Mesenchymal Hamartomas of the Kidney

THE JOURNAL OF UROLOGY

Vol. 83, No. 3, March 1960 Printed in U.S.A.

MESENCHYMAL HAMARTOMAS OF THE KIDNEY MAURICE L. PEROU

AND

PETER T. GRAY

From the Community General Hospital, Sterling, Ill.

The term hamartoma as used in relation to renal tumors is generally applied ahnost exclusively to those tumor-like lesions which are nonencapsulated, gray or gray-yellow and which microscopically are composed of a miJdure of mesenchymal tissue, namely, fat tissue, smooth muscle and blood vessels. These lesions may be small or large and have been variously called angiomyolipoma (Allen, Brody and Lipshutz, Rusche), lipomyohemangioma (Heckel and Penick), angiolipoleiomyoma (Tweeddale and associates), benign arterioleiomyoma (Gordon and associates), myoangiolipoma (Bartsch), benign mesenchymoma (Lucke and Schlumberger) and angiolipomyosarcoma (Berg). They may occur isolately or in association with a larger disease complex, namely tuberous sclerosis and certain allied conditions. Recently Inglis has challenged the hamartial origin of these tumors when they occur in connection with tuberous sclerosis. The hamartial origin of the isolated angiomyolipomas seems however fairly well established. Still there is much mystery and confusion connected with the renal hamartomas in particular and the hamartomas in general. The purpose of this article is to publish five cases of mesenchymal hamartomas of the kidney, two of which were from patients with Bourneville's disease. Also an attempt will be made to revaluate with the help of these cases the general concept of hamartoma and specifically the concept of renal hamartoma. In so doing we will study the renal hamartomas in relation to allied tumor and tumor-like proliferations and try to differentiate them from certain other lesions with which they are often confused. Finally an outline and discussion of the general characteristics of the mesenchymal hamartomas of the kidney will be made. REPORT OF CASES

Case 1. A. B., a 64-year-old white woman, had a partial colectomy performed at Michael Reese Hospital, Chicago, Ill. on September 27, 1953 for "adenocarcinoma of the sigmoid colon." She ex-

Accepted for publication July 18, 1959.

pired on the twelfth postoperative day as a result of fecal peritonitis due to leakage in the suture line at the site of anastomosis. A small cortical renal "tumor" was found incidentally at necropsy. The "tumor" was not attached to the renal capsule. It was fairly well defined, yellow-gray, firm and measured 0.3 cm. in diameter. Microscopic examination revealed a mixture of fat tissue and smooth muscular tissue (fig. 1). The fat tissue appeared to be mature, but the smooth muscular tissue contained scattered, seemingly immature cells with large and hyperchromatic muclei. The pathologic diagnosis, made by Dr. Otto Saphir, was "hamartoma of renal cortex." Case 2. C. M., a-38-year-old white woman, was admitted to the Community General Hospital of Sterling, Ill. on October 1, 1958 because of restlessness, nausea and vomiting 2 days in duration. These symptoms started about 3 hours following an automobile accident and resulted from a fainting episode that caused the patient to lose control of her car which hit a cement abutment head-on. The past history and the family history were noncontributory. Physical examination revealed an acutely ill, pale and slightly jaundiced patient. There was no apparent evidence of trauma except for a few small contusions on both legs. Physical examination was negative except for some right upper quadrant tenderness. X-rays of the chest, skull and abdomen yielded no significant findings. A liver profile indicated hepatocellular jaundice and a diagnosis of viral hepatitis was made. The patient was hospitalized for 20 days. She was thoroughly examined 1),2 months after the accident and found to be in good health. However the day after this examination the patient was again hospitalized because of pain in the left loin and left hemi-abdomen. The pain was severe, spasmodic but did not radiate. There was no abdominal rigidity but the left hemi-abdomen was exquisitely tender on palpation. An emergency flat fihn of the abdomen revealed a shadow occupying the left hemi-abdomen which completely obscured the underlying structures. Following

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MIDSENCHYMAL HAMARTOMAS OF KIDNJ,JY

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F'rn. L Case l. Small solitary mesenchymal hamartoma. (myolipoma.) Van Gieson st.ain, X2,5

this examination tlH" patient went into shock. Four pints of blood were given and an emergency exploratory laparotomr was performed. At surgery, the liver and spleen appeared normal but a large rctroperitoneal bematoma was found in the region of the left kidney. The rause of the bleeding was located in the upper pole of the left kidney which seemed to contain a tumor-like mass. Frozen section of the turn.or was diagnosed as "hamartorna (angiomyolipoma)." A left nephrectomy was performed. The right kidney on cursory examination was found to be apparC'ntly normal and contained no tumor masses. Follmring surgery the patient made a quick and uneventful recovery. Because of the possibility of tuberous sclerosis, complete physical examination was repeated and the usual stigmata of the clisC'ase (phacoma of retina, adenoma seba.ceum etc ... .) were searched for but in vain. Pathologic examination Examination of the gross specimen revealed a kidney partly encased in a mass of hemorrhagic tiRsue and dotted blood. The renal capsule stripped with ease. The clenudate outer surface of the kidney contained six distinct scattered small tumors and a large tumor perched over the upper pole of tbe kidney (fig. 2, . This tumor measured ,5 by 3.5 by 3 cm. Its outer surface wa~ yellmY-gray, bosselated,

ragged and hemorrhagic. The renal capsule wa::, not identifiable over the tumor. The cut surface revealed a moderately firm and somewhat friable tissue containing irregular gray and yellow area~. There was also a large hematoma mca:cmring 2)\ by 2 em. and located in the lateral aspert of the tumor, close to the lateral border of the (fig. 2, B). The line of demarcatiou between the renal parenchyma and the tumor was ill-definPd and there was apparent gross infiltration of th<: kidney by the tumor. The other five tumop, measured from 0.2 to 0.8 cm in diameter. were yellow, firm, glistening, raised and seemed to consist mostly of fat tissue. All the tumors wP
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areas the fat tissue was fairly abundant but in general the smooth muscle and vascular components were more conspicuous and dominated the picture. The blood vessels were generally thick-walled, often hyalinized and as a rule were distributed in irregular compact groups (fig. 3, A). There were broken elastic fibers in the outer part of the vessels' walls (fig. 3, B). The smooth muscles were composed of elongated cells with oval-shaped or fusiform nuclei with blunt ends. They formed thick bundles both around the

blood vessels and outside these structures so that in areas the tumor had a frank leiomyomatous appearance. Often the smooth muscle cells appeared to radiate from the vessels' walls. There was some nuclear hyperchromatism and pleomorphism of the smooth muscle cells but mitoses were absent. There was a moderate amount of reticulum throughout the tumor and particularly within and around the blood vessels' walls. There was also a moderate amount of fibrous tissue and neurofibrils were extremely scarce. Some sections

Fm. 2. Case 2. A, large complex mesenchymal hamartoma (angiomyolipoma) of upper pole of kidney. Note also two small fatty hamartomas (arrows). B, cut surface of large angiomyolipoma. Note hematoma (arrows).

lVIESENCHYi\IAL HAi\IARTOMAS OF KID:'-:EY

FIG. 3. Case 2. A, ser:tion of ,mg;iomyolipoma shows blood vessels, smooth m11scle a!ld fn l Lissun HenrntoxY!in and eosi11 B, blood vessels show broken peripheral elrlstic fibers nml nbs0t1c(, elastic tissue stain, X150.

intenrnl <{lastic lmnella.

