumors embedded in paraffin, using the biotin-strept avidin amplified method. Details of immunostaining and characteristics of primary antibodies used were previously reported, ls-2° Immunoreactivities with P450c17 (17alpha-hydroxylase), P450c21 (21-hydroxylase), P450cll (1 lbeta-hydroxylase), and DHEA-ST (dehydroepiandrosterone sulfotransferase) were present in some tumor cells, but neither P450scc (cholesterol side chain-cleavage enzyme) nor 3[3-HSD (hydroxysteroid dehydrogenase) reactivitywas detected. Heterogeneity ofimmunoreactivity was observed, but Ad4BP immunoreactivitywas shown in the great majority of the tumor cells (Fig 2E). The immunolocalization of steroidogenic enzymes in nonneoplastic adrenal gland did not differ from that of normal adrenal cells. 1s,I9 GENETIC FINDINGS

Extraction of DNAs Genetic analysis in the present study was performed with the informed consent of the patient and his family. Constitutional DNAs of patient and his sister were prepared from peripheral white blood cells according to methods described previously.21 Tumor specimens of the patient's adrenal gland and his mother's colon polyps, cancers, and metastatic and normal lymph nodes were fixed in formalin and embedded in paraffin. Under a microscope, cells were microdissected and their DNAs were extracted according to methods described previously.22 DNAS of 10 patients with sporadic forms of adrenal tumor were also prepared from specimes fixed in formalin and embedded in paraffin.

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To elucidate the role of mutations of APC in adrenal tumors, we subsequently examined four adrenal cancers and six adrenal adenomas. All of them were sporadic cases, and we analyzed the MCR of the APC gene using PCR-SSCP method for the first screening. However, no mutations were detected in any of these tumors (data not shown).

DISCUSSION Adrenocortical tumors have been reported in patients with FAP as an extracolonic manifestation. The present case had two interesting features. First, previously reported cases of adrenocortical tumors associated with FAP have had all the classical morphological features of adrenocortical neoplasms (Table 1), but the adrenal tumor in the present study did not have any typical features of adrenocortical or steroidogenic tumors except for scattered loci of the cells with clear or eosinophilic cytoplasms. Not all of the enzymes involved in corticosteroidogenesis were expressed in the tumor, but the presence of Ad4BP, a transcription factor that plays roles in steroidogenesis 19 and in the development of adrenal cortex, 19 indicated that this tumor has the capacity to produce steroids, and thus was adrenocortical origin. Ad4BP has been recently shown as a good immunohistochemical marker for steroid producing tumors including adrenocortical tumor. 26Histological features found in this adrenocortical tumor have never been reported previously but resemble those of adrenocortical primordia and gonadal sex-cord stromal tumor. Adrenal

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FIGURE 2. Histopathologic and immunohistochemical features of the adrenocortical tumor. (A) T, tumor; A, adjacent adrenal cortex (original magnification × 75); M, medulla; C, capsule. The adjacent adrenal cortex was not atrophic, and the tumor was encapsulated. (B) Tumor cells formed follicular or nest-like structures (Hematoxylin & eosin staining; original magnification × 200). (C) Tumor cells formed glandular or trabecuiar like structures. Foam cells were present inside of these glandular structures or in the stroma (original magnification × 200). (D) High power magnification of the tumor cells. Prominent nucleoli were present in the tumor cells (original magnification ×400). (E) Immunohistochemistry of adrenal 4 binding protein (Ad4BP). The great majority of the tumor cells showed nuclear immunoreactivity for Ad4BP (original magnification ×200).

cortical primordia are known to originate fi'om the mesenchyme between the root of mesentery and the developing gonad, z7 Therefore, sex-cord stromal-like neoplasms theoretically might occur in this location, although such tumors have not been previously reported. The postoperative follow-up period is limited, but this tumor is considered to be benign according to the criteria of adrenocortical malignancy of Weiss et al. 16,17There was no evidence of the increased mitotic activity and cell atypia sometimes observed in malignant gonadal sex-cord stromal tumors. The other interesting feature of this case is the complete inactivation of the APC gene. Among extracolonic lesions associated with FAP, Iwama et als reported two mutations of the APC gene in desmoid tumors, but no mutations were

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detected in the H-ras, K-ras, and N-ras genes or in the p53 gene. Kurahashi et al lz reported that inactivation of both copies of APCis closely related to tumorigenesis of hepatoblastoma in FAP patients. In brain tumors which had developed in FAP patients (Turcot syndrome), no somatic mutations were detected. 14 As shown in Table 1, adrenal tumors in FAP patients developed at relatively younger ages; the patient in the present study was the youngest, only 14 years of age. The fact of a two-hit mutation in the APC gene may reflect an important role for APC in the development of this unique adrenal tumor, as has been postulated in desmoid tumors 7~ and hepatoblastomas. 11,12 There are very few reports of genetic alterations in extracolonic manifestations of patients with FAP. However,

CASE STUDIES

A

,

A

G

C

TABLE | .

