Histopathology 1978, 2, 363-371

An unusual nodular lesion of the liver: probable partial nodular transformation

S.VARIEND* Department of Histopathology, City Hospital, Hucknall Road, Nottingham

Accepted for publication 23 March 1978

VARIEND S. (1978) Histopathology 2, 363-371

An unusual nodular lesion of the liver: probable partial nodular transformation

An unusual nodular lesion of the liver is reported. The appearances closely resembled those described in cases referred to as partial nodular transformation, but there were several unusual features; these included areas with the appearances of cirrhosis, and significantly raised alkaline phosphatase and gamma glutamyl transpeptidase. Differentiation of this condition from other nodular lesions described in the literature is discussed. In the case reported here the Rose Waaler and Latex tests were also positive and this may be significant in view of certain types of nodular conditions described in some rheumatoid conditions. Although it is quite possible that these various lesions are related histogenetically, until more information becomes available, it is proposed that the lesion described here represents a variant of partial nodular transformation in which the changes in some areas have progressed to a stage of fibrosis.

Keywords : liver, nodules, nodular transformation

Introduction

Partial nodular transformation of the liver is a recently recognized entity character- ized by a typical nodular deformity. The paucity of case reports in the literature since the first description of the lesion more than 10 years ago (Sherlock, Feldman, Moran & Scheuer 1966) probably reflects its rarity. The pathogenesis is essentially unknown but several theories have been proposed. Portal hypertension is usual. The liver is characteristically of normal size and liver function is only slightly impaired. Nodules replace most of the liver parenchyma although the periphery is usually spared or atrophic. Fibrosis is minimal or absent. In the case reported here the liver showed features similar to partial nodular transformation, but the histology of some of the areas also showed appearances of cirrhosis; there was also some evidence of rheuma-

Address for correspondence : S. Variend, Department of Pathology, The Children’s Hospital, Western Bank, Sheffield SIO 2TH.

0309-0167/78/0900-0363 $02.00 01978 Blackwell Scientific Publications 363

364 S. V a r i e d

toid disease. The alkaline phosphatase was markedly raised. Other findings strongly suggested associated portal hypertension.

Case report

A 54-year-old female was first seen with a 6-month history of bronchitis and weight loss over one year. There was no past history of jaundice and her alcohol intake was recorded as a half pint of beer per day. On examination she was apyrexial ; there was no evidence of cardiac failure and she was normotensive. Her hands and lips showed telangiectasia and there was marked splenomegaly. There were no clinical stigmata of rheumatoid disease. Special investigations showed a haemoglobulin of I I . I gm/Ioo ml, white blood cell count I .o x 109/L (neutrophils 460, lymphocytes 440, monocytes 50, eosinophils 50), platelets 33.0 x ro9/L and E.S.R. 96 mm in the first hour. Bone marrow examination was normal. Serum calcium 2.2 mmol/l ; serum inorganic phosphate 1.0 mmol/l; S.G.P.T. 9 IU/L (normal 2-19); serum alkaline phosphatase 1,241 IU/L (normal 46-190); gamma glutamyl transpeptidase 208 IU/L (normal

Figure I. Shows nodularity mainly around the larger portal triads.

Nodular transjormation of lives 365

4-1 8); serum proteins and immunoglobulins-normal. The Paul-Bunnell, urea and electrolytes and prothrombin time were all normal. Chest X-ray showed left lower lobe collapse. The bone scan was normal. The Latex test and Rose Waaler test (16) were positive.

Follow-up in the out-patient clinic showed that the physical findings and haema- tological parameters remained essentially unchanged. She presented about 2 months after the initial admission with signs of a cerebro-vascular accident. Haemoglobin was I 1.3 g/ioo ml, white blood cell count 6.4 x 109/L, platelets 45 x 109/L. She died 3 days later.

GROSS A P P E A R A N C E S

A large cerebral haematoma was found in the left frontal lobe. The pericardial cavity was obliterated by dense fibrous tissue; the heart was normal in size and showed no significant feature. Oesophageal varices were present; the spleen (960 g) was consider- ably enlarged with a uniform brownish cut surface. The portal vein was moderately thickened and dilated. There was no ascites. The liver (1,245 g) was not enlarged; the cut surface revealed an unusual nodular pattern that involved both lobes diffusely

Figure 2. Shows widespread distribution of the nodules, especially conspicuous in the region of the porta hepatis.

366 S . Variend

apart from a narrow zone of subcapsular parenchyma which appeared relatively normal. Partly confluent nodules (up to 0.6 cm in diameter) surrounded the larger portal tracts (Figure I) and were most conspicuous in the region of the porta hepatis (Figure 2). These nodules appeared to bulge into portal tracts and were otherwise generally clearly delineated, although in occasional areas they seemed to merge with the adjacent parenchyma. In addition, the remaining liver tissue in many areas showed clusters of smaller more discrete nodules measuring up to 0.2 cm in diameter (Figure I). The main bronchus to the left lung was considerably narrowed by firm white tumour; patches of white tumour were also present in the left lower lobe.