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M. L. PEROU AND P. T. GRAY

of the tumor showed a large vein surrounded by tumor (fig. 4). The wall of the vein in areas was thickened and in other areas thinned. Tumor tissue was seen infiltrating the wall at several points (fig. 5). The vein had ruptured at one point, seemingly as a result of tumor infiltration (fig. 4). Serial sections failed to reveal any evidence of an arteriovenous aneurysm. The small tumors were composed in general of fat tissue (fig. 6). Some contained a few large blood vessels and others small agglomerations of elongated cells resembling smooth muscle cells. Occasional immature cells with one or several hyperchromatic nuclei were seen. These tumors were all nonencapsulated and ill-defined. In a few areas they contained peripheral inclusions of renal tubules. The final diagnosis was 1) large hamartoma (angiomyolipoma) of upper pole of kidney, 2) invasion and rupture of large intratumoral vein with massive perirenal hemorrhage and hema-

toma, 3) multiple small hamartomas of kidneys (lipomas and myolipomas). Case 3. E. M., a-64-year-old white woman, was admitted to Michael Reese Hospital, Chicago, Ill. on October 29, 1953 with a typical history of right renal colic. X-ray examination of the kidneys revealed a "radiopaque calculus of the right kidney" and "tumor or cyst of the lower pole of the left kidney." On November 4, 1953 a right pyelolithotomy and nephropexy were performed. Recovery was uneventful. On November 15, 1953 a left nephrectomy was performed for a renal tumor. At surgery the tumor seemed poorly delineated and so infiltrative that it was felt by the surgeon that his efforts to remove the entire tumor had met only with limited success. The senior author of this article had the opportunity to study both the gross specimen and the microscopic sections. Pathologic examination: The gross specimen consisted of the kidney which was partially re-

FIG. 4. Case 2. Low power view of ruptured and bleeding renal vein. Note tumor surrounding vessel. Hematoxylin and eosin, X14.

MESENCHYMAL HAMARTOMAS OF KIDNEY

Fm. 5. Case 2. A, higher magnification of vessel's wall shows infiltration of this structure by tumor. Hematoxylin and eosin, X72. B, still higher magnification of vessel's wi,11 in another nrca shows ,,edge i)f infiltrating tumor within markedly thickened outer media. Hematoxylin nnd eosin, X 110

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placed by a large tumor seemingly arising in the lower pole of the organ. The tumor was glistening, yellow, soft and contained scattered small islands of gray, firm tissue. It replaced practically the entire lower pole of the kidney and extended toward the renal pelvis which it obliterated partly. However both the renal pelvis and the main renal vessels were not infiltrated by the tumor. Microscopic examination revealed that the tumor was basically similar to the larger tumor of case 2 but contained a much greater proportion of mature fat as well as many elongated cells with hyperchromatic and pleomorphic nuclei. These cells in general resembled young smooth muscle cells but occasionally had all the appearances of steatoblasts. l'viitoses were absent (fig. 7). The final diagnosis was: "infiltrative hamartoma (angiomyolipoma) of kidney." However several competent pathologists had examined the sections and a few had arrived at a diagnosis of angiomyoliposarcoma. Followup data: Because of the diversification of opinion and the possibility of some residual tumor at the site of the left nephrectomy, irradiation therapy was administered. The patient re-

ceived 16 treatments (7500 r) over the left kidney area within a 21 day period. Subsequently she has been followed periodically at the Michael Reese Clinic and was last seen in January 1959. All examinations pertinent to the kidney have failed to show any evidence of recurrence of the left renal tumor or of metastases six and one half years after the original operation. Case 4. 0. B., a 4-year-old white boy, was admitted to the Dixon State Hospital on May 11, 1938 because of mental deficiency and epilepsy. He was apparently normal at birth but started to have "spasms" at 5 weeks and "muscular twitchings" at 5 months of age. Physical examination revealed a poorly developed child with relatively large head, convergent strabismus, accentuated knee jerks and right Babinski. Pneumoencephalography disclosed some dilatation of the lateral ventricles. During his hospital stay the patient's condition remained stationary with an average of 1 to 8 epileptiform attacks yearly. Sebaceous adenomas of the face were noted 10 years after admission to the hospital. The patient expired suddenly on November 29, 1956 at the age of 22. At necropsy there were typical sebaceous

Fro. 6. Case 2. Small fatty hamartoma. Hematoxylin and eosin, X75

J\IESENCHYM.\L HAMARTOMAS OF KID1,l~Y

Fw. 7. Case :3 . .11, thick ,rnlled 11rtery-like vessels of isolntecl and infiltrntive m1giomyolipoma. (ham-ar\.onrn). Note a.lso clad, smooth muscle cells and fat tissue. Hematoxylin and eosin, X85. high power view of A shows markPd nuclear hyperchromatism and nuclear pleommphism. Xotc giant (n,nows;, Hematoxylin and eosin, X·HJO.

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adenomas of the face. The heart contained no tumor. Bilateral bronchopneumonia was present. The liver, spleen, adrenals, pancreas, gastrointestinal tract and parathyroids were not remarkable. The kidneys were larger than usual and together weighed 425 gm. Both the cut surface and the outer surface contained multiple large, medium-sized and small, yellow-gray and yellow tumor masses or nodules (fig. 8). The tumors measured from 0.5 to 3 cm. in greatest dimension. The renal pelves and ureters were unremarkable. The thyroid was of normal size but on section revealed, in the left lobe, near the superior parathyroid glands, three small nodules measuring 0.3 to 0.5 cm. in diameter. The brain was examined by Dr. B. W. Lichtenstein and the senior author of this article. Externally it contained many hard nodules and presented large and thick convolutions. Coronal sections revealed a large tumor seemingly arising from the subependymal region and overlying the head of the caudate nucleus (fig. 9). It was gray-white to purple-gray and had focal hemorrhagic areas. In its inferior portion there was a firm, gray-white nodule measuring 0.8 cm. in diameter. The basal ganglia were deformed. The ependyma of the right and left lateral ventricles was verrucous. Microscopic examination of the kidneys revealed multiple tumors of all sizes and shapes. They were fairly well defined but not encapsulated. Some of the tumors were small, and composed either of fat tissue or smooth muscles arranged in irregular fascicles. Other larger tumors were primarily vascular and contained many

Fm. 8. Case 4. Multiple hamartomas of left kidney in patient with tuberous sclerosis. Right kidney was equally involved.

