FOCAL NODULAR OF T H E L I V E R
HYPERPLASIA
A Clinicopathologic Study and Review of the Literature Daniel M. Knowles H, M.D.,* and Marianne Wolff, M.D.-~
Abstract We reviewed the clinical records and pathologic material of 20 patients with biopsy proven hepatic focal n o d u l a r hyperplasia. T h e majority of tim patients were females of child bearing age, five of whom had a history of oral use of contracel~tives. In every instance focal nodular hyperplasia was an incidental finding; liver function tests were always normal. Focal nodular hyperplasia is a distinct histopathologic entity, distinguishable from liver cell adenoma. Specifically it consists of nodular aggregates of cytologically norlnal hepatocytes with foci o f intranodular bile duct proliferation. Focal nodtflar hyperplasia appears to be a benign entity, even in patients in whom the lesion was not excised. T h e association between focal nodular hyperplasia and oral use of contraceptives may be coincidental, a h h o u g h lmrmonally related vascular changes may be responsible for r u p t u r e of the lesion.
Benign hepatic neopiasms have been reported sporadically in the literature, but their clinical manifestations have not been reviewed and considerable confilsion exists over their histopathologic classification despite general acceptance o f the scheme proposed by E d m u n d s o n Y ~ Multiple diagnostic synonyms for focal nodular hyperplasia and use of the term "hepatic a d e n o m a " for all benign hepatic neoplasms h a v e confilsed liver cell a d e n o m a with focal nodular hyperplasia. T h e malignant potential misattributed to focal nodular hyperplasia 3-5 reilects con-
fusion with liver cell adenolna, ~ ~ which is believed to possess malignant potential? T h e natural history of focal nodular hyperplasia, if not surgically excised, is not known? Recently an association between oral contraceptive agents, "hepatic adenomas," and focal nodular hyperplasia has received attention, s-v' Clarification of this association is desirable and is d e p e n d e n t upon proper histopathologic characterization o f focal nodular hyperplasia and its delineation fi'om true hepatic neoplasms. We reviewed 20 cases of biopsy
*Postdoctoral Fellow, Rockefeller University. Resident, l)eparlmcnt of Pathology, Columbia University College of i'hysici:msand Surgeons, New York, New York. TAssociate l'rofcssor of Clinical Surgical l'athology, Colunllli:tUniversityCollegeof l'hysiciansand Surgeons. Associate Surgical l'athologist. Presbyterian ltospital of tile ('it)' of New York, New York, New York.
533
H U M A N P A T H O I . O G Y - V O 1 , U M E 7, NUMBER 5 p r o v e n focal n o d u l a r h y p e r p l a s i a in l i v i n g p a t i e n t s , a t t e m p t i n g to d e f i n e the e n t i t y clinically a n d p a t l m l o g i c a l l y . W e also surveyed the English literature, analyzing cases r e p o r t e d u n d e r tim v a r i o u s s y n o n y m s o f focal n o d u l a r h y p e r p l a s i a .
PATIENTS
AND
METHODS
T w e n t y cases o f h e p a t i c focal n o d u l a r h y p e r p l a s i a , 16 local a n d f o u r c o n s u h a t i o n cases, w e r e f o u n d i n t h e files o f t h e Laboratory of Surgical Pathology, Columbia U n i v e r s i t y , b e t w e e n 1950 a n d 1973.
T A B L E 1.
534
September 1976
T h e slides f r o m all cases p r e v i o u s l y diagn o s e d as focal n o d u l a r h y p e r p l a s i a , focal n o d u l a r cirrhosis, hepatic h a m a r t o m a , a n d h e p a t i c a d e n o m a were r e v i e w e d . O n l y tlmse cases c o n s i s t e n t with focal n o d u l a r hyl~erplasia as d e f i n e d b y E d m u n d s o n ~ w e r e i n c l u d e d . T i m o r i g i n a l blocks w e r e r e c u t a n d s t a i n e d as n e c e s s a r y to a l l o w v e r i f i c a t i o n o f e a c h case. T h e h o s p i t a l r e c o r d s o f 15 o f tim 1 6 , local cases w e r e available for s t u d y , a n d private physicians often provided add i t i o n a l i n f o r m a t i o n f r o m t h e i r office r e c o r d s . Clinical i n f o r m a t i o n was p r o v i d e d b y r e f e r r i n g p a t l m l o g i s t s in each c o n s u h a t i o n case.
ACCEPTABLE LITERATURE CASES OF FOCAL NODULAR HYPERPLASIA
Author
Year
Age
Sex
Hoffm:.,n':
1941
38
F
Incidental abd. m a s s
Benign hepatoma
Bensol?4
1942
7 too.
F
Incidental abd. mass
tlamartoma
Brancl?5
1945
32
F
Abd. pain, abd. mass
Adenoma
Franklin~6
1947
23
M
Abd. mass, nausea, vomiting
ttepatoma
llunter 4
1949
28
F
Abd. mass, nausea, vomiting
Benign hepatoma
-
McBurne)'~r
1950
28
F
Abd. pain, abd. mass
Solitary hyperplastic nodule
-
Ka)"~s
1950
7 too. 13
F M
Incidental abd. m a s s Abd. mass, nausea, vomiting
Mixed type adenoma Mixed type adenoma
Died postop. 18 too.
Gertlingr~
1951
M
Incidental abd. mass
tlamartomatous cholangiohepatom;l
-
Levenson -~~
1952
15 too.
M
Incidental abd. m a s s
Mixed type adelmnla
--
Begga
195q
59
M
lllcidental abd. m a s s
46
F
RUQ pain, RUQ mass
23
F
Abd. mass
47
F
limidemal abd. mass
Isolated nodules of regen erat ire hypcrplasia Isolated nodules of regenerative hyperplasia Isolated nodules of regenerative hyperplasia Isolated nodules of regenerative hyperplasla
Benz21
193q
8
Symptoms
34 necropsy cases
Diagnosis
Foc,d cirrhosis
Follow-up -4 too.
3 yr. 2 yr. 2 yr. 18 too.
--
FOCAl.
I lYI'ERI'LASIA
OF THE
LIVER--I,~Nowt.ES, WoLvv
ACCEPTAP,LE LITERATURE CASES OF FOCAL NODULAR HYPERI'LASIA (Continued)
T A B L E 1.
Author
NOI)ULAR
Year
Age
Sex
Symptoms
Diagnosis
Follow-up
Christopherson 2
1953
12 7
M F
Abd. pain, abd. mass Abd. paiq, abd. mass
tlamartoma tlamartoma
9 too. 3 yr.
ltensoff2-'*
1956
5 28 39
F F F
Abd. pain, abd. mass Abd. paiq, abd. mass Incidental
tlepatoadenoma tlepatoadenonm tlepatoadenoma
47 yr. '2 yr. 3V', yr.
Cla) -04
1958
63
F
Abd. mass, weight loss
Benign h e p a t o m a
27 too.
Palubi,lskas 7
1967
'2'2
F
hlcidental
Liver cell a d e n o m a
--
E d m u n d s o n 25
1968
37
F
Abd. pain, abd. mass
Focal n o d u l a r hypcrl)lasia
-
Aronscn 26
1968
23
M
Incidental
Focal n o d u l a r cirrhosis 8 too.
Garanis 27
1969
8
M
tlepatic a d e n o m a
8 14
18
F F F
Abd. pain, nausea, vomiting Incidental abd. mass Incidental abd. mass Incidental
-
-
Necropsy case
18
F
lncidcntal
40
F
Incide,ual
38
F
Incidental
40
F
l,acidental
Focal n o d u l a r hyperplasia
9 too.
34
F
Incideqtal
5 too.
