Download pdf - Focal cirrhosis of the liver: Its relation to the so-called hamartoma (adenoma, benign hepatoma)

FOCAL CIRRHOSIS OF THE LIVER: ITS RELATION TO THE

BENIGN HEPATOMA)

EDWARD J. BENZ, M.D., AND ARCHIE H. BAGGENSTOSS, M.D.

SO-CALLED HAMARTOMA (ADENOMA,

OCAL OR SOLITARY NODULAR hiAssu are oc- F casionally observed in human livers that show no other significant pathological changes. These include metastatic neoplasms, an occasional primary hepatic-cell carcinoma, focal subcapsular hyperplasia of bile ducts, hemangiomas, granulomas, and adrenal rests. In addition there is the lesion that has been reported under a variety of names such as adenoma. hamartoma, benign hepatoma, solitary hyperplastic nodule, and focal cirrhosis. This lesion occurs in both sexes and at any age. It is usually solitary but may be multiple and varies in size from a diameter of a few millimeters to several centimeters. I t is seen by the surgeon when its size is great enough to cause a palpable abdominal mass. More frequently it does not cause the patient any disturbance and occurs as an incidental finding at laparotomy or the post- mortem examination, in which cases it must be distinguished from metastatic cancer and primary carcinoma of the liver. Despite the multi- plicity of terms that have been used to denote this entity in the literature, the pathological descriptions, photographs, and clinical behavior of the lesion have been strikingly similar. Our present knowledge of the subject is based largely on isolated case reports. No investiga- tions of the problem have included a sufficient number of cases to justify any conclusions re- garding histogenesis.

The present communication is based on a study of thirty-four examples of this entity that were found at necropsies performed at the Mayo Clinic. These cases not only provided am- ple material for the investigation of the fully developed phases of the lesion but also afforded the opportunity to observe the earliest stages of its development. This study was undertaken in an attempt to follow the development of the lesion in question and possibly to elicit information of value in understanding its histogenesis, classification, and possible relationship to

From the Mayo Foundation and the Section on Patho- logic Anatomy, Mayo Clinic, Rochester, Minnesota.

Received for publication, January 16, 1955.

primary hepatic-cell carcinoma occurring in the absence of generalized cirrhosis.

SUMMARY OF THE LITERATURE

The problem of differentiating localized nodular hyperplasia in the liver from true neoplasm was discussed as early as 1884 by Sim- monds. At necropsy he found, as an incidental lesion, a localized oval mass in the left lobe of the liver. The remainder of the liver was normal. In his discussion, he regarded the nodule as a peculiar response of the liver to injury but suggested that i t might have been congenital in origin. Ribbert, Yamagiwa, and Pepere also suggested that these “adenomas” of the liver were a congenital malformation consisting of a separation of a group of cells from continuity with the rest of the organ or a dislocation from bile ducts. In Schmelling’s case, there were multiple hamartomas associated with hypospadias, bilateral syndactylia of the toes, and bilateral hydroceles. Shaw and Turner in separate publications reported the same case, which was called an adenoma (hepatoma) but which had a close resemblance to a localized area of cirrhosis. Shaw stated that these lesions occurred in childhood, were solitary, were commoner in the right lobe of the liver than in the left, and were found in the absence of cirrhosis.

The relationship of these “adenomas” to primary carcinoma of the liver was mentioned by Milne who suggested that they might be “encapsulated cancer growths.” Wright reported a case of a man, aged 60 years, from whom an or- ange-sized mass in the right lobe of the liver was removed. This mass was encapsulated and lay in a surrounding area of cirrhosis, though the rest of the liver showed no cirrhotic change. Although the lesion was considered to be a primary carcinoma, the patient was alive and well three years later. The possibility of neoplastic change arising from “benign hepatomas” has been discussed by Hoffman and by Franklin and Downing.

743

744 CANCER July 1953 Vol. 6

TABLE 1 CASES OF HEPATIC HAMARTOMAS, ADENOMAS, AND SO FORTH REPORTED FROM 1940-1951

Surg. Age or

Author Cases Sex necr. Size, cm. Lobe Diagnosis Comment

Wallace, 1941

Benson & Penber- thy, 1942

Hoffman, 1942

Sierra & Ardao, 1944

Branch, Tonning Pr Skinner, 1945

van Prohaska, 1945

Hershey, 1946

Duckett 8; Mont- gomery, 1947

Franklin & Down- ing, 1947

ando. 1947 Pasquale & Ferdin-

Patton; 1948

Hunter, 1949

Greinacher, 1950

Kay Pr Talbert, 1950

McBurney, Woolner & Wollaeger, 1950

Bartlett & Shellito, 1951

Gerding, Popp & Martineau, 1951

Josephy, 1951

Roth, 1951

1

1

1

1

1

1

1

3

1

1

1

1

3

2

1

1

1

1

1

23 S F

7mo. S F 38 S F 41 S F 32 S F 47 s M

14 S F 73 s M 3 s

A1 20 mo. S

23 S M 56 S F

16% mo. s F 28 s F

7%mo. N F

8mo. N F 67 N M

7mo. S F 13 S M

28 S F

RI

22 mo. S F

8 s R.I 88 N M 35 s F

15X13X.5 Rt. Hepatoma

6 diam. Rt. Hamartoma

7.5 diam. Rt. Benign hepatoma

7 x 5 x 5 Rt. Adenonia

6 diam. Lt. Adenonia

wt. 240 gm. Lt. Chronic focal hepatitis

10 diam. Lt. Hepatorna (adenoma)