Fm. 9. Case 4. Cross section of brain. Note large tumor filling right lateral ventricle. Arrow points toward small nodule in lower portion of tumor. atypical artery-like vessels with thick hyalinized media. Most of the tumors were composed of an admixture of mesenchymal tissue, namely, fat tissue, smooth muscle and blood vessels (fig. 10, A). In general the pattern of the tumor was basically similar to the ones described above (see cases 2 and 3). However, there seemed to be two distinct elements in these tumors. First, in both the small and large tumors there were scattered tubules or small groups of tubules as well as a few glomeruli. These structures did not seem to participate in the tumor but rather seemed to have been caught within the tumor or within adjacent tumor masses (fig. 10, B). The second distinguishing factor was the presence of blastomatous elements, resembling steatoblasts, many of which were giant-sized and multinucleated (fig. 11, A). A few tumors were almost entirely blastomatous but in general the blastomatous elements were scattered throughout apparently mature tissue. Careful scanning of the sections failed to reveal any mitosis or blood vessel invasion. Occasional cysts of the so-called retention type were seen. Sections of the thyroid showed several small papillary adenoma-like structures which were not encapsulated (fig. 11, B). Sections of the brain revealed the typical changes of tuberous sclerosis with glial hernias in the lateral ventricles and large glial nodules containing bizarre "monster" cells and located within the substance of the brain. In addition, sections of the above described brain tumor showed a variegated pattern. The predominant cells seemed to be the astrocytes and in areas large numbers of plump protoplasmic astrocytcs

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Fw. 10. Case-LA, complex hamartonm (angiomyolipoma). Compare with figure :3, l1 and figm·e , '.\;ote reel bloorl cells within lumen of vessels. Hematoxylin and eosin. X85. B, high power view of Nok inclusions of renal 1.uhules (arrows) Hematoxylin and eosin, X200.

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FIG. 11. Case 4. A, high power view of hamartoblastoma of same patient shown in figure 10. Note marked nuclear pleomorphism and hyperchromatism. Note also several large steatoblasts. Hematoxylin and eosin, X 185. B, small papillary "adenoma" of thyroid. Note absence of capsule. Hematoxylin and eosin, X90.

MESENCHYMAL HAMAHTOMAS OF KIDNEY

wt,re seen. In other areas the turnor had the appearance of a glioblastonm. The final diagnosis was 1) tuberous sclerosis with a.) sebaceous "aclcnornas' 1 of face, b) mul-tiplc bilateral renal hamartomas and hamartoblastomas, e) small papillary "adenomas" (hamartomas) of thyroid, d) enlarged cerebral convolutions; 2) subependymaJ glial nodules and large ''glioma" (hamartoblastorrm) causing marked distortion of ventricular system; 3) aspiration bronchopneumonia. Case 5. C. V., a.n 8-year-olcl white girl, was admitted to the Dixon State Hospital on October 14, 1932 because of epilepsy and mental deficiemy. The family history was negative except for mental deficiency and epilepsy in a younger sister. Labor and ddiw,ry were normal. Convulsions began at 7 months of age. They were genr,mlly intermittent, appearing sometimes at the rate of 10 or 11 a day for a few days then subsiding for several weeks or months. Physical examination revealed a fairly well nourished young girl with sebaceous adenomas of the face. The rest of the examination was noncontributory. The diagnosis in the patient and her sister was tuberous sclerosis. During her 20 year stay at the Dixon State Hospital the patient's condition deteriorated slowly. She became mon1 and more unmanageable, was alwa:rn quarrelling, often loud untidv and uncooperative. In :\Tovember 1952 the p:tient contracted bronchopneumonia and died after 5 days of illness at the age of 28 ,,ears. · At necropsy there \1·en~ typical sebaceous adenmmrn of the facP. Bilateral bronchopneumonia was found. The ]wart, liver, spleen, adrenals, pr1ncrcas, gastrointestinal tract, thyroid and parathyroids wc;rp described as being normal. The kidne,'s were of nonnal size but irregular, bosselatecl · and studded 1Yith multiple, unevenly distributed cysts of 1'arious sizes and several gray and yellow-gray nodular arras (fig. 12). The bra.in was examined b~- Dr . B. '\'\T Lichtenstein. The entire left cerebral hemisphere was small(!r than the right and the rmffolutions of the left frontal lobe 1n1n: atrophic. The ldt lateral ventricl(" \Yas moderatd_1° dilated. Both lateral ventricle's, but particularly the left one, 1n're stuclcled with numerous nodule~ 1d1ich ,·ariccl from 2 to 10 mm. in greatest dimension. .\Iirroscopic sections of the kidne.1· were not antilahle for reviewing. 11·erc· described as

:Fm. 12. Case 5. Kidneys of patient with tu berous sclerosis and congenital polycystic disem,r,. Note distribution of cysts unlike usnal of common type of congenital polyeystic kidneys. showing several "tumors" compmed of fat ticmue or fat tissue and smooth muscles and also many cysts containing a pinkish material ancl lined focally hypcrplastic epithelium. .\Jicroscopic amination of the liver and pancreas was made the senior author of this artidr. Three parnilin blocks containing liver tissue were serially ,,f'('.· tioned and revealed multiple hamartomatou:., lesions scatkrecl throughout the liver L::l). They were all of portal origin and had a ntri\' gated pattern. Some hamartoma, wne only of fat tissue; others of bile ducts; still othr·ns had a mixture of mesenchymal and entticlernw,i tissues (fig;. 1:3, A) . The bilr duct hamartom:i., were microscopic and similar to thos(' obsrcrved in polycystic disease of the liv<'r (fig. l:3, B) The mixed hanmrtomas wen· larger and containPd a slight amount of red fibrous tissue with ,,orne elastic: fibers and a moderate amount of staining fusiform celb n,sembling smooth mtrncl1; cells (fig. J:3, A). In addition they contained small agglomerations of bile ducts and scattcn,cl small. but thick-walled blood vessels (fig. J :-!, . Occ:I sional immature cells with bypcrcl1rnrnatic :rnd pleomorphic nuclei W<'rc also scr,11. Two pa rnltin blocks containing pancreatic tissm' m'rc scetionecl. They revealed deep within the pnn

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FIG. 13. Case 5. A, mixed portal hamartoma of liver. Note participation of bile ducts (arrows). Note also elongated cells resembling smooth muscle cells and small but thick walled blood vessels (arrows). Hematoxylin and eosin, X70. B, "deep" microhamartoma or microadenoma of liver. Note cystic dilatation of bile ducts. Hematoxylin and eosin, X200.

J\IES1'J~CHYMAL HAMAHTOMAS OF KID~EY

Fm. 14. Case 5. l'vlieroadenomn, or microlrnnrnrtonrn of pa.nereas. Note dilated aeini filled with con,µ;u--

Iated material. Henrntoxylin and eosin, X200. crcatic parenchyma scattered microadenomas (hamartomas) 1Yhich were non-encapsulated and composwl of dilated acini filled with coagulated acidophilic material (fig. 14). In a few of the lesions both thr acini and thr islands of Langerlmns seenwd to participate in the proliforativc process. In addition some unusually large islands of Langerharrn were found The pancreatic ducts and strorna were not remarkable. J\Iicroseopic examination of the brain revealed the typical change:, of t11berous sclerosis. The final diagnosi:, wa:, 1) tuberous sclerosis 1rith a) multiple sub-1·pendymal glial nodules, h) sPbacPous "adenomas" of face, c) hamartomas and polycystic disease of kidneys, liver and pancreas; 2) hronchopneumonia.