--
--
Necropsy case
Focal nodtflar hyperplasia Focal n o d u l a r hypcrplasia
Malt 5
Ramchand -"s
1970
1970
-
tlepatic aclenoma ! lepatic a d e n o n m ttepatic a d e n o m a tlepatic a d e n o m a Focal n o d u l a r hyperl)lasia Focal n o d u l a r hyperplasia Focal nodtflar hyl)erplasia
---
Crispin 8
1971
20
F
Abd. pain, abd. mass
1lepatic a d e n o n m
llertzer z'J
1971
14
M
Abd. mass
Focal cirrhosis
i'hillips 3~
1973
6 cases without clinical data
Ilepatic h a n m r t o m a
-
*Ma)'s '2
1974
42
F
Abd. I)ain
-
26
F
Abd. h e m o r r h a g e
25
F
Abd. paiq, abd. ,nass
Focal n o d u l a r hyt)erl)lasia Focal n o d u l a r hyperplasia Focal n o d u l a r h)perlflasia
41
F
Incidental
26
F
Incidental
58
F
Incidental
O'Reilly 31
1974
Focal ,lodular hypcrl~lasia Focal n o d u l a r hyperplasia Focal n o d u l a r hyperplasia
11/9 yr.
-
m
D
*tlistory o f oral contraceptive medication fox four to seveq )ears.
535
HUMAN
I':kTHO1.OGY--VOLUME
7,
NUMBER
september1976
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NODULAR
ltYI'ERIq.ASIA
OF THE
9
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HUMAN I'ATHOLOGY--VOLUME 7, NUMBER 5 September 1976 REVIEW OF THE LITERATURE
Review of the English literature revealed only 82 acceptable cases of focal nodular hyperplasia, 42 of which lacked clinical data or were necropsy findings (Table 1). Among the 40 patients for whom clinical information was available, only 29 were 18 )'ears of age or older. Twenty-five (86 per cent) of the latter were women. The meau age of the adult males was 42 )'ears and the mean age of the adult females was 34 )'ears. Focal nodular hyperplasia was an incidental finding in 16 I)atients, but in 13 others either a mass was palpated by the patient or the lesion produced symptoms of abdominal discomfort, nausea, and vomiting. Mays et al? 2 described a 26 year old female taking contraceptives orally for seven years who presented with i n t r a - a b d o m i n a l h e m o r r h a g e d u e to rupttn'e of a large area of focal nodular hyperplasia. Follow-up in the previously reported cases has been sporadic and 1)oor (Table 1). However, no patient appears to have developed evidence of hepatic dysfunction, other hepatic disease, recto:rent focal n o d u l a r h y p e r p l a s i a , or hel)atocelhflar carcinoma. However, in each reported case the lesion of focal nodular hyperplasia had been totally excised. There are no follow-up data available for an)" patient wlmse lesion was simply subjected to biopsy examination and not surgically excised. RESULTS
Clinical Fin dings
538
The 20 patients we studied, 17 females and tlu'ee males, ranged in age from 21 to 66 years (Table 2). T h e mean age of the male patients was 52 )'ears and that of the female patients, 46 years. (No pediatric patients were included in tim present series, althougll they have been included in the literature review.) In each case focal nodular hyperplasia was an incidental finding; in no instance was the disorder symptomatic. Most commonly it was an incidental finding at the time of cholecystectomy for cholelithiasis (nine cases, 47 per cent). Focal nodular hyperplasia
was also found incidentally during abdominal hysterectomy (three cases), laparotomy for acute upper gastrointestinal llemorrhage (two cases), and exploratory laparotomies, which revealed a retroperitoneal ganglioneuroma, a gastric Idomyonla, a gastric nicer, and a carcinoid tumor of the jejunum. In one instance a hepatic nodule was seen during laparoscopic tubal ligation; the patient subsequently was subjected to exploration and the nodule of focal nodular hyperplasia diagnosed by frozen section. l'hysical findings retlected the underlying pathologic lesion with which focal nodular hyperplasia was coincidentally associated. Hepatomegaly was described in three patients but nodular masses were never palpated. It is doubtful-that the relatively small nodules in these cases could be responsible for hepatomegaly. Jaundice was never noted in any patient and liver ftmction tests were ahvays normal. An extensive gynecologic history was available in 14 of the 17 female patients. Five women had been postmenopausal for fi'om nine to 24 years witlmut a history of oral use of contraceptives. Two patients were u n d e r g o i n g hysterectomy for adenomyosis at the time of discovery of focal nodular hyperplasia. Five women, ages 21 to 3 6 , had taken contraceptives orally for six months to seven )'ears prior to discovery of focal nodular hyperplasia. Oral use of contraceptives was not mentioned in the charts of four premenopausal women said to have had regular and normal menses. In one patient multiple nodules of focal nodular hyperplasia were discovered (one of which was subjected to biopsy examination) d u r i n g hysterectomy (Table 2, No. 9). She was subsequently given ethinylestradiol and diethylstilbestrol for 16 months postoperatively for postmenopausal syxnptoms. She remained asymptomatic with a normal physical examination and normal liver function tests 103 months later. Another patient whose lesion was totally excised was taking contraceptives orally and was alive and well 36 months later (Table 2, No. 5). The nodules of focal n o d u l a r hyperplasia were totally excised in ten patients and merely examined by biopsy study in
FOCAl. NODUI.AR ItYPERIq.AS1A OF T H E IAVER--KxowLcs, WOLVV TABLE
3.
Total patients Number of patients followed Duration of followup (months) Deceased
FOLLOW-UP DATA
g e s t i n g llepatic No. 17).
Biopsy Only
Excision
10
10
7
7
1O- 130 (mean :55) 0
16-198 (mean :74) 0
ten o t h e r s , i n c h t d i n g t h r e e p a t i e n t s witli m o r e t h a n o n e n o d u l e ( T a b l e 3). Seven patients in e a c h g r o u p w e r e f o l l o w e d f o r ten to 198 montlls. N o p a t i e n t llas dev e l o p e d a b n o r m a l liver f n n c t i o n tests o r clinical e v i d e n c e o f h e p a t i c disease o r has died. O n e p a t i e n t ( T a b l e L2, No. 8) at the time o f writing h a d b i o p s y p r o v e n h e p a t i c nmetastases f r o m a p a n c r e a t i c c a r c i n o m a (tim s u r g e o n did not r e c o r d tlle a p p e a r a n c e o f tile n o d u l e o f focal n o d u l a r h y p e r p l a s i a at t h e t i m e o f b i o p s y ; T a b l e 2, No. 8), a n d a p a t i e n t witll a j e j u n a l carcinoid h a d the c a r c i n o i d s y n d r o m e a n d m u l t i p l e focal d e f e c t s o n liver scan, s u g -
metastases
(Table
2,
Pathology Focal n o d u l a r h y p e r p l a s i a usually p r e sents as a discrete, well c i r c u m s c r i b e d , firm, tan to y e l l o w - b r o w n , m u l t i n o d u l a r , cirrlmtic-like mass in a n o t h e r w i s e u n r e m a r k a b l e liver. T h e lesion is usually subc a p s n l a r , b u t it ilia}' also e i t h e r lie d e e p within the liver or p r o j e c t fi-om tile s u r f a c e (Fig. 1). Occasionally two o r even m u h i p l e n o d u l e s a r e p r e s e n t . 3 A h l t o u g l l it Iias b e e n a s s e r t e d tllat focal n o d u l a r l l y p e r p l a s i a m o s t c o m m o n l y occurs in t h e rigllt lobe,' we f o u n d that it o c c u r r e d j u s t as c o m m o n l y ill tile left lobe. M o r e o v e r , the lesions w e r e f o u n d all o v e r t h e liver: s u p e r i o r l y , laterally, a n d inferiorly. A m o n g t h e p r e s e n t cases tim d i a m e t e r o f t h e lesion r a n g e d fi'om 1 to 7 cm. ( m o s t c o m n a o n l y 2 to 3 cm.). N u n m r o t t s l a r g e r lesions, r a n g i n g u p to 15 cm. in d i a m e t e r , a n d w e i g h i n g as m u c h as 700 gin., h a v e b e e n r e p o r t e d . ~' '"' ,9, ,_q T l l e s e large lesions o f t e n p r o j e c t fi-om tim s u r f a c e o f tim liver a n d m a y be attaclled o n l y by a thin p e d icle.3, 16, '.,4, '.,;
Figure 1. A 7 cm. nodule of focal nodular hylmrplasia fimnd incidentally in all elderly man at autopsy. It shmvs tile typical gross features of focal nodular hyperl)lasia: a subcapsular, well circumscribed, pale inass with a central stellate scarlike area. l'eripherally radiating septa subdivide tile mass into multiple, variably sized nodules, simulati,lg a focal cirrhotic pattern.