18X17X8.5 Lt. Benign hepatoma

? Rt. Pr Lt. Benign hepa toina

3 . 5 X 1 Rt. Adenoma with malignant tendencies

13 diam. Rt. Benign hepatoma

wt. 760 gm. Lt. Solitary adenoma

17X17X9 .5 Rt. Hamartoma

5.6X5X1.9 Lt. Benign hepatoma

? Rt. Hamartoma

? Rt. Hamartoma

? Rt. 7

9.5 X 7.5 X 6 Caud. Hamartoma

7 LRt. & Lt. Harmatoma

6X4X3 Lt. Solitary hyperplastic nodule

1 6 X 1 5 X 8 Rt. Hamartoma

Rt. & Lt. Cholangio- hepatoma

adenoma

12 diam.

1 2 X 9 X 9 Lt. Benign

11 .5X lOX5 ? Adenoma

Patient alive and well 5 yr. postop.

Noted resemblance to cirrhosis



Suspected a t operation as a metastasis (patient had multiple primary carcinomas)

Specimen not completely removed-recurrence

Follow-up not noted

Peduriculated

Cyst in lesion

Calls attention to- possi- bility of lesion being a reparative process

Necrosis in mass

Question of carcinosar- coma

Incomplete removal a t operation

Biopsy only-called attention t o resemblance to cirrhosis

History of hepatitis

“Adenoma with marked fibrous displacement”


Alcoholic history

Found incidental to hy- sterectomy

In 1904, Albrecht introduced the term “hamartoma,” which was defined as a “tumor-like malformation in which actually can be seen only an abnormal mixture of normal elements of the organ in which they appear, whether it be in amount, arrangement, or the degree of maturity, or in all of these aspects.” This term was subsequently applied to many solitary inasses in the liver whose descriptions fit the

“adenomas” and “hepatomas” of many authors. McBurney and associates described a lesion

identical in its salient features with the majority of cases described by others as adenomas, hepatomas, or hamartomas but they rejected a neoplastic concept by a diagnosis of “solitary hyperplastic nodule.” Previously Huguenin had suggested the possibility of a “focal cirrhosis,” a term later used by Stewart and associates

No. 4 FOCAL HEPATIC CIRRHOSIS AND HAMARTOMA - Benz 6 Baggenstoss 745

to describe a nodule in an otherwise noncirrhotic liver.

Warvi discussed criteria for distinguishing adenomas (hamartomas) from localized nodular hyperplasia. T h e distinction depended upon such features as the presence or absence of encapsulation, bile ducts, and secretion of bile-criteria that have not been, and probably could not be, adhered to in individual cases reported in the literature.

Our review of the literature prior to 1940 (lid not disclose any well-documented cases that were not considered by Keller, Warvi, or Hoff inan in their comprehensive reviews of the subject. Cases recorded since 1940 pertinent to this comniunicatioii in which there was adequate docunientation are summarized in Table 1.

MATERIALS AND METHODS

Cases selected for this study were obtained from the records of necropsies at the Rlayo Clinic over a period of thirty years (1922 to 1951). All cases in which there was generalized cirrhosis were excluded. Histological sections of focal lesions in noncirrhotic livers recorded in the protocols as aclenoma, hepatoma, hamartoma, localized regenerative hyperplasia, or focal cirrhosis were examined. In this group were numerous nodules recorded as bile-duct adenomas that were actually subcapsular col- lections of proliferating bile ducts morphologi- cally similar to those described by Edwards and White in rats. These were excluded from this study.

Thirty-four cases occurred in which the hepa tic lesions, though usually smaller than lesions seen surgically, were consistent with those cases in the literature in which a diagnosis of adenoma, hamartoma, benign hepatoma, or solitary hyperplastic nodule was made. Histories were reviewed in all cases. Gross specimens containing the lesions were available for study in twenty cases, and, in the majority of the remainder, the entire diameter of the lesion was available for study, since it was included in a single histological section.

In addition, four cases of proved primary hepatic-cell carcinoma occurring in the absence of generalized cirrhosis, previously studied by Hoyne, were also examined grossly and histologically.

All tissues were fixed in 10 per cent foymalin solution and sections were stained with hematoxylin and eosin. When possible the following special stains were employed in selected cases:

Verhoeff’s elastic-tissue stain with van Gieson counterstain, and Sudan IV stain for fat.

RESULTS

Localized Nodules. There were fifteen men and nineteen women ranging in age from 27 to 74 years. There were eleven patients between the ages of 40 and 49 years. All hepatic lesions were incidental findings at the necropsy and had not caused the patient symptoms. Data of possible significance in the medical histories of these patients included pneumonia (sixteen cases), peptic ulcer (six cases, proved a t necropsy) and previous operative procedures requir- ing general anesthesia (thirteen cases). A history of jaundice was obtained in only two cases, in one of which the jaundice had been due to choledocholithiasis. T h e heavy use of alcohol was recorded only twice in the series.