Hamartoma (from the Greek hamartia, defect or hamartenein, err, miss) literally mca1rn a nodule of superflumrn tissue- resulting from a de-fed in tissue combination during development. :\.lhrecht eoined the term in 1904 as a designation for those "turnor-likc· malformations in which

thl're is only abnormal mixing of the normal components of the organ in which they occur." Jfo add1·d that the frwlty mixing "mar be manifested as a change in quantity, arrangc'ment, or of maturation, or may comprise all three.'' Subsequently, the word hamartoma became a fixtnrn of the medieal literature. Va.n cler Valk the concPpt of hamartoma to include n.11 tumors of embryonal origin with a11 structure. Lever extended the meaning of the word to include "all such tumors, even tlwsc witl suborganoid ancl nonorganic Rtrueturr." It quite apparent that the original definition of Albrecht, although well rmmciated, allows nnious interpretations. Comequently, the of the word hamartoma became vag;uc and t!rn line of demarcation brtwecn thesr tLimors, cl1ori,,-tornas and teratomas became blurrrcl. Karnncr for example considerPd hamartrnrnts to be ''unde veloped forms of tcratomas." Shields Warrrn classified the hamartoma together with the dcrmoid cyst am! the mixed tumor of the glands in the histological category of meaning "derived from more than one gc!rrn

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layer or more than one derivative of a single germ layer." Many qualified authors still use the words hamartomas and choristomas interchangeably, particularly in speaking of the renal hamartomas. According to Tweeddale and associates, "the definition of a hamartoma implies the presence of all the normal elements of an organ but in abnormal arrangement." Consequently, a renal hamartoma is not a true hamartoma "since it lacks identifiable epithelium." In view of these seemingly conflicting opinions one begins to wonder what does the word hamartoma really mean and what does it really imply. In order to answer this double question we will try to analyze the basic propositions of Albrecht's original definition and offer our own interpretation of the implications contained therein. The three main propositions of Albrecht are: 1) Hamartomas are tumor-like malformations, 2) hamartomas are made up only of the normal components of an organ, 3) hamartomas show faulty mixing of these components as to quantity, arrangement and degree of maturation. 1) Hamartomas are tumor-like malformations. The first proposition is basically correct, but can be, and has been challenged. Actually the hamartoma "straddles a line between malformation and tumor in that the malformed tissue sometimes exhibits tumorous qualities" (Popper and Schaffner). Also, some hamartomas may have only one tissue type and cannot be differentiated from a true tumor composed of the same tissue. For example, a true adenoma or a true fibroma cannot be distinguished from a hamartial adenoma or a hamartial fibroma. The proposition that hamartomas are tumor-like malformations need not be modified since the only possible implication is that the hamartoma resembles a true tumor, the degree of resemblance being variable. 2) H amartomas are made up only of the normal components of an organ. The second proposition is also correct and seemingly not controversial. However, much misunderstanding has arisen concerning the word "normal." We must assume that the normal components of an organ are the components which normally make up this organ. For example, the normal components of the kidney are: tubules, glomeruli, connective tissue and blood vessels, all of mesodermal origin. However, the normal components of an organ, as for example, the connective tissue of the kidney, may in turn be abnormal and contain foci of

embryonic cells or of pluripotent "reserve" cells capable of differentiation in several directions at any period of mature life. These foci may be composed of unripe connective tissue cells or mesenchymal cells which are capable of differentiation into fat tissue, smooth muscle, elastic tissue, fibrous tissue and blood vessels, all known components of the classical renal hamartomas. If these embryonic or "reserve" cells are younger and represent "rests" of mesodermal tissue one will expect to have differentiation into mesenchymal and epithelial tissues. The second proposition needs no modification if the term normal is not taken in a strictly histologic connotation but is broadened to its embryologic meaning. 3) Hamartomas show faulty mixing of these components as to quantity, arrangement and degree of maturation. The third proposition is more complex and needs clarification. It embodies "change in quantity, arrangement and degree of maturation." Albrecht in his original article did not elaborate on the change in quantity. If one goes according to his examples (renal and hepatic hamartomas, fibroadenoma of the breast) it is apparent that he meant that two or several components of an organ were involved in the making of a hamartoma. However modern pathological studies have shown that some so-called adenomas (thyroid "adenomas" of case 4; pancreatic "adenomas" and bile duct "adenomas" of case 5), the "deep" or medullary renal fibromas, (Albrecht, Allen, Campbell, Genewein), many renal leiomyomas (Bhende, Gordon and associates), and lipomas (Hunt and Simon, Lower and Belcher, Robertson and Hand), the renal hemangiomas (Rappoport, Swan and Balme, Waterfall) and lymphangiomas (Lucke and Schlumberger), and certain epithelial tumors of the renal pelvis (Mallory), have incontestably a hamartial origin. The evidence of unilateral growth in a given hamartoma should be accepted. Nonetheless, a great number of hamartomas and the so-called classical hamartomas are "mixed tumors" or "complex tumors" because they are composed of a mixture of tissues. We prefer to use the word "complex" instead of "mixed" which should be reserved for those instances when tissues from different germ layers are involved. The tissues of the hamartoma may originate from several germ layers or more often from the derivatives of one germ layer. The proportion of the different tissues in a given tumor will be

MESENCHYMAL HAMARTOMAS OF KIDNEY

variable. For example, some mesenchymal hamartomas will contain more fat, others more smooth muscle and still others more blood vessels. Some mesodermal tumors likewise will contain much mesenchymal tissue and only little epithelial tissue, as, for example, some hepatic hamartomas found in Bourneville's disease (case 5). Others will contain a little amount of connective tissue or no connective tissue but a great amount of epithelial tissue, as, for example, the "hamartoma of cloacal tissue" of Mallory. The arrangement of the different tissues in a given tumor in general is quite capricious and one may expect all sorts of patterns. Concerning the degree of maturation in a hamartoma, we cannot agree with Potter that it is "similar to that found in the rest of the organ." The very nature of the hamartoma implies the existence of "germ cells" or embryonic "rests." In many published cases of renal hamartomas (Berg, Feriz, Gordon and associates, Inglis, 1954; Woolten) as well as in our cases 3 and 4, typical immature cells were seen. The degree of maturity or immaturity of the entire tumor and its clinical behavior will indicate whether it is a hamartoma or a hamartoblastoma. The third proposition of Albrecht need not be modified either if one agrees that a hamartoma may be composed of one or several tissues and that these tissues although generally mature may be focally or partially immature. We have defined the hamartoma and have tried to arrive at a clear understanding of its meaning as a pathological entity. However, in order to comprehend fully the concept of hamartoma, one needs to study the hamartial "tumor" alongside related tumors or tumor-like conditions; namely, the hamartoblastoma, the progonoma, the choristoma and the teratoma. A hamartoblastoma is an immature, clinically and histologically malignant tumor arising from "hamartial rests" and different from the hamartoma only in degree of maturation. The question as to whether a hamartoblastoma arises always from a hamartoma is not different from the same question as applied to malignant neoplasms arising from benign tumors. Also, as it is the case for many other tumors, there will be transition forms between hamartomas and hamartoblastomas. A progonoma (literally: before-sperm-tumor) is a special type of hamartoma in which dysgenesis results in structures which are similar to