A

T

G

G

T Case

Normal Allele

B

1

2

5'

3

Mutant Allele

Thirteen Cases of A d r e n a l Neoplasms Associated with FAP

Age

Sex

Description

1

36

F

Adenoma

2 3

36 17

F F

Adenoma Carcinoma

4 5 6

42 60 39

M M M

7 8 9

48 36 27

F M F

Adenoma Adenoma Bilateral Adenomas Adenoma Adenoma Adenoma

10 11 12

24 18 63

M M F

Adenoma Adenoma Adenoma

13

14

M

"Tumor

Clinical Diagnosis Adenomatous polyposis Gardner's syndrome Gardner's syndrome (Cushing's disease) Gardner's syndrome Gardner's syndrome Gardner's syndrome FAP FAP FAP with ovarian and thyroid carcinomas Gardner's syndrome FAP FAP with carcinoma of the thyroid and ampulla of Vater FAP

Reference No. 29 30 31 32 33 34 35 36 35 36 35 35

this case

Abbreviations:FAP, familial adenomatous polyposis.

4

REFERENCES

75 bp 70 bp

FIOURE3, Mutation analyses of the APC gene in DNA samples of peripheral blood cells and adrenal tumor of the patient, (A) Nucleotide sequencing analysis of the constitutional DNA of the proband. A 5 bp deletion at codon 1061 in the APC gene (boxed) was detected in the mutant allele. (B) Coexistence of somatic and germ-line mutations of the APC gene in the adrenal tumor. Lane 1, control DNA of a normal individual; Lane 2, negative control (without DNA); Lane 3, patient's constitutional DNA; Lane 4, DNA of the patient's adrenal tumor. Sizes of normal and mutant alleles (75 and 70 bp, respectively) were indicated by arrows on the right.

FAP p a t i e n t s s o m e t i m e s die o f e x t r a c o l o n i c m a n i f e s t a t i o n s . 2s T h e r e f o r e , it is v e r y i m p o r t a n t to e x a m i n e m u t a t i o n s o f A P C in t h e s e e x t r a c o l o n i c t u m o r s . I f we f o u n d t h a t two-hit m u t a tions of APC were responsible for m o s t o f the extracolonic m a n i f e s t a t i o n s , we w o u l d o b t a i n a b e t t e r u n d e r s t a n d i n g o f t u m o r i g e n i c p a t h w a y in t h e s e t u m o r s . I n t h e p r e s e n t study, we c o u l d n o t d e t e c t a n y s o m a t i c m u t a t i o n s in APC in s p o r a d i c adrenal tumors. However, the n u m b e r of t u m o r s a n d the r e g i o n e x a m i n e d w e r e limited. F u r t h e r i n v e s t i g a t i o n s a r e n e c e s s a r y to clarify t h e r o l e o f A P C in t h e p a t h o g e n e s i s o f adrenocortical neoplasms.

Acknowledgment. T h e a u t h o r s a r e g r a t e f u l to Dr. K o k i c h i K i k u c h i a n d Dr. M a s a a k i S a t o h ( S a p p o r o M e d i c a l University) f o r p r o v i d i n g s a m p l e s a n d to H i r o m i S h i w a k u a n d K a t s u h i k o O n o f o r t h e i r a s s i s t a n c e in p r e p a r a t i o n o f t h e m a n u s c r i p t . 305