I n sixteen cases there were primary malignant neoplasms in sites other than the liver, five of which had hepatic metastasis. In two instances, i t is noteworthy that competent ob- servers on gross examination had mistaken the focal lesion in question for a metastasis at the time of necropsy.

An occasional case presented multiple benign or malignant extrahepatic neoplasms or congenital malformations in addition to the solitary nodule in the liver. T h e most striking examples of these are as follows:

Case 1. A 72-year-old woman had carcinoma of the stomach, Meckel’s diverticulum, a dupli- cation of the right ureter, and “focal cirrhosis of the liver.”

Cnse 2. A 47-year-old woman had parathy- roid adenomas (previously extirpated), acinar adenocarcinoma of the tail of the pancreas, bilateral adrenal cortical adenomas (left, 38 gm.; right, 69 gm.), cyst of Brunner’s glands, adrenal rest of the left kidney, and “adenoma of the liver.”

Case 3 . A 27-year-old woman had retroperi- toneal sarcoma, macrocephaly, interventricu- lar septa1 defect in the heart, congenital defect of the maxillary arch, and “regenerative nodule” of the liver.

Gwss Pathological Changes. T h e livers were of normal weight in nineteen cases, more than 2000 gm. in fourteen cases, and 1010 gm. in one case with cachexia caused by a neoplastic lesion. Hypertrophy was usually accounted for by a metastatic tumor, diffuse fatty change, or congestion. Seven of the livers contained single


FIG. 1. Right lobe of the liver showing a typical nodule of focal cirrhosis (upper right) and a cavernous hematigiorna (lower left). Hemangiomas were found in the liver in 20.6 per cent of the cases in the series.

FIG. 2. Multiple nodules of focal cirrhosis in the liver. There is no distortion of Glisson’s cap-. sule though cohpression of the adjacent hepatic parenchyma is evident. Note that there is cirrhosis elsewhere in the liver.

FIG. 3. Cut surface of a nodule of focal cirrhosis showing a moatlike ridge around the mass. FIG. 4. Mounted histological section of a nodule of focal cirrhosis showing sharp demarcation

from normal surrounding parenchyma and tendency to pedunculation. (H. & E. XIIA.)

or multiple small cavernous hemangiomas in addition to the solitary cirrhotic nodule (Fig. 1). This incidence (20.6 per cent) is higher than that observed in routine necropsies.

T h e focal cirrhosis fornled a solitary nodule in twenty-nine cases. In four cases there were two nodules and in another, three nodules. T h e lesions were in the right lobe in twenty livers, in the left lobe in four, in the right and left lobes in three, and in the caudate lobe in two, and they could not be located from available data in five instances. T h e nodules were immediately beneath Glisson’s capsule in about

half the cases. T h e largest lesion was 5.5 cm. in its greatest dimension; the smallest, 0.3 cm.; the average, 1.2 cm. Those that abutted on Glis- son’s capsule caused surprisingly little distortion (Fig. 2). Though there were cases in which the masses projected above the surface of the liver, there were several instances in which there was neither elevation nor depression ex- cept for a shallow moatlike ridge about the periphery (Fig. 3). Puckering and thickening of the overlying capsule were noted in only two cases. There were no pedunculated lesions in the series though the lesion in Fig. 4 might

No. 4 FOCAL HEPATIC CIRRHOSIS AND HAMARTOMA Renz 5 Bnggenstoss 717

FIG. 5. Well-circumscribed area of localized cirrhosis, which measured 5.5X4X4 cm., showing the typical cut surface of these lesions. I t is composed of numerous lnilging regenerative nodules and interlacing bands of fihrous tissue. There is compression of surrounding par- eiichynial structures but no encapsulation.

represeiit the incipient stage of such a process. T h e larger lesions were well circumscribed and frequently were lobulated with a sharp demarcation from the surrounding hepatic parenchyma (Fig. 5). This demarcation was the result of a conspicuous compression atrophy of the surrounding parenchyma or was due to a partial, rarely complete, encirclement by a zone of fibrous tissue. Even when such a “capsule” was present, there were often one or more nodules beyond the limits of this boundary but dis- tinctly a part of the main mass. On section, the cut surface was usually irregular owing to a slight bulging of lobular masses of parenchymal tissue beyond the confines of interlacing fibrous trabeculae. The fibrous trabecular pattern consisted of a dense, centrally or eccentrically lo-

cated, and often stellate-shaped area from which thin strands radiated toward the periphery dividing the parenchymal structures into nodules of diverse sizes and shapes (Fig. 6).

T h e vast majority of lesions were yellow- gray or tawny, variegated in individual cases by the red of blood or, rarely, the green of bile. In two cases, the entire lesions were round and were composed entirely of a reddish-brown, lobular mass of tissue without a capsule.

In the very small lesions, the features described in previous paragraphs were less apparent, aIthough the tendency of the lobular masses to be gathered about a central focus of stroma was noted.

Histological Changes. Of the forty lesions in the thirty-four livers that were stuc?ied histologically, only two were considered as adenomas in a strict sense; that is, while they had some features in common with the other nodules in the series, they differed by having a uniform type of cell, which, while resembling the normal liver cell, was sufficiently different to set i t apart from normal or regenerating hepatic cells. In these two adenomas there were no bile ducts, portal triads, or conspicuous inflammatory cells within the tumor as was char-

Frc. 6. Nodule showing central focus of fibrosis and elevation of Glisson’s capsule. Though this mass shelled out with ease, some peripheral regenerative nodules were left behind in its lower aspect.