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those in primitive species, as for example the hairy nevi (Karsner, 1955). The implication is that these lesions represent atavic defects. The literature contains no example of progonoma of the kidney. The word choristoma (from the Greek choristos, separate) was also coined by Albrecht in his original article for these "tumor-like structures which consist of components of an organ placed in an abnormal position and because of this aberrant localization mimic a true tumor." By definition then a hamartoma and a choristoma are fundamentally different. The first is composed of tissue or tissues which belong to the organ where the "tumor" is found. The second is composed of tissue foreign to the organ where the "tumor" is found. Fat tissue which occurs in the kidney or the liver "sui generis", or as a result of certain pathologic conditions (arteriosclerosis, malnutrition) does not represent a choristoma. Adrenal cortical tissue in the kidney may be a choristoma or possibly a hamartoma. The last word on this subject has not yet been spoken. The existence of heterotopic adrenal tissue cannot be denied (Mitchell and Angrist, Saphir) but hamartial transformation of mesodermal tissue into adrenal cortical tissue has not yet been proven to occur in the kidney or elsewhere. A teratoma (literally: monster-tumor) is a "true tumor or neoplasm composed of multiple tissues foreign to the part in which it arises" (Willis). An angiomyolipoma is not a teratoma because its components are clearly derived from indigenous renal tissue. Renal teratomas are extremely rare. In considering hamartomas of the kidney one need also to differentiate these "tumors" from the so-called "capsulomas" and try to clarify the meaning of such confusing expressions as "true kidney hypernephroma" and "mixed hypernephroid tumors." The term capsuloma was introduced by Colvin to designate "certain capsular and subcapsular mixed tumors of the kidney." However, one should try to distinguish between a tumor of the renal capsule and a tumor of the renal parenchyma or of the perinephric tissue. Histologically the capsuloma cannot be distinguished from the hamartoma and for that matter many so-called capsulomas are renal hamartomas (Allen, Colvin). Conceivably hamartial capsulomas may also

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exist. In order to have a true capsuloma one must be able to demonstrate that the tumor in question arose from the capsule. Such tumor, then, must be attached to the capsule and must be composed only of capsular tissue or the embryologic derivatives of this tissue. The question of "true kidney hypernephroma" is directly related to the presence of adrenal cortical rests in the kidney or their derivation from renal mesoderm. The word hypernephroma (literally: over-kidney-tumor) means by definition, a renal tumor whose tissue is akin to that of adrenal cortical tissue. Consequently, the name "true kidney hypernephroma" should be reserved for this tumor-whether it exists or not-that arises from heterotopic intrarenal adrenal cortical tissue. It would then be a choristoblastoma and not a hamartoblastoma. However, the great majority of the renal tumors loosely classified as hypernephromas are in reality renal carcinomas originating either from adult tubules or from islets of nephrogenic tissue which have persisted in the renal cortex, thus bringing them into line with the embryoma (Boyd, Wilson). In other words certain hypernephromas, that is those arising from embryonic rests, could be classified as hamartoblastomas. We failed to find any evidence of "hypernephroma" in any one of our five cases. The renal hamartomas are also related to the Wilms tumor of children and the rare "mixed tumor" of "mixed hypernephroid tumor" of adults (Tedeschi and associates). We believe with Allen that these tumors belong to one large group whether they are called embryoma, carcinosarcoma, nephroblastoma, mixed tumor, mixed hypernephroid tumor or Wilms tumor. They are all mesodermal tumors and contain only indigenous renal tissues and their embryologic or metaplastic derivatives. On that basis one could classify them as mesodermal hamartoblastomas, younger, more immature and consequently more malignant than their mesenchymal counterparts. All the aforementioned tumors are either related to or confused with the classical renal hamartoma which is a mesenchymal tumor-like growth. The latter lends itself to certain clinical, pathological and biological considerations. Clinical considerations. In general, renal neoplasms present no single symptoms or groups of symptoms which could permit to differentiate

one type of neoplasm from another type. This is true whether the tumor arises in the cortex, the medulla or the renal pelvis. Renal hamartomas are no exception. The mesenchymal hamartomas comprise the small and large tumors and tumorlike lesions. The small, isolated or multiple, medullary or cortical tumors are clinically silent with the exception of the hemangioma which may cause severe hematuria (Rappoport, Swan and Balme, Waterfall). The larger tumors may or may not be aymptomatic. The simple renal lipomas, fibromas and leiomyomas which are not always of hamartial origin will be only mentioned here, and it will suffice to say that according to the many published reports (Friedman and Ash, Gordon and associates, Hunt and Simon, Lower and Belcher, Robertson and Hand, Zuckerman and associates) they do not present any characteristic clinical features. The classical, that is the "mixed" or complex, hamartomas are in general silent but may present a few clinical manifestations which can be very useful and in occasions may even be diagnostic. Of 52 cases of classical renal hamartomas recorded in the Registry of the Armed Forces Institute of Pathology up to 1952, only 8 had clinical manifestations (Campbell). However, there are two important symptoms which when present may help focus attention on the angiomyolipoma. These two symptoms-sharp pain in the kidney area and acute syncopal distress indicating internal hemorrhage-are closely related. We believe that they have not been emphasized enough. Massive hemorrhage within and around the tumor has been mentioned in many of the previously reported cases (Bhende, Gordon and associates, Heckel and Penick, Moolten, Rusche, Taylor and Genters) and was present in our case 2. This hemorrhage is responsible for the acute pain and the signs of acute distress with shock. It may be the first indication of the illness with or without any history of previous trauma. This should not be surprising because of the great vascularity of these tumors and because of their invasiveness. Hematuria may or may not be present (Rusche, Tweeddale and associates) and occurs independently of the size of the tumor. Its incidence is relatively low. Fever may be observed (Hulse and Palik, Rusche), but is inconstant. Also, in all cases of angiomyolipomas and multiple small hamartomas of the kidney, one should make a thorough search for the