1. Ando H, MiyoshiY,Nagase H, et al: Detection of 12 germ-line mutations in the adenomatous polyposis coli gene by"polymerase chain reaction. Gastroenterology 104:989-993, 1993 2. Utsunomiya J: The concept of hereditary colorectal cancer and the implication of its study, in Utsunomiya J and Lynch HT (eds): Hereditary Colorectal Cancer, Tokyo,Japan, Springer-Velag, 1990, pp 3-16 3. Kinzler KW, Nilbert MC, Su LK, et al: Identification ofFAl? locus genes from chromosome 5q21. Science 253:661-665, 1991 4. Nishisho I, Nakamura Y, MiyoshiY, et al: Mutations of chromosome 5-21 genes in FAYand colorectal cancer patients. Science 253:665-669, 1991 5. Joslyn G, Carlson M, ThliverisA, et al: Identification of deletion mutations and three new genes at the familial polyposislocus. Cell 66:601-613,1991 6. GrodenJ, Thliveris A, SamowitzW, et al: Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589-600, 1991 7. Okamoto M, Sato C, Kohno Y, et a]: Molecular nature of chromosome 5q loss in colorectal tmnors and desmoids from patients with familial adenomatous polyposis. Hum Genet 85:595-599, 1990 8. Miyaki M, Konishi M, Kikuchi-YanoshitaR, et al: Coexistence of somatic and germ-line mutations of APC gene in desmoid tumors from patients with familial adenomatous polyposis. Cancer Res 53:5079-5082, 1993 9. Scott RJ, Froggatt NJ, Trembath RC, et al: Familial infiltrative fibromatosis (desmoid turnouts) (MIM135290) caused by a recurrent 3' APC gene mutation. Hum Mol Genet 5:1921-1924, 1996 10. Bell B, Mazzaferfi EL: Familial adenomatous polyposis (Gardner's syndrome) and thyroid carcinoma: A case report and review of the literature. Dig Dis Sci 38:185-190, 1993 11. Oda H, ImaiY, Nakatsuru Y, et al: Somatic mutations of the APC gene in sporadic hepatoblastomas. Cancer Res 56:3320-3323, 1996 12. Kurahashi H, Takami K, Oue T, et al: Biallelic inactivation of the APC gene in hepatoblastoma. Cancer Res 55:5007-5011, 1995 13. Kropilak M, Jagelman DG, Fazio VW, et al: Brain tumors in familial adenomatons polyposis. Dis Colon Rectum 32:778-782, 1989 14. Mori T, Nagase H, Hofii A, et al: Germ-line and somatic mutations of the AYC gene in patients with Turcot syndrome and analysis of APC mutations in brain tumors. Genes Chromosom Cancer 9:168-172, 1994 15. Foulkes WD: A tale of four syndromes: Familial adenomatous polyposis, Gardner syndrome, attenuated AYC and Turcot syndrome. Q J Med 88:853-863, 1995 16. Weiss LM: Comparable histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. AmJ Surg Pathol 8:163-169, 1984 17. Weiss LM, Medeiros LJ, VickeryAL: Pathologic features of prognostic significance in adrenocorfical carcinoma. AmJ Surg Patho113:202-206, 1989 18. Sasano H: Localization of steroidogenic enzymes in adrenal cortex and its disorders. EndocrJ 41:471-482, 1994 19. Sasano H, Sato F, Shizawa S, et al: Immunolocalization of dehydroepiandrosterone sulfotransferase in normal and pathologic human adrenal gland. Mod Pathol 8:891-896, 1995 20. Sasano H, Shizawa S, Suzuki T, et al: Ad4BP in the human adrenal cortex and its disorders.J Clin Endocrinol Metab 80:2378-2380, 1995

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21. Baas F, Bikker H, van Ommen GJ, et al: Unusual scarcity of restriction site polymorphism in the human thyroglobulin gene. A linkage study suggesting autosomal dominance of a defective thyroglobulin allele. Hum Genet 67:301305, 1984 22. Kimura M, Abe T, Sunamura M, et al: Detailed deletion mapping on chromosome arm 12q in human pancreatic adenocarcinoma: Identification of a 1-cM region of common aUelec loss. Genes Chromosom Cancer 17:88-93, 1996 23. Orita M, Iwahana H, Kanazawa H, et al: Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci U S A 86:2766-2770, 1989 24. Miynshi Y, Nagase H, Ando H, et al: Somatic mutations of the APC genein colorectal tumors: Mutation cluster region in the APC gene. Hum Mol Genet 1:229-233, 1992 25. Aoki T, Takeda S, Yanagisawa A, et al: APC mad p53 mutations in de novo colorectal adenocarcinomas. Hum Mutat 3:342-346, 1994 26. Sasano H, Shlzawa S, Suzuku T, et al: Transcription factor adrenal 4 binding protein as a marker of adrenocortical malignancy. HuM PATHOL 26:1154-1156, 1995 27. Neville AM, O'Hare MJ: Histopathology of the human adrenal cortex.J Cfin Endocrlnol Metab 14:791-820, 1985

28. Belchetz LA, Berk T, Bapat BV, et al: Changing causes of mortafity in patients with familial adenomatous polyposis. Dis Colon Rectum 39:384-387,1996 29. Devic A, Bussy MM: Un cas de polypose adenomateuse: Generalisee a tout l'intesfin. Arch Mal Appar Dig 6:278-279, 1912 30. MacDonaldJM, Davis WC, Crago HR, et al: Gardner's syndrome and periampullary malignancy. AmJ Surg 112:425-430, 1967 31. Marshall WH, Martin FIR, Mackay IR: Gardner's syndrome with adrenal carcinoma. Aust Ann Med 16:242-244, 1967 32. Puig R: Gardner's syndrome. Prensa med Argent 56:831-836, 1969 33. Gosserez M, Treheux A, Hoeffel JC, et al: Une etiologic rare de tumeurs des maxillaires: le syndrome de Gardner. J Radiol Electrol 51:503-506, 1970 34. Coli RD, MooreJP, La Marcha PH, et al: Gardner's syndrome. A revisit to a previously described family. AmJ Dig Dis 15:551-568, 1970 35. Ono C, Iwama T, Mishima Y: A case of familial adenomatous polyposis complicated by thyroid carcinoma, carcinoma of the ampulla of Vater and adrenocortical adenoma. Jpn J Surg 21:234-240,1991 36. Naylor EW, Gardner EJ: Adrenal adenomas in a patient with Gardner's syndrome. Cfin Genet 20:67-73, 1981