FIG. 7. Periphery of a regenerative nodule showing regenerating hepatic cells one of which has three nuclei. (H. & E X430.)

748 CANC:ER J u l y 1953 Vol. 6

FIG. 8. Section of a focal nodule, measuring 0.5 cm. in diameter, showing a central area of inflammation and proliferation of bile ducts surrounded by cords of hepatic cells. Note that even in this early stage of development there is compression of surrounding hepatic parenchyma. (H. 8: E. X50.)

FIG. 9. Larger nodule from the same liver as in Fig. 8. There is a central area of fibrosis from which radiate bands of fibrous tissue that set off nodules of regenerative hepatic cells. Note the absence of encapsulation. (H. & E. X2.)

acteristic of the other nodules. However, neither lesion was encapsulated and both were less than 0.5 cm. in diameter. The other thirty- eight lesions were related to one another by one basic feature, the nodules of regeneration composed of hepatic cells identical to those comprising the regenerative nodule of cirrhosis and, in some instances, the recovery phase of an acute hepatitis. In no instance was there evidence of neoplasia, though cells with hyperchromatic or multiple nuclei were not uncom- mon about the periphery of the regenerative nodule (Fig. 7). There was, however, a con- siderable variation in the stage of development of the lesion and in the predominance of secondary features such as infiltration with fat, fibrosis, bile-duct proliferation, and inflammation. Differences in the stages of development are shown in Figs. 8 and 9, which represent two different nodules in the same liver.

The earliest change observed consisted of a spherical mass of normal-appearing hepatic cells that was conspicuous as a nodule only because of compression of the surrounding parenchyma or infiltration of fat within the cells of the nodule greater than that in the liver as a whole. Four such examples were found, all of which were 1 cm. or less in diameter. Portal triads were present but decreased in number. There was infiltration by lymphocytes and polymorphonuclear leukocytes. There was no encapsulation. It is noteworthy that the lesions

were more conspicuous grossly than micro- scopically.

T h e more fully developed lesions consisted of a central or eccentric stellate zone of fibrosis from which radiated thin bands of fibrous tissue partially or completely encircling nodules of hepatic parenchymal cells. The individual regenerative nodules varied in size and shape (Fig. lo). Evidence of proliferation of the parenchymal cells was confined to the periphery of the nodule. In the fibrous tissue were dilated vascular channels, proliferating bile ducts, conspicuous lymphocytic infiltration, and isolated cords of hepatic cells. The hepatic parenchyma adjacent to the mass showed compression and atrophy of the normal lobules. Frequently, compressed columns of hepatic cells from these lobules protruded into the mass between regenerative nodules (Fig. 11). Though a suggestion of encapsulation was occasionally present, the encirclement was rarely complete and isolated nodules were present beyond the limits of the encircling fibrous band (Fig. 12).

About half of the lesions were intermediate in development between early and late changes. In these, the development of pseudoencapsula- tion could be traced. It is believed that the pseudocapsule was contributed by pre-existing stroma of the adjacent liver, since compressed vessels and bile ducts were often present in it, In some instances the picture was that of an

No. 4 FOCAL HEPATIC CIRRHOSIS AND HAMARTOMA . Benz 6. Baggenstoss 749

active focal hepatitis with areas of necrosis, polyniorphous inflammatory exudate including phagocytes, marked proliferation of bile ducts, shrunken hepatic cells with pyknotic nuclei, and regenerating parenchymal cells with hyperchromatic or double nuclei (Figs. 13, 14).

In addition to the presence of inflammatory response, which was noted in twenty-six of the lesions, the following secondary features are of importance:

vanced degree of infiltration with fat in the regenerative nodules in several cases (Fig. 15). Tliough the livers in ten cases showed some infiltration with fat in the uninvolved parenchyma, the infiltration within the nodules in eight cases was much greater than in the parenchyma. By contrast, the nodules in the other two cases contained little or no fat.

ALCOHOLIC HYALIN. In three lesions there were cytoplasmic deposits of discrete, globular, or irregular masses of red hyaline material identical under the hematoxylin and eosin stain with the alcoholic hyalin described by Mallory in alcoholic cirrhosis (Fig. 16). Unfortunately, special stains for this material could not be done because of previous formalin fixation.

BILE DUCTS AND BILE RETENTION. There was a conspicuous proliferation of bile ducts in the majority of cases. Occasionally they would form a nidus around which several regenerative nodules would be clustered. In the bile canaliculi of several nodules, bile casts were present though the remaining portion of the liver showed no biliary stasis.

BLOOD VESSELS. Not infrequently displaced “central” veins and venous compression by the regenerative nodule, features common in cirrhosis, were demonstrated. Occasionally venous thrombi were present within the lesion. It is noteworthy that in livers showing severe passive congeition, there was no evidence of congestion in the lesion (Fig. 17).