539
H U M A N I ' A T H O L O G Y - - V O L U * I E 7, NUMBER 5
September1976
Figure 2. The hepatocytes of focal nodular hyperplasia (lower left; note the edge of a central fibrous area) blend imperceptibly into the surrounding normal hel)atic i)arenchyma (Upl)er right); there is no evidence of encapsulation. (Trichrume stain, x38.) /"
The gross appearance of the liver on c u t s e c t i o n is p a t h o g n o m o n i c in n e a r l y all i n s t a n c e s . T h e r e is a c e n t r a l s t e l l a t e o r linear, scarlike, fibrous connective tissue
540
a r e a f r o m w h i c h fibrotis c o n n e c t i v e tissue radiates peripherally, di('iding the mass into multiple, variably sized nodules, s i m u l a t i n g t h e p a t ' t e r n o f c i r r h o s i s . AI-
Figure 3. Characteristically, focal nodular hyperplasia coqsists of large aggregates of normal appearing hepatocytes (inset). without true portal triads or central veins, subdivided by strands of fibrous tissue with proliferating bile dt,cts and chronic inllammatory cells. (llematoxylin-i~hloxine-safran stain, x38 and X375.)
FOCAL NODULAR
HYI'ERPLASIA OF THE
LIVER--KNOWLES, WOLFV
Figure 4. In contrast with the pattern in Figure 3, some lesions display nodules of hepatocytes widely separated by fibl-otls connective tissue containing chronic inflammatory cells and loci of proliferating bile ducts. (ttematoxyliu-phloxine-safran stain, x35.)
though not encapsulated, these nodules grossly appear to be well demarcated from the surrounding hepatic parenchyma (Fig. 1). The lesion is nearly always solid without areas of hemorrlmge or necrosis. Microscopically the nodtfles of focal nodular hyperplasia usually blend imperceptibly into the surrounding liver parenchyma, althongi~ occasionally they may appear partially encapsulated (Fig. 2). The clmracteristic central stellate "scar" is composed of variably vascnlarized, dense fibrous connective tissue, wlfich often contains chronic inflanmmtory cells. The peripherally radiating fibrous septa may be narrow, subdividing the lesion into mnltiple, variably sized, interconnecting nodules of cytologically normal appearing hepatocytes (Fig. 3). Conversely the fibrous septa ilia)' be so wide that the nodules lie generally isolated fi'om one another (Fig. 4). Intranodular and internodular bile duct proliferation is abundant (Figs. 5, 6). Often the haphazardly arranged, proliferating bile duct elements nlerge inq)erceptibly with tile hepatocytic elements (Fig. 6). In such instances the unwary pathologist, without the appropriate clinical information, nlay wrongly identify the lesion as cholangiocarcinoma arising ill a cirrhotic liver.
Two llistologic characteristics define focal nodular hyperplasia and pernlit its recognition and differentiation from cirrllosis, even with only a small biopsy specinlen. Tile first feature is the conlplete lack of normal lobular arcllitecture, tile lesion consisting of large nodular aggregations of nornlal appearing hepatocytes without central veins or portal fields (Fig. 3). Both tilin walled venous clmnnels and arterial vessels are present, but there is no apparent organization of tile hepatocytes around them. The second histologic feature is the presence of areas of intranodular bile duct proliferation, which appeal" to blend into the hepatocytic elements (Fig. 6). In combination with the gross features already specified, these histologic features define focal nodular llyperplasia. T h e helsatocytes of focal nodular hyperplasia appear cytologically nornlal, indistinguishable from nornlal liver (Fig. 3). The sinusoids are bordered by Kupffer cells. Neither cholestasis nor hemosiderosis was seen in the present cases, hi one case fatty metamorphosis of the hepatocytes of focal nodular hyperplasia was present. In contradistinction to focal nodular hyperplasia, liver cell adenomas occur as solitary snlooth encapsulated masses with-
541
HUMAN
PATHOI~OGY--VOLUME
7, N U M B E R 5
September1976
Figure 5. A characteristic histologic feature of focal nodular hyperl~lasia is the presence of a focus of haphazardly arranged, proliferating bile ducts in the midst of a large aggregate of hepatocytcs-intranodular bile duct proliferation. (ttematoxylin-pl~loxine-safran slain, x88.)
out the central scar, radiating fibrous septa, or nodularity of focal nodular hyperplasia. Histologically they are composed entirely of generally normal appearing
542
hepatocytes without bile ducts OF central veins. Bile stasis is occaSionally present. Foci of l~emorrhage are more c o m m o n ? ~ . Electron microscopically the hepatocytes,
Figure 6. Bile duct proliferation is often abundant :it the periphery of the hepatocyte nodtdes. The bile duct epitheliunl merges iml~erceptibly with the cords of hepatocytes--internodular bile duct proliferatioq. (ltematoxylin-phloxine-safran stain, x 160.)