BOOK REVIEWS Urologic Surgical Pathology Eels: David G. Bostwick, MD and Jon N. Eble, MD (ed). St. Louis, MO, Mosby Company, 1997, 788 pages, $225.00. There are 14 chapters covering nine anatomic areas of the urinary tract and, as a dividend, the adrenal gland. Four organs, kidney, urinary bladder, prostate, and testes, are divided into separate chapters on non-neoplastic and neoplastic diseases. The 16 coauthors are experienced and highly reputed in their knowledge of urinary tract conditions. Each chapter follows a similar format presenting embryology, development, malformation, gross and microscopic anatomy, and pathology of non-neoplastic and neoplastic diseases. Urologic Surgical Pathology is encyclopedic in coverage. The many references are listed, thankfully, in order of referral in the text rather than alphabetically. Only a few of the many highlights in this book can be mentioned. Stephen Bonsib's chapter on non-neoplastic conditions of the kidney is surely destined to become a classic, as is Robert Young's contribution on non-neoplastic diseases of the urinary bladder. Each has excellent descriptive diagrams, gross photos in both color and black and white, and diagnostic photomicrographs. Their description of embryogenesis and clinical relevance is very fine. Dr. Grignon's discussion of papillary processes of the urinary bladder is also especially notable. Johathan Epstein's chapter on non-neoplastic diseases of the prostate, unfortunately listed as of the prostrate in the Table of Contents, presents excellent discussions of benign conditions that may mimic carcinoma. These are illustrated with first-class photomicrographs. This reviewer would have appreciated a section on radiation effects. Dr. Bostwick's chapter on cancers of the prostate is also outstanding, with especially fine discussions of prostatic intraepithelial neoplasia and the prognostic implications of grading. The chapter on non-neoplastic diseases of the testes also will undoubtedly become a classic! Neoplasms of the testes by Ulbright presents a clear discussion of the histogenesis of testicular tumors, an excellent working classification, and detailed diagnostic criteria. A fine chapter! Other useful chapters on the renal pelvis and ureters, urethra, spermatic cord and seminal vesicals, penis, and scrotum complete the pathology of the urinary tract. The adrenal gland chapter fills the gap in available texts and meets the

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standard of excellence found in other chapters of this fine book. This reviewer only wishes that there was more on an important adrenal condition, bilateral massive adrenal hemorrhage. Technically, the book is of high quality. The paper stock is heavy and has reproduced both color and black and white photographs well. The Preface and Table of Contents pages, as well as chapter title pages, are printed on an arty background of the urinary tract in tan-obscure colors, making reading awkward. Tables, so very important in books of this scope, have a dark gray background, making reading a chore. When will we all learn that legibility is best with old-fashioned black letters or numbers on a white background. This is a superb book and a must for all surgical pathologists. But it is also an outstanding encyclopedic reference for the general autopsy pathologist, as well as urologists, internists, and pediatricians who also have interests in complexities of diseases of the urinary tract. Drs. Bostwick and Eble and their coauthors, as well as Moshy Company, are to be congratulated!--MoRGAN BERTHRONG, MD, Penrose Hospital,

Colorado Springs, CO Diseases of the Thyroid, Lewis E. Braverman (ed). Totowa, NJ, The H u m a n a Press, 393 pages, $125.00. This is one of a series entitled "Contemporary Endocrinology" edited by an acknowledged leader in iodine metabolism and its relationship to thyroid dysfunction supported by an impressive roster of contributors. The book reflects the interest of the endocrinologisteditor with chapters on the management of hypothyroidism, thyrotoxicosis and cancer, resistance to thyroid hormone, the euthyroid patient with nodular and diffuse goiter, the recognition of thyroid disease in older persons and the consequences and treatment of iodine deficiency. Despite a somewhat clinical bent as reflected by the chapters referenced earlier, this reviewer found much of this book to be mainstream to the interests of the general pathologist. The chapter on the molecular mechanisms of thyroid action at the genomic and nongenomic levels are outstanding with a clear text supported by very helpful diagrams. The chapters on neonatal screening for thyroid disease, thyroid testing in general, and the pathogenesis of the "sick thyroid syndrome" will be of significant