INFILTRATION WITH FAT. There Was an ad-

PRIMARY CARCINOMAS OF THE LIVER

T h e four primary carcinomas of the liver examined were of the hepatocellular type and occurred in livers that were not cirrhotic. Three were in men 28, 58, and 72 years of age respectively. T h e fourth occurred in a girl 5 years of age. In three cases there was a palpable abdominal mass produced by the tumor. In one case, however, the cancer was discovered at necropsy and had presented no symptoms dur-

FIG. 10. Nodule of focal cirrhosis emphasizing vari- ability in the size of the regenerative nodules. (H. & E.

Fiti. 11. Regenerative nodules among which are compressed columns of hepatic cells from the adjacent hepatic parenchyma. Note the eccentric central vein at the lower left. (H. & E. X50.)

ing life. It was associated with a small heman- gioma in the liver and an adenoma in the left adrenal gland that was 3 cm. in diameter. In all cases conclusive evidence of malignancy was present cytologically or in the form of metastasis (three cases) and venous invasion (four cases).

Xl’/.)

FIG. 12. Periphery of a nodule of focal cirrhosis (left) showing isolated regenerative nodules beyond the limits of apparent encapsulation (right). This was a frequent finding (Verhoeffs elastic-tissue stain with van Gieson counterstain. X30.)

FIG. 13. Nodule showing active hepatitis characterized by loss of hepatic parenchyma and intiltration by polymorphous inflammatory cells. Note the pyknotic nuclei in the hepatic cells at the upper right. (H. & E. X75.)

FIG. 14. Another area from the lesion in Fig. 13 showing proliferation of bile ducts. (H. & E.

FIG. 15. Nodule showing typical cirrhosis with marked infiltration of fat. The rest of the liver

750

X75.)

showed only minimal infiltration of fat. (H. & E. X40.)

No. 4 FOCAL HEPATIC CIRRHOSIS A N D H A M A R T O M A - Benz 6. Bnggenstoss 75 1

FIG. 1G. Area from a nodule of focal cirrhosis showing a swollen hepatic cell containing alco-

FIG. 17. Small regenerative nodule that shows no congestion in a liver that is the scat of holic hyalin in the cytoplasm. (H. & E. X450.)

marked chronic passive congestion. (H. 8: E. XIO.)

The gross characteristics of one of these four cases are shown in Fig. 18. T h e over-all archi- tectural pattern of these tumors is not dissimi- lar to those of the benign nodular masses in this study. I n view of this apparent resemblance, multiple sections were taken from each of the tumors, especially about the periphery, to ascertain whether or not there was evidence of localized cirrhosis or benign nodular hyperplasia in addition to carcinoma. Such evidence was completely lacking in three cases. In the other case (Fig. 18) there were peripheral regenerative nodules and thin bands of fibrous tissue that were. the seat of marked infiltration with fat but did not appear neoplastic in them- selves (Fig. 19). The clumps of cells that in- vaded veins were not fatty and resembled the frankly malignant areas of the tumor.

T h e results of this study must be interpreted in the awareness of several important ques- tions: Are the nodular inasses in the livers in thirty-two of thirty-four cases in this series neoplasms or a congenital malformation as has been suggested so frequently in the literature? Are they simply a regenerative or cirrhotic

process that is localized? Are they a reparative process occurring because focal aberrations ol vascular supply or biliary drainage predisposed a localized area in the liver to damage?

In the literature, most authors have assumed a neoplastic or hamartomatous origin for these lesions. Perhaps this concept has arisen from the fact that the lesion frequently presents as a tumor, apparently encapsulated and occasionally pedunculated when it is seen at abdominal exploration. Furthermore, because of the fact that cirrhosis has classically been considered a diffuse process in the liver, there has been reluctance to accept a circumscribed mass as a focal cirrhosis despite its gross and micro- scopic appearance. The terms “hamartoma,” “adenoma,” “mixed adenonia,” “benign hepatoma,” and “cholangiohepatoma” have all been used as descriptive diagnoses and have often been used synonymously, thus adding a problem in semantics to the already existing confu- sion in classification. Warvi included the hamartomas with the adenonias in his classification of the primary tumors of the liver. He gave, as one of their characteristics, the absence of bile ducts. However, in cases reported by Kay and Talbert and by Gerding and associates as hamartomas, the photomicrographs emphasized the

7 52 CANCER . Ju l y 1953 Vol. G

FIG. 18. Primary carcinoma of the liver not associated with generalized cirrhosis. There is a superficial resemblance to the nodules of focal cirrhosis.

proliferation of bile ducts. Rolleston and RIc- Nee stated that a hepatic adenoma has no bile ducts but regarded all the adenomas as hamartomatous in nature. According to Albrecht’s original definition, a hamartoma implies a localized congenital malformation of the normal mature components of an organ. Clearly, a hamartoma is not a neoplasm, for by difinition i t does not possess the basic features of neoplasia. T h e m e of the term “hepatoma” is superfluous, since i t must be subdivided into the benign, which are the adenomas, and the malignant, which are the hepatocellular carcinomas (Warvi).

Examples of tumors of the liver that are true adenomas have been described by Kidd, WiI - ens, Chiray and associates, and others. How- ever, their histological appearance was more uniform than that of the majority of lesions so classified in the literature and did not show an active process of destruction, repair, and inflammatory response so characteristic of the lesions in this study. It is these latter characteristics that cast a suspicion on the correct- ness of classifying most localized regenerative masses as hamaratomas and adenomas.