FOCAL NODULAR ItYPERI'I.ASIA OF THE LIVER--KNOWLES,WOLVV biliary epithelium, and Kupffer cells of focal nodular hyperplasia are almost identical to those of normal liver, whereas the hepatocytes of liver cell adenomas differ in several respects fi'om those of norreal liver and focal nodular 1wperplasia. 3~ DISCUSSION
Tile misconception that focal nodular hyperplasia can undergo malignant change a-5 is lfistorically related to Ewing's belief that a gradation exists between hepatic hamartoma, hepatic adenoma, and hepatic carcinoma'-'" and to confusion generated by the nmhiplicity of terms used in the literature to denote focal nodular hyperplasia (Table I). The indiscrimate u~e of the term "hepatic adenoma" to denote focal nodular hyperplasia has particularly hindered clinicopathologic characterization of focal nodular hyperplasia and has maligned any prognostic significance attached to the pathologic diagnosis. T r u e liver cell adenomas are reputed to lmve the potential for undergoing malignant change, ~ although some cases reported as such are questionable, a2 The 20 per cent recurrence rate of hepatic adenomas noted by Warvi aa probably indicates that a significant number of well differentiated, uninodular hepatocelhflar carcinomas were misdiagnosed as adenomas in the older literature, making true liver cell adenomas seem potentially more malignant than they probably are. The attachment of such stigmata to the patient with focal nodular hyperplasia is not warranted. Numerous eases of "hepatic adenomas" have recently been reported, several of the patients presenting with henlol~eritolleunl due to rupture of the a d e n o l n a . Z L s-11,34-3s S o l n e o f these patients had been taking contraceptives orallys't~ or had been pregnant 39 at the time of diagnosis, leading some observers to suggest an association between the hormonal effects of oral adnfinistration of contraceptive medication and the developinent of liver cell adenomas, s' 9, H Mays v-' reported three young women with focal nodnlar hyperplasia who had been taking contraceptives orally. One patient presented with ruptnred focal
nodules, and focal intratumor hemorrhage was present in the two other patients. The only other literature cases with intratumor helnorrlmge were two patients reported by Begg and Berry. 3 Mays t2 suggested that some of the aforementioned cases might be lesions of focal nodular hyperplasia, inappropriately labeled hepatic adenomas, or benign hepatomas.S, 9 Thus, the indiscriminate use of the term hepatic adenoma has clouded clinical understanding of focal nodular hyperplasia and its possible association with the orally administered contraceptives. Focal nodular hyperplasia has always been a rare lesion, occurring predominantly in young women. Since a high percentage of young women now take contraceptives orally, an occasional case in such a patient is expected. Relating the development of focal nodular hyperplasia to hormonal effects alone is impossible at the present time. However, tile presentation of the disorder as hepatic rul)ture is distinctly unusual and tiffs aspect may indeed be hormonally influenced. Mays t'- described vascular changes of the afferent vessels, in particular the interlobular branches of tile portal vein, in his three cases of focal nodular hyperplasia. The association between orally administered contraceptives and tliromboembolic phenomena is well known? ~ Hepatic vein thrombosis recently has been described in young women taking contraceptives orally,43-4(; and a case of fatal endophlebitis and hepatic vein thrombosis with infarction and rupture has also been reported. 47 Hepatic rupture during pregnancy is an unconnnon but well known phenomenon. 4s Various hepatotoxic effects of orally administered contraceptives and other hormonal preparations, including the development of hepatocellular carcinoma, have also been described, both in humans and in anin l a l s . 4-9-55
At tile present time focal nodular hyperplasia appears to be a completely benign hepatic lesion of unknown etiology, removal of which is not necessary unless the lesion is symptomatic by virtue of its large size. Very rarely a large lesion of focal nodular hyperplasia may rupture.l-~ Hormonally induced vascular changes
543
HUMAN
PATHOI.OGY--VOI.UME
7, N U M B E R 5
h a v e b e e n s u g g e s t e d as all e t i o l o g i c m e c h a n i s m , b u t n o c a u s a l a s s o c i a t i o n is e s t a b l i s h e d at t h e p r e s e n t t i m e . r'
ACKNOWLEDGMENTS
T h e a u t h o r s a r e g r a t e f i f l to n u n m r o u s p h y s i c i a n s at t h e C o l u m b i a - P r e s b y t e r i a n M e d i c a l C e n t e r a n d to D r . R i c h a r d S a b b i a of the White Plains Hospital Association for providing clinical follow-up data rel a t i n g to s e v e r a l p a t i e n t s . T h e y a r e i n d e b t e d to Dr. R a f f a e l e L a t t e s f o r c o n s t r u c t i v e c r i t i c i s m , to M i s s I d a N a t h a n a n d M r . Ulisses Martin for l)hotographic assistance, a n d to M r s . B a r b a r a A. J o h n f o r s e c r e t a r i a l assistance.
REFERENCES
544
1. Edmundson, II. A.: Tumors of the Liver and Intrahepatic lille Ducts. Atlas of Tumor l'athology, Fascicle 25. Washington, D.C., Armed Forces Institute of l'athology, 1958. 2. Edtmmdson, I I. A.: Differential diagnosis of tttmors and tumor-like lesions of liver in itffancy and childhood. A.M.A.J. Dis. Child., 91:168i 86, 1956. 3. Begg, C. F., and Berry, W. t1.: Isolated nodules of regenerative hypcrl)lasia of the liver. Amer. J. Clin. Path.,23:447--163, 1953. 4. ttuntcr, W. R.: A ~:ase of benign hepatoma. Brit. J. Surg.,36:425-428, 19t9. 5. Mah, R. A., Ilershbcrg, R. A., and Miller, W. L.: Exl)erience with benign tunmrs of the liver. Surg. Gyncc. Obstct., 130:285-291, 1970. 6. Crispin, I 1. A.: A case of hepatic adcnoma. Acta Chlr. Belg., 70:91-110, 1971. 7. l'alubinskas, A. J., Baldwin, J., and McCormack, K. R.: Liver-cell adcnoma, angiogral)hic findings and report of a case. Radiology, 89:444447, 1967. 8. Baum, J. K., Bookstein, J. J., and llohz, F.: l)os sible associaticm between benign hepatomas and oral contraceptives. Lancet, 11:926-929, 1973. 9. Contostavlos, D. L.: l),enign hepatomas and oral contraceptives. Lancet, H: 1200, 1973. 10. Kelso, D. R.: Benign hepatomas and oral contraceptives, l.ancet, 1:315-316, 1974. 11. Knal) p, W. A., and Ruclmcr, B. 11.: llcpalomas and oral contraceptives. Lancet, 1:270-271, 1974. 12. Mays, E. T., Christophcrson, W. M., and Barrows, G. 11.: Focal nodular hyl)Crl)lasia of the liver: l)ossible relationship to oral contracel)tires. Amer. J. Clin. l'ath., 61:735-746, 1974. 13. I loffman, ft. S.: Benign hepatoma: review of the literature and report of a case. Ann. Int. Med., 17:130-139, 1942. 14. Bcnson, C. D. and Peabertby, G. C.: Surgical
September 1976
excision of primary minor of liver (hamartonm) in infant seven months old with recovery. Surgery, 12:881-886, 1942. 15. Branch, A., Tonning, D. J., aqd Skinner, G. F.: Adenoma of the liver. C,mad. Med. Assoc. J., 53:53-54, 1945. 16. Franklin, R. G., and Downing, C. F.: l'rimary liver ttlmors. Alller. J. Stlrg., 73:390-395, 1947. ! 7. Mcl),urney, R. P., Woolner, L. B., and Woolacger, E. E.: Solitary hyl)crplastic nodule of the liver simulating a neoplasm: report of a case. Proc. Mayo Clin., 25:606-61 I, 1950. 18. Kay, S., and Talbert, P. C.: Adenoma of the liver, mixed type (hamartoma). Cancer, 3:307-315, 1950. 19. Gerding, W. J., Pot) p, M. I:., and Martlneau, P. C.: ttamartomatous cholangio-hel)atoma: report of a case. J. Amcr. Mcd. Assoc., 145: 821-822, 1951. 20. I.evenson, R. M., and Mason, D. G.: Mixed adenoma (hamartoma) of the liver: report of a case. A,m. Int. Mcd.,38:136-141, 1953. 21. Benz, E. J., and Baggcnstoss, A. tt.: Focal cirrhosis of the liver: its relation to the so-ca/led hamartoma (adcnonm, benign hepatonm). Cancer, 6:743-755, 1953. 22. Christopherson, W. M., and Collier, tl. S.: Primary benign liver cell tumors in infancy and childhood. Cancer, 6:853-861, 1953. 23. I lenson, S. W., (;ray, tl. K., and Dockerty, M. B.: l',enign tumors of the liver. I. Adenomas. Surg. Gyncc. Obstct., 103:23-30, 1956. 24. Clay, R. C., and Finney, G. C.: 1.0bcctomy of the liver for benign conditions: Ann. Surg., 147: 827-834, 1958. 25. (_;all, E. A., Popper, i1~i and Edmundson, tt.: Selninar on diseases of the liver. Thirty-Third Seminar of the American Society of Clinical l'athologists, Chicago, 1968. 26. Aronscn, K. F., Ericsson, B., Lunderquist, A., Mahnl)org, O., and Norden, J. G.: A case of operated focal nodular cirrhosis of the liver. Scand. J. Gastrocm., 3:58-64, 1968. 27. Garanis,J. C.,Tang, T.,l'anares, R.,andjurcvics, I.: tlcpatic adclmma: biochemical aqd electron microscopic study. Cancer, 24:560-568, 1969. 28. Ramchand, S., Suh, 11. S., and Gonzalez-Crussi, F.: Focal nodular IDpcrlflasia of the liver. Canad.J. Surg., 13:22-26, 1970. 29. ttertzer, N. R., ttawk, W. A., and llerma,m, R. E.: lnllalnmatory lesions of the liver which simulate tumor: report of two cases iq children. Surgery,69:839-846, 1971. 30. l'hillips, M. J., Langer, B., Stone, R., Fisher, M. M., and Ritchie, S.: Benign liver cell tu,nors: classification and ultrastructural pathology. Cnncer,32:463-470, 1973. 31. O'Reilly, K.: Focal nodular hyl)crplasia of the liver. Aust. New Zeal. J. Surg., 44:142-143, 1974. 32. l'imparkar, B. D., Bhalcrao, P,. A., l)eodhar, K. P., Nerurkar, M. (,., and Mchta,J. M.: llepatic adcnoma with malignant change. J. Assoc, Phy. IHd.,20:391-396, 1972. 33. Warvi, W. N.: l'rimary neoplasms of the liver. Arch. l'ath.,37:367-382, 1944. 3t. Scorer, C. G.: Sponta)leous rtzl)ture of a hepatic
F O C A L N O D U I , A R I I Y P E R I ' L A S I A O F T H E L I V E R - - K N o w L E S , WOLFV
35. 36. 37.