MESENCHYMAL HAMARTOMAS OF KillXEY

uwal ~tigmata of tuberous sclerosis particularly in young individuals. Thrse stigmata (sebaceous adC'norna of the fae.e; plrncoma of the retina; epilepsy ancl mental dC'fieirncy) havr been known to appear in certain cases several yearn after tlw discovery of the initial renal hamartoma. The isolated angiornyolipoma is generally found in adults and predominantly in women. The hamartoma. of tuberous sclerosis is found in persons of either sex but of a younger age group. The "meclullary fibroma" is much more common during and after the fifth decade of life irrespective of sex. As a rule there are no characteristie radiologica.l findings. When an isolated a.ngiomyolipoma is suspeded one should preferably look for a tumor of the poles of tb<, kidney, more often of tlw lower pole. The treatrrn,nt of the nwsenchymal harrmrtoma. is either wide surgical excision or nephrec:tomy. The prognosis is good if the tumor or tumors involve only one kidney. If both kidneys are involved the prognosis should be guarded. Pathological considerations. The mcsenchymal ha.martoma of the kidney may contain one tissue type (fat; fibrous tissue; smooth muscle; blood or a. mixture of these tissues. The plain muscle tumor, the plain hernangioma, lymphangioma., and lipoma will not be discussed here beeause they represent each a morphologically distinct tumor with a clear-cut histopathologic picture. The so-called ''deep fibroma" is believed most qualified oncologists to be a hamartoma including Albrecht himself. They are generally small but may occasionally a.ttain a large size. They are found in the medulla of the kidney and are composed of fibrous tissue containing scattered renal tubules. One large "fibroma" described Gordon Taylor contained so many tubules that a diagnosis of adenofibroma was made. The true or classical renal hamartoma is the so-ca.lied mixed-or complex-mesenchymal hamartoma. It occurs either independently or in association with tuberous sclerosis and allied conditions. "\Vhen it occurs in patients without manifestations of tuberous sclerosis, the mesenchymal hamartoma or angiornyolipoma is generally large and solitary. However, occasionally there may be multiple tumors of various types (Lucke and Schlumberger) (case 2). In such instances one should wonder if these are examples of unilateral development of tuberous sclerosis and represent so-called "formes frustes" of the

disease. The asso<'iation of renal hamartmnns ancl epiloia is well known. A<:conling to rrrml hamartomas am present in 80 per cellt the cases of Bourneville's disease. For Lncke :ind Schlumbrrger, .'50 per cent of these tumors occur in patients suffering with various of tuberous scl<·rmis. In epiloia the rcrrnl lmm:1 tomas are often multiple ancl bilateral, rarelv unilateral and may occur ver\ and Dickson, .\lertz). The: consensm is that they are morphologically identical with tiH: large isola.tcd hamartomas or angiomyolipomas. However the renal hamart.oma of Bounw,,iHc ·~ disease contains often clc:ep within it8 substauu" scattered renal tubules and some glomendi n1 contrast with the isolated angiomyoliponrn. The opinion of the majority of writers is that tl1r: aforementioned tubules and glorneruli do 1101" participate in the neoplastic: process but ra.ther are simple incidental inclusions.. The 8tmw opinion is held concerning the tubules found .in the deep fibroma. Howc:ver, theoretically, the renal tubules may participate in the process just as the bile ducts participate in the neoplastic growth of the hepatic hamartom,1 (case 5). Also isolated renal hamartomas witl1 participation of both epitbelial aml elements have been described under the name. of fetal rests in adult kidney ( TJ. S. Naval i\fodir:n 1 Sehool: Color Atlas of Pathology). Another of differentiation between the isolakd myoliporna and the ba.martoma of epiloia rn the greater diversification of pattern a.ncl greater immaturity of the cells in the latter lesion. Also if generally one cannot distinguish between tli,, hamartoma of tuberous sclerosis and the isolated angiomyolipoma one should always keep mind that other organs besides the kidneys ,ire involved in epiloia. For example, one may find lesions in the brain, skin, heart, tbyroic!, Iiv:cr, thymus, breast and duodenum Fowler and Dickson, Murphy and associates, Pratt-Thomas, Taylor and Genters) Ca.s<, shows association of renal, cerebral aml lesions. Case 5 shows assoeiation of ren,d and hepatic lesions of tuberous sclerosis with other lesions generally found in congenital disease. These otber lesions are tlm congenital cysts of the kidney and the hepatic microadenomas or microlmmartomas. The association of tuberous sclerosis and con genital polycystic disease has been noted

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others (Inglis, 1954; Potter, Taylor and Genters) and is too frequent to be simply fortuitous. The finding of pancreatic microadenomas or microhamartomas is also worth emphasizing considering the known occurrence of pancreatic lesions in congenital polycystic disease of the kidneys and liver (Potter). Both the renal hamartoma of tuberous sclerosis and the isolated angiomyolipoma are composed of three main tissues: smooth muscle, blood vessels and fat tissue. There has been much discussion about the origin of these tissues. Our opinion, which closely follows that of Moolten, is that all three tissues probably arise "sui generis" from nests of "embryonal cells" or "reserve cells" in the kidney. Not everyone agrees with this interpretation of the histogenesis of these components. Smooth muscle is a normal component of the kidney but this is true only if one considers the smooth muscle of the renal pelvis, of the renal vessels, particularly of the stellate veins draining the renal cortex, and of the renal capsule. Isolated bundles of smooth muscle as such have not been found in the renal parenchyma, except by Busse. However his observation has never been confirmed. Conceivably the smooth muscle of the renal hamartomas could arise not only from the undifferentiated mesenchyme but also from blood vessel walls, within the tumor. Allen and also Bhende seem to favor the last hypothesis. However in some small mesenchymal renal hamartomas isolated smooth muscle cells are found independently of blood vessels. In the angiomyolipomas and the plain muscle tumors of the kidney large, smooth muscle masses are seen which have no relation whatever with any vascular structures. In epiloia many small isolated muscular hamartomas can be seen side by side with lipomas and angiomyolipomas. Also smooth muscle cells as well as rhabdomyoblasts are found in Wilms tumor indicating their embryonic origin. As for the blood vessels of the angiomyolipomas, although they are true vessels in the sense that they are functioning and contain many red blood cells, they are not normal vessels. They are neither arteries nor veins but in their general appearance favor the former. Besides these vessels one can see normal capillaries, normal veins and normal arteries within the tumor. One must conclude that the abnormal vessels described above result also from local dysgenesis as do the smooth muscles. Their

association and apparent blending are only reflections of maldevelopment and do not necessarily mean that one arises from the other or influences the other. For Tweeddale and many others the presence of fat tissue in the renal hamartomas "remains an enigma." We think that the belief that it arises from foci of undifferentiated mesenchymal cells or from potentially immature and pluripotent "rests" is logical and justifiable. Other theories that the fat tissue is the result of fatty metamorphosis of connective tissue (Hunt and Simon) or that it was carried into the renal parenchyma during the invasion of the metanephrogenic cap by the mesenteric bud (Robertson and Hand) leave many questions unanswered. The "embryonal rests" theory can answer them all: the presence of both mature and immature fat; its association with other abnormal tissues such as smooth muscle and blood vessels; its occurrence in multiple foci; its appearance subsequently in a seemingly normal organ; its presence simultaneously in multiple organs (Murphy and associates). All three components (fat, smooth muscle and blood vessels) participate in the making of the mesenchymal hamartoma and are to a certain degree neoplastic. Biological considerations. Albrecht in his original article stated in speaking of the renal hamartomas, "never has there been any sign of growth of these tumors after the kidney themselves ceased growing." This opinion is still held by many that the hamartoma grows only with the organ in which it arises and that its growth ceases with the growth of the organ. Although this is probably true of some renal hamartomas, this is certainly not true of all renal hamartomas. It is certain that the angiomyolipoma does grow independently of the kidney, as do the lipoma and the liposarcoma, as do the "hypernephroid tumor" and the Wilms tumor. As previously stated there are transition forms between hamartomas and hamartoblastomas. Our case 4 contained typical hamartomas, transition tumors and tumors that one could call hamartoblastoma on a pure morphologic basis. Case 3 contained also some anaplastic cells and was clinically a very invasive tumor. One can readily understand why some pathologists will consider such a tumor to be malignant. However the absence of mitoses and of metastases 6H years after incomplete resection of the tumor seems to