The basic features of cirrhosis from whatever cause are evidence of injury, either previous or concurrent, nodular regeneration, and fibro- s k 2 1 T h e most striking of these is nodular regeneration, for i t is the one phenomenon that sets apart the response to injury in the liver from that in other organs of the body. It was the regenerative nodule that was pre-eminent in the lesions of this study. T h e cells comprising the nodules were not neoplastic. They were

identical in appearance to the hepatic cells of the nodules of regeneration in cirrhosis.

Secondary features, such as proliferation of bile ducts, inflammation, evidence of destruction of cells, distortion of veins, and focal retention of bile, were present in varying amounts as they are in cirrhosis, particularly of the post- necrotic type. I n many cases, active destruction of parenchymal elements, as well as leukocytic and phagocytic reactions, was seen. It was not the ischemic necrosis that occurs in some neoplasms but was similar to that seen in an active hepatitis. T h e presence of alcoholic hyalin in the lesions of three cases, and in the cases reported by Shaw and by Stewart and associates, and the common finding of a marked degree of infiltration with fat confined to the parenchymal cells within the nodule are evidence supporting the relationship of these focal areas of regeneration to cirrhosis.

T h e partial encapsulation of these lesions is more apparent than real. T h e pseudocapsule is formed from pre-existing stroma of the adjacent liver and is often lost when it disappears among peripheral regenerative nodules. More important in setting off these nodules as a tumor are the compression and atrophy of the uninvolved adjacent hepatic parenchyma. These are logically related to the size of the mass and may explain why those lesions large enough to deserve clinical attention are apparently encapsulated when seen by the surgeon.

In the literature, however, there is a high incidence of this entity in infants and children. T h e association of some of these nodular hepatic lesions with heniangiomas of the liver, multiple neoplasms elsewhere in the body, and con- comitant congenital abnormalities has been noted in this study. In the latter regard, Schmel- ling’s case of multiple hepatic hamartomas and multiple congenital abnormalities is especially significant. As some authors2R- 309 36, 43 have in- dicated, i t is entirely plausihle that a localized area in the liver may show a special predilection to injury on the basis of congenital abnormalities in blood supply or biliary circulation to that region. In several of the nodules studied in this series, the lesions manifested some au- tonomy of vascularity and bile content. In some of the livers that were intensely congested, the focal nodules were relatively bloodless. In one case in which there was some retention of bile throughout the liver, the nodular lesion was not involved. Conversely, several of the nodules exhibited focal retention of bile when the liver as a whole showed none. We were unable to

No. 4 FOCAL HEPATIC CIRRHOSIS AND HAMARTOMA - Benz 6 Baggenstoss 753

determine from this study whether these dis- c rcpancies were developmental in origin or the result of the distortion that occurs in ciirhosis.

The solitary nodular masses in the livers ok inkants and children that resemble those described in this study must be considered sep- arately as regards their clinical behavior. A study of the reports of cases of hamartomas and adenomas of the liver in children that have been described in the literature frequently dis- closed that, though the histological picture ol the lcsions was similar to that in adults, the tuniors were very large, were difficult to remove completely at operation, and tended to grow rapidly despite a relatively benign appearance.

Whether or not the predilection for injury is congenital or acquired, anatomical or physi- ological, the response is localized nodular regeneration arid localized cirrhosis, which re- sponds in its own sphere in a manner similai to that of generalized cirrhosis of the liver. As such it presents the same difficulties in differentiating regenerative hyperplasia from neoplasia, a probIem that has been well discussed by Ewing.

Relatzon to Primary Hepatic-Cell Carcino- ma. Though one might expect that hepatocellular carcinomas may develop in these localized cirrhotic areas, our attempt to establish a defi- nite relationship on the basis of four cases of primary carcinomas in noncirrhotic livers must be considered inconclusive. The gross similarities in location and pattern are suggestive, but a cirrhotic change was demonstrated in or around the tumor in only one case.

The pattern of spherical nodules of cells enclosed by bands of fibrous tissue is repro- duced by many neoplasms (for example, hyper- nephroma), so that the apparent gross similar- i ty in the appearance of the four cases of primary hepatocellular carcinomas studied to an underlying cirrhotic process does not estaolish the relationship of one to the other. Some histological sections of almost any cancer may fail to reveal histological evidence of malignancy, so that, even in the one case of primary hepatocellular carcinoma that showed peripheral foci that appeared to be benign regenerative nodules, it is doubtful whether one should con- sider them as anything else than an integral part of the neoplasm. However, in view of the case reported by Wright and the known association of hepatocellular carcinoma with cirrhosis, study of additional cases of primary carcinoma of the noncirrhotic liver may supply evi-

FIG. 19. Section from the periphery of the tumor in Fig. 18, showing the carcinoma (right) Ranked by nodules of hepatic cells resembling fatty cirrhosis (left). (H. 8c E. Xlx.)

dence supporting the probability that some carcinomas of the liver may arise from an area of focal cirrhosis.