38. 39. 40. 41.
42. 43.
44. 45.
adenonm, a possible hazard of flying. Brit. J. Surg.,56:633-635, 1969. Motsay, G. J., and Gamble, W. G.: Clinical experience with hepatic adenomas. Snrg. Gynec. Obstet., 134:4 ! 5 - 4 1 8 , 1972. ltermano, R. E., and David, T. E.: Spontaneous rupture of the liver caused by hepatomas. Surgery, 74:7 ! 5-719, 1973. Davis, J. B., Schenken, J. R., and Zimmerman, O.: Massive hematoperitonet, m from rupture of benign hepatocelhdar adenonm. Surgery, 73:!81-184, 1973. Albritton, D. R., Tompkios, R. K., and Longnfire, W. P.: Hepatic cell adenoma: a report of fot,r cases. Ann. Surg.,180:14-19, 1974. Baird, J. N., and Hawley, R. G.: Spontaneous rupture of the liver during l)regnanc) ". J. Reprod. Med.,6:198-200, 1971. Drill, V. A., and Calhoun, D. W.: Oral contraceptives and thromboembolic disease. J. Amer. Med. Assoc.,206:77-84, 1968. Miller, D. R.: Unnsnal focal mesenteric venous thrombosis associated with contraceptive medication: a case report. Ann. St, rg., 173:135138, 1971. Vessey, M. P.: Oral contraceptives and thromboembolic disease. Amer. Iteart. J., 77:!53-157, 1969. Ecker, J. A.: Thrombosis of the hepatic veins: the Budd-Chiari syndrome: a possible link betweeq oral coqtraceptives aqd thron~bosis formation. Amer. J. Gastroent., 45:429-443, 1966. Sterup, K., and Mosbech, J.: Budd-Chiari syndrome after taking oral contraceptives. Brit. Med.J.,4:660, 1967. Grayson, M. J., and ReiIly, M. C.: Bndd-Chiarl syndrome after oral contraceptives. Brit. Med. .I.,1:512-513, 1968.
46. Rothwell-lacksoq, R. L.: l+,udd-Chiari syndrome after oral contraceptives. Brit. Med. J., 1:252, 1968. 47. Frederick, W. C., ttoward, R. G., aqd Spatola, S.: Spontaneous rupture of the liver iq patient using contraceptive pills. Arch. Surg., 108:9395, 1974. 48. Cerone, D. M., and Catalino, G.: Spontaneous rttptnre of liver during pregnancy. Obst. Gyncc., 12:459-461, 1958. 49. johnson, F. L., Lerner, K. G., Siegel, M., Feagler, J. R., Majerus, P. W., Hartmann, J. R., and "Iqlomas, E. D.: Association of androgenic anabolic sterokl tllerapy with development of IIcpatoccllular carciqo,na. Lancet, 11:12731276, 1973. 50. Linge,naq, C. ti.: Liver cell neoplasms and oral contraceptives. Lancet, 1:64, 1974. 51. Thalassinos, N. C., lo'mberatos, C., and ttadjioannou, J.: Liver cell carcinoma after long term estrogen-like drugs, l.ancet, 1:270, 1974. 52. Schalfner, F., l'oppcr, 1t., and Perez, V.: Changes in bile canalictdi produced by norethandrolone: electron microscopic stt,dy of human and rat liver. J. Lab. Clin. Med., 56:623-628, 1960. 53. Naiem, F., Cooper, P. t1., and Scmion, A. A.: Peliosis hepatis: possible etiologic role of anabolic steroids. Arch. Path., 96:284-285, 1973. 54. Perez, V., Gorosdisch, S., deMartire, J., Nicholson, R., and dil'aola, G.: Oral contraceptives: long term use produces fine structural changes In liver mitochondria. Science, 165:805-807, 1969. 55. Chai, L. S., Colson, J. G., Kirdani, R. Y., and Sandberg, A. A.: Uhrastructural study of hel)atic effects of a contraceptive steroid in babooll. Contraception, 10:79-93, 1974. Departnlent of Pathology College of l'll)'sicians and Surgeons Columbia University 630 West I68th Street New York, New York 10032 (Dr. Knowlcs)
545
HYPERPLASIA
A Clinicopathologic Study and Review of the Literature Daniel M. Knowles H, M.D.,* and Marianne Wolff, M.D.-~
Abstract We reviewed the clinical records and pathologic material of 20 patients with biopsy proven hepatic focal n o d u l a r hyperplasia. T h e majority of tim patients were females of child bearing age, five of whom had a history of oral use of contracel~tives. In every instance focal nodular hyperplasia was an incidental finding; liver function tests were always normal. Focal nodular hyperplasia is a distinct histopathologic entity, distinguishable from liver cell adenoma. Specifically it consists of nodular aggregates of cytologically norlnal hepatocytes with foci o f intranodular bile duct proliferation. Focal nodtflar hyperplasia appears to be a benign entity, even in patients in whom the lesion was not excised. T h e association between focal nodular hyperplasia and oral use of contraceptives may be coincidental, a h h o u g h lmrmonally related vascular changes may be responsible for r u p t u r e of the lesion.
Benign hepatic neopiasms have been reported sporadically in the literature, but their clinical manifestations have not been reviewed and considerable confilsion exists over their histopathologic classification despite general acceptance o f the scheme proposed by E d m u n d s o n Y ~ Multiple diagnostic synonyms for focal nodular hyperplasia and use of the term "hepatic a d e n o m a " for all benign hepatic neoplasms h a v e confilsed liver cell a d e n o m a with focal nodular hyperplasia. T h e malignant potential misattributed to focal nodular hyperplasia 3-5 reilects con-
fusion with liver cell adenolna, ~ ~ which is believed to possess malignant potential? T h e natural history of focal nodular hyperplasia, if not surgically excised, is not known? Recently an association between oral contraceptive agents, "hepatic adenomas," and focal nodular hyperplasia has received attention, s-v' Clarification of this association is desirable and is d e p e n d e n t upon proper histopathologic characterization o f focal nodular hyperplasia and its delineation fi'om true hepatic neoplasms. We reviewed 20 cases of biopsy
*Postdoctoral Fellow, Rockefeller University. Resident, l)eparlmcnt of Pathology, Columbia University College of i'hysici:msand Surgeons, New York, New York. TAssociate l'rofcssor of Clinical Surgical l'athology, Colunllli:tUniversityCollegeof l'hysiciansand Surgeons. Associate Surgical l'athologist. Presbyterian ltospital of tile ('it)' of New York, New York, New York.