MESENCHYMAL HAMAUTOMAS OF KIDNKY

indicate tlmt this was a benign lesion. The case of Berg was considered to be also an angiolipomyosarcoma but did not metastasize and seemingly was devoid of mitoses. Our case 2 as ,rnll as the case of Berg seemingly showed blood vessel invasion although the illustration offered Berg is far from convincing. A perusal of the literature confirmed our impression that the isolated angiomyolipomas even though they may contain immature cells and be invasive are not true malignant tumors. Not one single instance of metastasis has been recorded, when these tumors are found independently of tuberous sclerosis. 1Yhen the two arc associated, malignant lrnmartoma. or hamartoblastoma may and probably do occur (Campbell). In our case 4 although no metastases ,vere found, we believe that some of the renal tumors were actually lmmartoblastomas for the same reason that one of the "hamartial glial nodules" of the brain was also a true glioma. For that matter the association of tuberous sclerosis and brain tumors has been well established (Jli..lcnm and Pansini, Bielschowsky, Ferraro and Doolittle, Globus) and need not be cliscuss<,d here. CONCLUSIO;\J

Whether we are dealing with simple or complex, single or multiple hamartomas; isolated hamartomas or hamartomas of Bourneville's disease, Linclau's disease or Von Rccklinghausen's disease we cannot but subscribe to the implicit acceptance of the hamartial origin of these lesions. Their indigenous nature, absence of encapsulation, complrxity of pattern, slow growth, relative benignity :md their association with other similar or related lesions in instances of tuberous sclerosis speak strongly in favor of a congenital defect or malclevelopmcnt of local origin, often multicentrie. SUMMARY

Five eases of mescnchymal hamartomas arc presented. The first case is that of a small solitary mesenchymal hamartoma found incidentally at nPcropsy in a 64-year-okl man. The second case is characterized by the presence of multiple renal hamartomas in one kidney, onr of which invaded a large renal vein and caused a massive retrope.ritoneal lwmatonrn. The patient ,ms a 38-yearolcl woman ,Yho had none of the stigmata of tuberous sclerosis" This case is, we believe, the

first documented and illustrated invasion of a major blood vessel by a angiomyolipoma. The thircl rnse together w·Ltrt the second case illustrates the fact that the angiomyolipomas, independent of Bournevill(:'s disease, although clinically invasive and possessing microscopic evid en cc of are not malignant in the sense that they do not, metastasize and do not kill. Also case ;3 'ts of the very few reported cases of angiomyolipomu with more than a fi vc year followup. The fourth and fifth cases bring anatomical proof of th<., hamartial nature of tubc;rous sclerosis and of the renal lesions found in this disease" This rests in the simultaneous prescncc1 in one aged 22, of cerebral "gliomas," thyroid "acknomas" and renal "lipornas," "lciomyomas'' and angiomyolipomas; and in the other patient, 27, of cerebral glial nodules, hepatic hamartorrnk, pancreatic "adenomas'' and renal hanrnrtoma:,, In addition, case 5 not only illustrates the !'lmw· relationship between tuberous sclerosis certain types of congenital polycystic disease of the kidneys but also emphasizes the little kno1\T and rare evidence of coexisting renal and hamartomas (angiomyolipomas) in tuberotw sclerosis. In the light of these cases the com:cpt of hamartoma in general and of renal hamartomn in particular was revaluatccl. At the same time an attempt was made to differentiate tlrn n,na i harnartoma from the choristoma, the progonomu . the teratoma, the "capsuloma," t.h(c nephroma" and the nephroblastoma" . \!so son :e clinical, pathological and biological consideration.were presented and a conclusion was drawn in favor of the hamartial nature of the nwsenc·.hymal "tumors" of thr kidney. Dr. 0. Saphir gave permission for use of crwec, l and 3 from the files of the :\Iichael Hee,,(, Hospital, Chicago, Ill. Norma Fn1.nces Rink and ;\Iilclrcd Tress gave technical assistanc:c, ]\IL Zal l\fanclelstram made the graphs" REFERE:c-;;CES

E.: Ueber hamartome. Verha.ndl. rl deutsch. path. Gcsellsch., 7: 15:3, rno,L ALEMA, G. AND PANSIKI, A.: Sclerosi tuberoso, e tumore cerebra.le (c:outributo ana.tomo . clinico) Riv. neurol., 24: 1:3:3, 195cl. Ar.LE:\', A. C.: The Kidne;
1900. BARTSCH,

C.: Ueber eiuen Sdtenen FaII

vo1,.

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Nierenlipom (Thesis). Greifswald: H. Adler, 1951. BERG, J. W.: Angiolipomyosarcoma of kidney (malignant hamartomatous angiolipomyoma) in a case with solitary metastasis from bronchogenic carcinoma. Cancer, 8: 764, 1955. BHENDE, Y. M.: Plain muscle tumors of the kidney; showing angiomatous pattern produced by arterioles. Indian J. M. Sc., 6: 747, 1952. BIELSCHOWSKY, M.: Zur Histopathologie und Pathogenese der tuberosen Sklerose. J. f. Psych. u. Neural., 30: 167, 1924. BIRCH-HIRSCHFELD: Quoted by Melicow. BoYD, W. A.: Textbook of Pathology. Philadelphia: Lea and Febiger, 1953. BRODY, H. AND LIPSHUTZ, H.: Concomitant intrarenal and pararenal angiomyolipomas. J. Urol., 74: 741, 1955. BussE, L.: Ueber Bau, Entwickelung und Einteilung der Nieren-Geschwiilste. Virchows Arch. f. path. Anat., 167: 346, 1899. CAMPBELL, M.: Urology. Philadelphia: W. B. Saunders Company, 1954, vol. 2. COLVIN, S. H., JR.: Certain capsular and subcapsular mixed tumors of the kidney herein called "capsuloma." J. Urol., 48: 585, 1942. CRITCHLEY, M. AND EARL, C. J. C.: Tuberose · sclerosis and allied conditions. Brain, 66: 311, 1932. FERIZ, H.: Ein Beitrag zur Histopathologie der tuberosen Sklerose. Virchows Arch. f. path. Anat., 278: 690, 1930. FERRARO, A. AND DOOLITTLE, G. J.: Tuberous sclerosis (diffuse neurospongioblastosis). Studies in Psychiatry-New York State Psychiatric Institute, 8: 1, 1937. FowLER, J. S. AND DICKSON, W. E. C.: Tuberous (tuberose) sclerosis. Quart. J. Med., 4: 43, 1910-1911. FRIEDMAN, N. B. AND AsH, J.E.: Atlas of GenitoUrinary Pathology. Washington, D. C.: Army Institute of Pathology, 1946. GENEWEIN, F.: Ueber Hamartome (geschwulstartige Fehlbildungen) der Niere und Leber: Ein Beitrag zur Geschwulstlehre. Ztschr. Heilk., 26: 430, 1905. GLOBUS, J. H.: Glioneuroma and spongioneuroblastoma, forms of primary neuroectodermal tumors of the brain. Am. J. Cancer, 32: 163, 1938. GORDON, M. P., JR., KIMMELSTIEL, P. AND CABELL, C. L.: Leiomyoma of the kidney; report of a case with review of the literature. J. Urol., 42: 507, 1939. GoRDON-T AYLOR, G.: Gigantic benign tumor of kidney weighing 22 pounds. Nephrectomy: cure. Brit. J. Surg., 17: 551, 1930. HECKEL, N. J. AND PENICK, G. D.: A mixed tumor of the kidney; lipo-myo-hemangioma. J. Urol., 69: 572, 1948. HULSE, C. A. AND P ALIK, E. E.: Renal hamartoma. J. Urol., 66: 506, 1951. HUNT, V. C. AND SIMON, H. E.: Perirenal and intrarenal lipoma. Am. J. Surg., 4: 390, 1928. INGLIS, K.: Neurilemmoblastosis; the influence of intrinsic factors in disease, when development of the body is abnormal. Am. J. Path., 26: 521, 1950. - : The relation of the renal lesions to the cerebral lesions in the tuberous sclerosis complex. Am. J. Path., 30: 739, 1954.