Features of Focal Cirrhosis of Surgical Im- portance. Though this entity is very uncom- mon, it is likely that the surgeon will occasionally see a nodule of localized cirrhosis dur- ing laparotomy performed for other reasons. Since the small lesions are frequently subcapsular, hard, and yellow or gray-white, they may be mistaken for metastatic cancer. If the discovery of such a nodule in the liver has any influence on the choice of a conservative or radical surgical procedure for carcinoma elsewhere in the abdominal cavity, the nodule should be biop- sied and the patient given the benefit of frozen- section diagnosis. Dockerty has observed at least two cases in which a biopsy of such a lesion ruled out metastatic carcinoma. In the surgical removal of these nodular masses, it should be kept in mind that the pseudocapsule does not usually encircle the entire lesion. Therefore, simply shelling out the mass may leave nodules of regeneration behind that may later be interpreted as a recurrence and evidence of malignancy.


SUMMARY AND CONCLUSIONS

Thirty-four cases presenting hepatic lesions at necropsy typical of many described in the literature as hamartomas, adenomas, benign hepatomas, and solitary hyperplastic nodules were studied in an effort to elicit information concerning their histogenesis and classification. In the thirty-four cases were forty nodular lesions. Thirty-eight of them were identical in appearance to, though generally smaller than, those described in the literature as hamartomas or benign neoplasms. T h e other two were true adenomas of a homogeneous cell type.

These localized nodules were single or multiple, generally subcapsular, and most frequently found in the right lobe of the liver. They were associated with hemangionias of the liver in 20.6 per cent of cases and in several cases with other neoplasms or congenital abnormalities.

Grossly and histologically, these nodular masses are identical to a focal area of cirrhosis including such features as active hepatitis, infiltration with fat, alcoholic hyalin. proliferation of bile ducts, and fibrosis. I n tracing the

development of the lesion from the very small nodules encountered in the series, the essential characteristic is the nodule of regeneration.

The reasons for rejecting a neoplastic or hamartomatous concept of this entity are discussed. T h e possibility that focal cirrhosis may develop in an area with an aberrant blood supply or bile-duct malformation is considered, though such evidence is not conclusive from this study.

Tha t some primary carcinomas of the liver apparently occurring in the absence of generalized cirrhosis might arise from a localized cirrhosis is probable. However, our study of four such cases, while presenting similarities in gross architecture of the carcinomas, provided suggestive histological evidence of such a relationship in only one case.

Attention is drawn to two factors of surgical importance, namely, that the small nodules may he mistaken for metastatic cancer at laparotomy, and that, since most of the lesions lack a true capsule, removal of the nodular mass by shelling i t ou t may leave nodules of regeneration behind.

REFERENCES

1. ALBRECHT: Ueber Hamartoine. Verhandl. d . deutsch. path. Gese!lsch. 7: 153-157, 1904.

2. BARTLEIT, I V . C., and SIWLLITO, J. G.: Hamartoma of the liver. Surgery 29: 593-595, 1951.

3. BENSON. C. D., and PENBERTHY. G. C.: Surgical excision of primary tumor of liver (harmartoma [sic]) in infant seven months old with recovery. Surgery 12: 881- 886. 1942.

4. BRANCH, A.; TONNINC. D. J., and SKINNER, G. F.: Adenoma of the liver. Canad. M . A . J . 53: 53-54, 1945.

5. CHIRAY; BROCQ; ALBOT, and LANTHIER: Un cas d’adknonie solitaire du foie. Intervention. Gukrison optratoire, maintenue depuis dix-huit mois. MPm. Acad. de chir. 64: 911-919; disc. 919-923, 1938.

6. DOCKERTY, M. B.: Personal communication to thc authors.

7. DUCKETT, J. W., and MONTGOMERY. H. G.: Resec- tion of primary liver tumors. Surgery 21: 455-469, 1947.

8. EDWARDS, . E., and WHITE, J.: Pathologic changes, with special rejerence to pigmentation and classification of hepatic tumors in rats fed p-dimethylaminoazoben- zene (butter yellow). J. Nat . Cancer Inst. 2: 157-183, 1941.

9. EWING, J.: Neoplastic Diseases; A Treatise on Tumors, 4th ed. Philadelphia. W. B. Saunders Co.

10. FRANKLIN, R. G., and DOWNING, C. F.: Primary liver tumors. A m . J . Surg. 73: 390-395, 1947.

11. GERDINC, W. J.; POPP, M. F., and MARTINEAU, 1’. C.: Haniartomatous cholangiohepatoma; report of a case. J . A . M . A . 143: 821-822, 1951.

12. GREINACHER, 1.: Zur Kenntnis der Leber-Hamar- tome. Beifr . z .pnth . Anat. u . r .a l lg . Path. 111: 1-12, 1950.

13. HERSHEY. C. D.: Partial hepatectomy in certain primary tumors of the liver. South. Surgeon 12: 245-252, 1946.

1940. pp. 735-748.

14. HOFFMAN, H. S.: Benign hepatoma; review of the literature and report of a case. Ann. In t . M e d . 17: 130- 139. 1942.

15. HOYNE, R. M.: Primar carcinoma of the liver. [Master’s Thesis.] Graduate Sc8001, University of Minne- sota. 1944.

16, HUGLIENIN, B.: Ueber Verfettungsherde der Leber. Zentralbl. f. allg. Path. u. path . Anat . 36: 55-56, 1925. Cited by STEWART, H. L.: MORGAN. D. R., and SrRENKEL. v. L.