533
H U M A N P A T H O I . O G Y - V O 1 , U M E 7, NUMBER 5 p r o v e n focal n o d u l a r h y p e r p l a s i a in l i v i n g p a t i e n t s , a t t e m p t i n g to d e f i n e the e n t i t y clinically a n d p a t l m l o g i c a l l y . W e also surveyed the English literature, analyzing cases r e p o r t e d u n d e r tim v a r i o u s s y n o n y m s o f focal n o d u l a r h y p e r p l a s i a .
PATIENTS
AND
METHODS
T w e n t y cases o f h e p a t i c focal n o d u l a r h y p e r p l a s i a , 16 local a n d f o u r c o n s u h a t i o n cases, w e r e f o u n d i n t h e files o f t h e Laboratory of Surgical Pathology, Columbia U n i v e r s i t y , b e t w e e n 1950 a n d 1973.
T A B L E 1.
534
September 1976
T h e slides f r o m all cases p r e v i o u s l y diagn o s e d as focal n o d u l a r h y p e r p l a s i a , focal n o d u l a r cirrhosis, hepatic h a m a r t o m a , a n d h e p a t i c a d e n o m a were r e v i e w e d . O n l y tlmse cases c o n s i s t e n t with focal n o d u l a r hyl~erplasia as d e f i n e d b y E d m u n d s o n ~ w e r e i n c l u d e d . T i m o r i g i n a l blocks w e r e r e c u t a n d s t a i n e d as n e c e s s a r y to a l l o w v e r i f i c a t i o n o f e a c h case. T h e h o s p i t a l r e c o r d s o f 15 o f tim 1 6 , local cases w e r e available for s t u d y , a n d private physicians often provided add i t i o n a l i n f o r m a t i o n f r o m t h e i r office r e c o r d s . Clinical i n f o r m a t i o n was p r o v i d e d b y r e f e r r i n g p a t l m l o g i s t s in each c o n s u h a t i o n case.
ACCEPTABLE LITERATURE CASES OF FOCAL NODULAR HYPERPLASIA
Author
Year
Age
Sex
Hoffm:.,n':
1941
38
F
Incidental abd. m a s s
Benign hepatoma
Bensol?4
1942
7 too.
F
Incidental abd. mass
tlamartoma
Brancl?5
1945
32
F
Abd. pain, abd. mass
Adenoma
Franklin~6
1947
23
M
Abd. mass, nausea, vomiting
ttepatoma
llunter 4
1949
28
F
Abd. mass, nausea, vomiting
Benign hepatoma
-
McBurne)'~r
1950
28
F
Abd. pain, abd. mass
Solitary hyperplastic nodule
-
Ka)"~s
1950
7 too. 13
F M
Incidental abd. m a s s Abd. mass, nausea, vomiting
Mixed type adenoma Mixed type adenoma
Died postop. 18 too.
Gertlingr~
1951
M
Incidental abd. mass
tlamartomatous cholangiohepatom;l
-
Levenson -~~
1952
15 too.
M
Incidental abd. m a s s
Mixed type adelmnla
--
Begga
195q
59
M
lllcidental abd. m a s s
46
F
RUQ pain, RUQ mass
23
F
Abd. mass
47
F
limidemal abd. mass
Isolated nodules of regen erat ire hypcrplasia Isolated nodules of regenerative hyperplasia Isolated nodules of regenerative hyperplasia Isolated nodules of regenerative hyperplasla
Benz21
193q
8
Symptoms
34 necropsy cases
Diagnosis
Foc,d cirrhosis
Follow-up -4 too.
3 yr. 2 yr. 2 yr. 18 too.
--
FOCAl.
I lYI'ERI'LASIA
OF THE
LIVER--I,~Nowt.ES, WoLvv
ACCEPTAP,LE LITERATURE CASES OF FOCAL NODULAR HYPERI'LASIA (Continued)
T A B L E 1.
Author
NOI)ULAR
Year
Age
Sex
Symptoms
Diagnosis
Follow-up
Christopherson 2
1953
12 7
M F
Abd. pain, abd. mass Abd. paiq, abd. mass
tlamartoma tlamartoma
9 too. 3 yr.
ltensoff2-'*
1956
5 28 39
F F F
Abd. pain, abd. mass Abd. paiq, abd. mass Incidental
tlepatoadenoma tlepatoadenonm tlepatoadenoma
47 yr. '2 yr. 3V', yr.
Cla) -04
1958
63
F
Abd. mass, weight loss
Benign h e p a t o m a
27 too.
Palubi,lskas 7
1967
'2'2
F
hlcidental
Liver cell a d e n o m a
--
E d m u n d s o n 25
1968
37
F
Abd. pain, abd. mass
Focal n o d u l a r hypcrl)lasia
-
Aronscn 26
1968
23
M
Incidental
Focal n o d u l a r cirrhosis 8 too.
Garanis 27
1969
8
M
tlepatic a d e n o m a
8 14
18
F F F
Abd. pain, nausea, vomiting Incidental abd. mass Incidental abd. mass Incidental
-
-
Necropsy case
18
F
lncidcntal
40
F
Incide,ual
38
F
Incidental
40
F
l,acidental
Focal n o d u l a r hyperplasia
9 too.
34
F
Incideqtal
5 too.
--
--
Necropsy case
Focal nodtflar hyperplasia Focal n o d u l a r hypcrplasia
Malt 5
Ramchand -"s
1970
1970
-
tlepatic aclenoma ! lepatic a d e n o n m ttepatic a d e n o m a tlepatic a d e n o m a Focal n o d u l a r hyperl)lasia Focal n o d u l a r hyperplasia Focal nodtflar hyl)erplasia
---
Crispin 8
1971
20
F
Abd. pain, abd. mass
1lepatic a d e n o n m
llertzer z'J
1971
14
M
Abd. mass
Focal cirrhosis
i'hillips 3~
1973
6 cases without clinical data
Ilepatic h a n m r t o m a
-
*Ma)'s '2
1974
42
F
Abd. I)ain
-
26
F
Abd. h e m o r r h a g e
25
F
Abd. paiq, abd. ,nass
Focal n o d u l a r hyt)erl)lasia Focal n o d u l a r hyperplasia Focal n o d u l a r h)perlflasia
41
F
Incidental
26
F
Incidental
58
F
Incidental
O'Reilly 31
1974
Focal ,lodular hypcrl~lasia Focal n o d u l a r hyperplasia Focal n o d u l a r hyperplasia
11/9 yr.
-
m
D
*tlistory o f oral contraceptive medication fox four to seveq )ears.