KARSNER, H. T.: Human Pathology, 6th ed. Philadelphia: J.B. Lippincott Co., 1942. -: Human Pathology, 8th ed. Philadelphia: J. B. Lippincott Co., 1955. KIRPICZNIK, J.: Ein Fall von tuberoser Sklerose und gleichzeitigen multiplen Nierengeschwiilsten. Virchows Arch. f. path. Anat., 202: 358, 1910. LEVER, W. F.: Histopathology of the Skin. Philadelphia: J. B. Lippincott Co., 1949. LOWER, W. E. AND BELCHER, G. W.: Massive lipoma of the kidney. Surg., Gynec. & Obst., 46: 1, 1927. LucKE, B. AND ScHLUMBERGER, H. G. :l Tumors of the kidney, renal pelvis and ureter. Atlas of Tumor Pathology. Washington, D. C.: Armed Forces Institute of Pathology, section 8, fascicle 30, 1952. MALLORY, T. B.: Case records of the Massachusetts General Hospital, case 35221. New Eng. J. Med., 240: 891, 1949. MELICOW, M. M.: Classification of renal neoplasms; a clinical and pathological study based on 199 cases. J. Urol., 61: 333, 1944. MERTZ, H. 0. : Tuberous sclerosis and renal tumor. Trans. Amer. Assoc. Genito-Urin. Surg., 36: 73, 1942. MITCHELL, N. AND ANGRIST, A.: Adrenal rests in the kidney. Arch. Path., 36: 46, 1943. MITTASCH: Demonstration makroskopischer und mikroskopischer Praparate von Organveranderungen bei tuberoser Hirnsklerose. Miinchen med. Wchnschr., 69: 571, 1922. Cited by Feriz and also Tweeddale. MooLTEN, S. E.: Hamartial nature of the tuberous sclerosis complex and its bearing on the tumor problem; report of a case with tumor anomaly of the kidney and adenoma sebaceum. Arch. Int. Med., 69: 589, 1942. MORGAN, G. s., STRAUMFJORD, J. V. AND HALL, E. J.: Angiomyolipoma of the kidney. J. Urol., 66: 525, 1951. MURPHY, E. s., FUJII, Y., YASUNDA, A. AND SASABE, S.: The tuberous sclerosis complex; a study of a new case. A.M.A. Arch. Path., 66: 166, 1958. POPPER, H. AND SCHAFFNER, F.: Liver: Structure and Function. New York: McGraw-Hill Book Co., Inc., 1957. POTTER, E. L.: Pathology of the Fetus and the Newborn. Chicago: The Year Book Publishers, Inc., 1953. PRATT-THOMAS, H. R.: Tuberous sclerosis with congenital tumors of heart and kidney; report of a case in a premature infant. Am. J. Path., 23: 189, 1947. RAPPOPORT, A. E.: Hematuria due to papillary hemangioma of the renal pelvis. Arch. Path., 40: 84, 1945. RIOPELLE, J. L.: The nature and origin of the so-called true kidney hypernephroma. Cancer 4: 789, 1951. ROBERTSON, T. D. AND HAND, J. R.: Primary intrarenal lipoma of surgical significance. J. Urol., 46: 458, 1941. RuscHE, C.: Renal hamartoma (angiomyolipoma); report of three cases. J. Urol., 67: 823, 1952. SAPHIR, 0.: A Text on Systemic Pathology. New York: Grune and Stratton, 1958, vol. 1. SWAN, R.H. J. AND BALME, H.: Angioma of the kidney; report of a case with an analysis of

MESENCHYMAL HAMARTOMAS OF KIDNEY

26 previously reported rnses. Brit. J. Surg., 23: 282, Hl35. TAYLOR, ,) . :\". A'\D GENTirns, K. · Renal angiomyolipoma and tuberous sclerosis. J. Urol., 79: 685, 1958. TKDESCHI, C. G., HoLTHAl\L W. H. AND l\!IrNOR, C. L. · ?1Iixed hypernephroid tumors of the kidneys (metanephromas). J. Urol., 61: 981, 1949. T1n,EDDALE, D. 1'L. DA,VE, C. J., l\IcDo"'iALD, J. R. AND CULP, 0. S.: Angiolipoleiomyoma of the kidney; report of a case with observations on histogenesis, Cm1cer, 8: 75\l, ID55. U. S. Naval Medical School: Color Atlas of Pathology. Philadelphia: J. B. Lippincott Co., 1951.

DER VALK, J. w.: Adenorne sclmce OU theliorna sebace primaire. Bull. (fo frarn;:. pour I' etude du cancer., 13: VVAH.REN, S.: Neoplasm. In: Anderson, \V. Pathology. St. Louis: C. V. lVfosby Co., WA'l'~JH.FALL, Y./. B.: Renal angioma causing seven•, hr1ematmia. Brit. J. Urol., 22: 142, l \l.50. vVrr,Lrs, R. A.: Teratomas. In: Atla.s of 1\m10r Pathology. Washington, D. C.: Armed Fon·es Institute of Pathology, HJ5l, section fascile 9. WILSON: Quoted by Boyd. ZccKERMAN, I. C., KERSHXER, IJ., LAY'l'NKn., B. D. AND HrRSCHE, D.: Leiomyorna of kidney. Ann. 8mg., 126: 220, 1947.

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