17. HUNTER, W. R.: A case of benign hepatoma. Brit. 1. Sirrg. 36: 425-428, 1949.

18. JOSEPHY, H.: Benign solitary adenoma of the liver in a male aged 88 years. Illinois M . J . 99: 270-275, 1951;

19. KAY, S., and TALBERT, P. C.: Adenoma of the liver, mixed type (hamartoma); report of two cases. Cancer 3: 307-315, 1950.

20. KELLER, R. M.: Zusammenstellung der wihrend der letzten 50 Jahre in der Literatur beschrieben Falle von Leteradenom mit Beriicksichtigung der Beziehung- en zur knotigen Hyperplasie und zum Carcinom der Leber. Wurzburg. N. Seubert. 1908.

21. KELTY, R. H.; BAGCENSTOSS, A. H.. and Bum. H. R.: T h e relation of the regenerated hepatic nodule to the vascular bed in cirrhosis. Proc. Stafl Meet., Mayo Clin. 25: 17-26, 1950.

22. KIDD, F.: Case of primary tumour of the liver removed by operation. Proc. Roy. SOC. Med. 16 (Pt. 3) (Surgery Sect.): 61-62, 1923.

23. MCBURNEY, R. P.; WOOLNLR, L. B., and WOL- LAEGER, E. E.: Solitary hyperplastic nodule of the liver simulating a neoplasm: report of case. Proc. Stafl Meet ., Mayo Clin. 25: 606-611. 1950.

24. MALLORY, F. B.: T h e Principles of Pathologic Histology. Philadelphia. W. B. Saunders Co. 1914; pp.

I>P. 273-274.

504-508.

No. 4 FOCAL HEPATIC CIRRHOSIS AND HAMARTOMA Benz &- Baggenstoss 755 25. MILNE, L. S.: Primary epithelial tumour growth

in the liver. /. Path. C Bact. 13: 348-361, 1909. 26. PASQUALE, I., and FERDINANDO, S.: Su di un caso

di adenoma solitario del fegato. Ann. i f n l . d i chir. 24:

27. PATTON, R. J.: Haniartonia of the liver. Ann. Sztrg. 127: 180-186, 1948.

28. PEPERE, A.: Dell’origine congenita dell’adcnoma solitario. Arch. per le sc. med. 26: 117-156, PI. VIII , 1902. Cited by SHAIV, A. F. B.

29. PROHASKA, J. VAN: Rcscction of the left lobe of the liver in a patient with four separate carcinomas. A n n . Sicrg. 122: 1092-1097, 1945.

30. RIBBERT. H.: Das rnaligne Adenom der Leber. Deutsrhe med. Wchnschr. 35: 1607-1609, 1909. Cited by SIIAW, A. F. B.

31. ROLLESTON, H., and MCNEE, J. W.: Diseases of the Liver, Gall-bladder arid Bile Ducts, 3d ed. London. hlachlillan and Co. 1929; p. 458.

117-127, 1947.

32. ROTH, F.: Ober das solitare gestielte Leberzell- adenom. Zentralbl. f. a&. Path. u. p n f h . Anat. 87: 216-220, 1951.

33. SCHMELLING, J. W.: Een bijzonder geval van aan- geboren, multiple gezwellen in de lever (hamartomen) bij een kind van vier maanden. Nederl. tijdsclrr. u. ge- neesk. 3: 35GG-3571, 1934.

34. SHAW, A. F. B.: Primary liver-cell adenoma (hepa-

toma). /. Path. C Bact. 26: 475-484; PI. 44, 1923. 35. SIERRA, R. P., and ARDAO, H. Adenoma hepatico;

operacibn-curaci6n. Arch. urug. de med., cir. y espe- cialid. 25: 207-215; disc. 215-216, 1944.

36. SIMMONDS, M.: Die knotige Hyperplasie und das .i\denom der Leber. Deufsches Arch. f. klin. Med. 34: 388-408, PI. 5, 1884.

37. STEWART, H. L.; MORGAN, D. R., and SPRENKEL, \!. L.: Focal fatty change of liver and focal cirrhosis. Ant. I . Clin. Path. 8: 405-421, 1938.

38. TURNER, G. G.: A case in which an adenoma weigh- ing 2 Ib. 3 oz. was successfully removed from the liver: with remarks on the subject of partial hepatectomy. PYOC. Roy. SOC. Med. 16 (Pt. 3) (Surgery Sect.): 43-56, 1923.

39. WALLACE, R. H.: Resection of the liver for hepatoma. Arch. Surg. 43: 14-20, 1941.

40. WARVI, W. N.: Primary neoplasms of the liver. Arch. Path. 37: 367-382, 1944.

41. WILENS, G.: Adenoma of the liver. A m . J . Dis. Child. 55: 792-797, 1938.

42. WRIGHT, G.: Primary carcinoma of the liver ex- used by operation. Proc. Roy. SOC. Med. 16 (Pt. 3 ) (Sur- gery Sect.): 56-58, 1923.

43. YAJrAciwa, K.: Zur Kenntnis des primaren paren- chymatosen Leberkarzinoms (“Hepatoma”). Virchows Arch. f. pa th . Anat . 206: 437-467, 1911. Cited by SHAW.