535
HUMAN
I':kTHO1.OGY--VOLUME
7,
NUMBER
september1976
5
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536
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FOCAL
NODULAR
ltYI'ERIq.ASIA
OF THE
9
LIVER--K,XOWLES, WoLvv
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537
HUMAN I'ATHOLOGY--VOLUME 7, NUMBER 5 September 1976 REVIEW OF THE LITERATURE
Review of the English literature revealed only 82 acceptable cases of focal nodular hyperplasia, 42 of which lacked clinical data or were necropsy findings (Table 1). Among the 40 patients for whom clinical information was available, only 29 were 18 )'ears of age or older. Twenty-five (86 per cent) of the latter were women. The meau age of the adult males was 42 )'ears and the mean age of the adult females was 34 )'ears. Focal nodular hyperplasia was an incidental finding in 16 I)atients, but in 13 others either a mass was palpated by the patient or the lesion produced symptoms of abdominal discomfort, nausea, and vomiting. Mays et al? 2 described a 26 year old female taking contraceptives orally for seven years who presented with i n t r a - a b d o m i n a l h e m o r r h a g e d u e to rupttn'e of a large area of focal nodular hyperplasia. Follow-up in the previously reported cases has been sporadic and 1)oor (Table 1). However, no patient appears to have developed evidence of hepatic dysfunction, other hepatic disease, recto:rent focal n o d u l a r h y p e r p l a s i a , or hel)atocelhflar carcinoma. However, in each reported case the lesion of focal nodular hyperplasia had been totally excised. There are no follow-up data available for an)" patient wlmse lesion was simply subjected to biopsy examination and not surgically excised. RESULTS
Clinical Fin dings
538
The 20 patients we studied, 17 females and tlu'ee males, ranged in age from 21 to 66 years (Table 2). T h e mean age of the male patients was 52 )'ears and that of the female patients, 46 years. (No pediatric patients were included in tim present series, althougll they have been included in the literature review.) In each case focal nodular hyperplasia was an incidental finding; in no instance was the disorder symptomatic. Most commonly it was an incidental finding at the time of cholecystectomy for cholelithiasis (nine cases, 47 per cent). Focal nodular hyperplasia
was also found incidentally during abdominal hysterectomy (three cases), laparotomy for acute upper gastrointestinal llemorrhage (two cases), and exploratory laparotomies, which revealed a retroperitoneal ganglioneuroma, a gastric Idomyonla, a gastric nicer, and a carcinoid tumor of the jejunum. In one instance a hepatic nodule was seen during laparoscopic tubal ligation; the patient subsequently was subjected to exploration and the nodule of focal nodular hyperplasia diagnosed by frozen section. l'hysical findings retlected the underlying pathologic lesion with which focal nodular hyperplasia was coincidentally associated. Hepatomegaly was described in three patients but nodular masses were never palpated. It is doubtful-that the relatively small nodules in these cases could be responsible for hepatomegaly. Jaundice was never noted in any patient and liver ftmction tests were ahvays normal. An extensive gynecologic history was available in 14 of the 17 female patients. Five women had been postmenopausal for fi'om nine to 24 years witlmut a history of oral use of contraceptives. Two patients were u n d e r g o i n g hysterectomy for adenomyosis at the time of discovery of focal nodular hyperplasia. Five women, ages 21 to 3 6 , had taken contraceptives orally for six months to seven )'ears prior to discovery of focal nodular hyperplasia. Oral use of contraceptives was not mentioned in the charts of four premenopausal women said to have had regular and normal menses. In one patient multiple nodules of focal nodular hyperplasia were discovered (one of which was subjected to biopsy examination) d u r i n g hysterectomy (Table 2, No. 9). She was subsequently given ethinylestradiol and diethylstilbestrol for 16 months postoperatively for postmenopausal syxnptoms. She remained asymptomatic with a normal physical examination and normal liver function tests 103 months later. Another patient whose lesion was totally excised was taking contraceptives orally and was alive and well 36 months later (Table 2, No. 5). The nodules of focal n o d u l a r hyperplasia were totally excised in ten patients and merely examined by biopsy study in
FOCAl. NODUI.AR ItYPERIq.AS1A OF T H E IAVER--KxowLcs, WOLVV TABLE
3.
Total patients Number of patients followed Duration of followup (months) Deceased
FOLLOW-UP DATA
g e s t i n g llepatic No. 17).
Biopsy Only
Excision
10
10
7
7
1O- 130 (mean :55) 0
16-198 (mean :74) 0
ten o t h e r s , i n c h t d i n g t h r e e p a t i e n t s witli m o r e t h a n o n e n o d u l e ( T a b l e 3). Seven patients in e a c h g r o u p w e r e f o l l o w e d f o r ten to 198 montlls. N o p a t i e n t llas dev e l o p e d a b n o r m a l liver f n n c t i o n tests o r clinical e v i d e n c e o f h e p a t i c disease o r has died. O n e p a t i e n t ( T a b l e L2, No. 8) at the time o f writing h a d b i o p s y p r o v e n h e p a t i c nmetastases f r o m a p a n c r e a t i c c a r c i n o m a (tim s u r g e o n did not r e c o r d tlle a p p e a r a n c e o f tile n o d u l e o f focal n o d u l a r h y p e r p l a s i a at t h e t i m e o f b i o p s y ; T a b l e 2, No. 8), a n d a p a t i e n t witll a j e j u n a l carcinoid h a d the c a r c i n o i d s y n d r o m e a n d m u l t i p l e focal d e f e c t s o n liver scan, s u g -
metastases
(Table
2,
Pathology Focal n o d u l a r h y p e r p l a s i a usually p r e sents as a discrete, well c i r c u m s c r i b e d , firm, tan to y e l l o w - b r o w n , m u l t i n o d u l a r , cirrlmtic-like mass in a n o t h e r w i s e u n r e m a r k a b l e liver. T h e lesion is usually subc a p s n l a r , b u t it ilia}' also e i t h e r lie d e e p within the liver or p r o j e c t fi-om tile s u r f a c e (Fig. 1). Occasionally two o r even m u h i p l e n o d u l e s a r e p r e s e n t . 3 A h l t o u g l l it Iias b e e n a s s e r t e d tllat focal n o d u l a r l l y p e r p l a s i a m o s t c o m m o n l y occurs in t h e rigllt lobe,' we f o u n d that it o c c u r r e d j u s t as c o m m o n l y ill tile left lobe. M o r e o v e r , the lesions w e r e f o u n d all o v e r t h e liver: s u p e r i o r l y , laterally, a n d inferiorly. A m o n g t h e p r e s e n t cases tim d i a m e t e r o f t h e lesion r a n g e d fi'om 1 to 7 cm. ( m o s t c o m n a o n l y 2 to 3 cm.). N u n m r o t t s l a r g e r lesions, r a n g i n g u p to 15 cm. in d i a m e t e r , a n d w e i g h i n g as m u c h as 700 gin., h a v e b e e n r e p o r t e d . ~' '"' ,9, ,_q T l l e s e large lesions o f t e n p r o j e c t fi-om tim s u r f a c e o f tim liver a n d m a y be attaclled o n l y by a thin p e d icle.3, 16, '.,4, '.,;
Figure 1. A 7 cm. nodule of focal nodular hylmrplasia fimnd incidentally in all elderly man at autopsy. It shmvs tile typical gross features of focal nodular hyperl)lasia: a subcapsular, well circumscribed, pale inass with a central stellate scarlike area. l'eripherally radiating septa subdivide tile mass into multiple, variably sized nodules, simulati,lg a focal cirrhotic pattern.
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Figure 2. The hepatocytes of focal nodular hyperplasia (lower left; note the edge of a central fibrous area) blend imperceptibly into the surrounding normal hel)atic i)arenchyma (Upl)er right); there is no evidence of encapsulation. (Trichrume stain, x38.) /"
The gross appearance of the liver on c u t s e c t i o n is p a t h o g n o m o n i c in n e a r l y all i n s t a n c e s . T h e r e is a c e n t r a l s t e l l a t e o r linear, scarlike, fibrous connective tissue
540
a r e a f r o m w h i c h fibrotis c o n n e c t i v e tissue radiates peripherally, di('iding the mass into multiple, variably sized nodules, s i m u l a t i n g t h e p a t ' t e r n o f c i r r h o s i s . AI-
Figure 3. Characteristically, focal nodular hyperplasia coqsists of large aggregates of normal appearing hepatocytes (inset). without true portal triads or central veins, subdivided by strands of fibrous tissue with proliferating bile dt,cts and chronic inllammatory cells. (llematoxylin-i~hloxine-safran stain, x38 and X375.)
FOCAL NODULAR
HYI'ERPLASIA OF THE
LIVER--KNOWLES, WOLFV
Figure 4. In contrast with the pattern in Figure 3, some lesions display nodules of hepatocytes widely separated by fibl-otls connective tissue containing chronic inflammatory cells and loci of proliferating bile ducts. (ttematoxyliu-phloxine-safran stain, x35.)
though not encapsulated, these nodules grossly appear to be well demarcated from the surrounding hepatic parenchyma (Fig. 1). The lesion is nearly always solid without areas of hemorrlmge or necrosis. Microscopically the nodtfles of focal nodular hyperplasia usually blend imperceptibly into the surrounding liver parenchyma, althongi~ occasionally they may appear partially encapsulated (Fig. 2). The clmracteristic central stellate "scar" is composed of variably vascnlarized, dense fibrous connective tissue, wlfich often contains chronic inflanmmtory cells. The peripherally radiating fibrous septa may be narrow, subdividing the lesion into mnltiple, variably sized, interconnecting nodules of cytologically normal appearing hepatocytes (Fig. 3). Conversely the fibrous septa ilia)' be so wide that the nodules lie generally isolated fi'om one another (Fig. 4). Intranodular and internodular bile duct proliferation is abundant (Figs. 5, 6). Often the haphazardly arranged, proliferating bile duct elements nlerge inq)erceptibly with tile hepatocytic elements (Fig. 6). In such instances the unwary pathologist, without the appropriate clinical information, nlay wrongly identify the lesion as cholangiocarcinoma arising ill a cirrhotic liver.
Two llistologic characteristics define focal nodular hyperplasia and pernlit its recognition and differentiation from cirrllosis, even with only a small biopsy specinlen. Tile first feature is the conlplete lack of normal lobular arcllitecture, tile lesion consisting of large nodular aggregations of nornlal appearing hepatocytes without central veins or portal fields (Fig. 3). Both tilin walled venous clmnnels and arterial vessels are present, but there is no apparent organization of tile hepatocytes around them. The second histologic feature is the presence of areas of intranodular bile duct proliferation, which appeal" to blend into the hepatocytic elements (Fig. 6). In combination with the gross features already specified, these histologic features define focal nodular llyperplasia. T h e helsatocytes of focal nodular hyperplasia appear cytologically nornlal, indistinguishable from nornlal liver (Fig. 3). The sinusoids are bordered by Kupffer cells. Neither cholestasis nor hemosiderosis was seen in the present cases, hi one case fatty metamorphosis of the hepatocytes of focal nodular hyperplasia was present. In contradistinction to focal nodular hyperplasia, liver cell adenomas occur as solitary snlooth encapsulated masses with-
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Figure 5. A characteristic histologic feature of focal nodular hyperl~lasia is the presence of a focus of haphazardly arranged, proliferating bile ducts in the midst of a large aggregate of hepatocytcs-intranodular bile duct proliferation. (ttematoxylin-pl~loxine-safran slain, x88.)
out the central scar, radiating fibrous septa, or nodularity of focal nodular hyperplasia. Histologically they are composed entirely of generally normal appearing
542
hepatocytes without bile ducts OF central veins. Bile stasis is occaSionally present. Foci of l~emorrhage are more c o m m o n ? ~ . Electron microscopically the hepatocytes,
Figure 6. Bile duct proliferation is often abundant :it the periphery of the hepatocyte nodtdes. The bile duct epitheliunl merges iml~erceptibly with the cords of hepatocytes--internodular bile duct proliferatioq. (ltematoxylin-phloxine-safran stain, x 160.)
FOCAL NODULAR ItYPERI'I.ASIA OF THE LIVER--KNOWLES,WOLVV biliary epithelium, and Kupffer cells of focal nodular hyperplasia are almost identical to those of normal liver, whereas the hepatocytes of liver cell adenomas differ in several respects fi'om those of norreal liver and focal nodular 1wperplasia. 3~ DISCUSSION
Tile misconception that focal nodular hyperplasia can undergo malignant change a-5 is lfistorically related to Ewing's belief that a gradation exists between hepatic hamartoma, hepatic adenoma, and hepatic carcinoma'-'" and to confusion generated by the nmhiplicity of terms used in the literature to denote focal nodular hyperplasia (Table I). The indiscrimate u~e of the term "hepatic adenoma" to denote focal nodular hyperplasia has particularly hindered clinicopathologic characterization of focal nodular hyperplasia and has maligned any prognostic significance attached to the pathologic diagnosis. T r u e liver cell adenomas are reputed to lmve the potential for undergoing malignant change, ~ although some cases reported as such are questionable, a2 The 20 per cent recurrence rate of hepatic adenomas noted by Warvi aa probably indicates that a significant number of well differentiated, uninodular hepatocelhflar carcinomas were misdiagnosed as adenomas in the older literature, making true liver cell adenomas seem potentially more malignant than they probably are. The attachment of such stigmata to the patient with focal nodular hyperplasia is not warranted. Numerous eases of "hepatic adenomas" have recently been reported, several of the patients presenting with henlol~eritolleunl due to rupture of the a d e n o l n a . Z L s-11,34-3s S o l n e o f these patients had been taking contraceptives orallys't~ or had been pregnant 39 at the time of diagnosis, leading some observers to suggest an association between the hormonal effects of oral adnfinistration of contraceptive medication and the developinent of liver cell adenomas, s' 9, H Mays v-' reported three young women with focal nodnlar hyperplasia who had been taking contraceptives orally. One patient presented with ruptnred focal
nodules, and focal intratumor hemorrhage was present in the two other patients. The only other literature cases with intratumor helnorrlmge were two patients reported by Begg and Berry. 3 Mays t2 suggested that some of the aforementioned cases might be lesions of focal nodular hyperplasia, inappropriately labeled hepatic adenomas, or benign hepatomas.S, 9 Thus, the indiscriminate use of the term hepatic adenoma has clouded clinical understanding of focal nodular hyperplasia and its possible association with the orally administered contraceptives. Focal nodular hyperplasia has always been a rare lesion, occurring predominantly in young women. Since a high percentage of young women now take contraceptives orally, an occasional case in such a patient is expected. Relating the development of focal nodular hyperplasia to hormonal effects alone is impossible at the present time. However, tile presentation of the disorder as hepatic rul)ture is distinctly unusual and tiffs aspect may indeed be hormonally influenced. Mays t'- described vascular changes of the afferent vessels, in particular the interlobular branches of tile portal vein, in his three cases of focal nodular hyperplasia. The association between orally administered contraceptives and tliromboembolic phenomena is well known? ~ Hepatic vein thrombosis recently has been described in young women taking contraceptives orally,43-4(; and a case of fatal endophlebitis and hepatic vein thrombosis with infarction and rupture has also been reported. 47 Hepatic rupture during pregnancy is an unconnnon but well known phenomenon. 4s Various hepatotoxic effects of orally administered contraceptives and other hormonal preparations, including the development of hepatocellular carcinoma, have also been described, both in humans and in anin l a l s . 4-9-55
At tile present time focal nodular hyperplasia appears to be a completely benign hepatic lesion of unknown etiology, removal of which is not necessary unless the lesion is symptomatic by virtue of its large size. Very rarely a large lesion of focal nodular hyperplasia may rupture.l-~ Hormonally induced vascular changes
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h a v e b e e n s u g g e s t e d as all e t i o l o g i c m e c h a n i s m , b u t n o c a u s a l a s s o c i a t i o n is e s t a b l i s h e d at t h e p r e s e n t t i m e . r'
ACKNOWLEDGMENTS
T h e a u t h o r s a r e g r a t e f i f l to n u n m r o u s p h y s i c i a n s at t h e C o l u m b i a - P r e s b y t e r i a n M e d i c a l C e n t e r a n d to D r . R i c h a r d S a b b i a of the White Plains Hospital Association for providing clinical follow-up data rel a t i n g to s e v e r a l p a t i e n t s . T h e y a r e i n d e b t e d to Dr. R a f f a e l e L a t t e s f o r c o n s t r u c t i v e c r i t i c i s m , to M i s s I d a N a t h a n a n d M r . Ulisses Martin for l)hotographic assistance, a n d to M r s . B a r b a r a A. J o h n f o r s e c r e t a r i a l assistance.
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