HISTOLOGY

The larger liver nodules contained thickened liver cell plates which were haphazardly arranged ; many such nodules included apparently normal portal tracts and central veins, but others showed these structures to be absent. The larger nodules were frequently clearly demarcated from adjacent parenchyma and from each other by a rim of compressed hepatocytes (Figure 3) or by irregular bands of fibrous tissue; sometimes both compressed parenchyma and fibrous tissue surrounded individual nodules.

In other areas the nodules fused almost imperceptibly with the surrounding

Figure 3. There is marked compression of hepatocytes at the periphery of a nodule but without fibrosis. H & E. x 315.

Nodular transformation of h e r 367

parenchyma, the latter being relatively normal or showed a lobular structure dis- torted by bands of fibrous tissue which linked adjacent portal tracts, or portal tracts to central veins. Occasional lobules with central veins were completely surrounded by fibrous tissue.

The fibrous tissue generally contained a mild to moderate lymphocytic infiltrate and numerous thin-walled blood vessels in addition to portal veins which were prominent and dilated. There were occasional foci in which the hepatocytes showed nuclei that were large and hyperchromatic (Figure 4), reminiscent of the dysplastic nuclei seen in some cases of cirrhosis. Occasional venous radicles in the large portal tracts appeared to be compressed by encroaching nodules, but there was no associated significant intimal thickening of the walls of these veins.

An unusual appearance was the presence of smaller more discrete nodules that also contained liver cell p1ates;which were thickened and haphazardly arranged. These smaller nodules were completely surrounded by fibrous tissue and generally lacked central veins (Figure 5 ) ; here the appearances were remarkably like those of cirrhosis.

Extensive sampling of the liver showed no evidence of recent or past intrahepatic portal vein thrombosis. There was no cholestasis and special stains showed no excess of iron. The bronchial tumour as well as the tumour in the left lower lobe showed the typical features of a plasmacytoma; there was no evidence of myelomatosis. The spleen showed severe congestive changes.

Figure 4. Liver cells show dysplastic nuclei. H & E. x 490.

368 S . Variend

Figure 5. Some areas show smaller nodules completely surrounded by fibrous tissue, resembling cirrhosis. Gordon 8i Sweet reticulin. x 22.5.

Discussion

Sherlock et al. (1966) reported four cases of an unusual hepatic lesion characterized histologically by non-cirrhotic nodules. These patients developed haematemesis at some stage during their illness, associated with evidence of portal hypertension ; liver cell dysfunction did not appear to be a significant feature. These authors labelled the condition ‘partial nodular transformation of liver’ (PNT). The aetiology is basically unknown, but it has been suggested that portal hypertension resulted from compres- sion of the portal veins by the parenchymal nodules.

The gross and microscopic features of the liver in the present case are essentially similar to those reported by Sherlock et al. (1966); however, in addition, there were areas showing nodules with evidence of regeneration, the central veins in many of these nodules were absent and they were completely surrounded by fibrous tissue. These areas were thus indistinguishable from cirrhosis. The presence of portal hyper- tension was strongly suggested by oesophageal varices, a large and congested spleen as well as a thickened and dilated portal vein.

It is important to differentiate PNT from other nodular lesions of the liver (Table I), the most significant of these being nodular regenerative hyperplasia (NRH); the latter condition was first described by Steiner (1959) mainly in patients with chronic hepatic congestion and cardiac decompensation. This author did not mention the presence of portal hypertension in his cases. The nodules in this condition are also

Nodular transformation of liver 369

Table I. Nodular lesions of the liver

Cirrhosis Partial nodular transformation Nodular regenerative hyperplasia Focal nodular hyperplasia Liver cell adenorna

characterized by features of regeneration, they are generally smaller than a normal liver lobule but there is a notable absence of fibrosis. The livers in Steiner’s series were said to be smaller than average size and to be uniformly involved by the nodularity.

The case reported here showed a fibrous pericarditis but there was no evidence of constriction ; there was also no clinical evidence of cardiac decompensation and, on histology, the liver showed no chronic congestion. Evidence of portal hypertension and the type of abnormal nodules, being on the whole, larger than those found in NRH are clearly inconsistent with the lesion described by Steiner (1959). The nodules in the present case also showed a striking periportal arrangement and there was accentuation in the region of the porta hepatitis; there was also a narrow subcapsular zone which appeared to be relatively spared. These features were more compatible with PNT described by Sherlock et a/., but differed from the latter in that there were also areas with the appearances of cirrhosis.

In a series of five patients with Felty’s syndrome the findings in the liver were described as being those of NRH (Blendis, Parkinson, Shilkin & Williams 1974); three of their patients showed portal hypertension. Although the weights of the livers in these cases were not stated, they were said to have been enlarged clinically. These authors were unable to find a single case of NRH in a series of 51 patients with rheumatoid arthritis and concluded that the liver lesion was specifically related to Felty’s syndrome.

Subsequently, Harris, Rash & Dymock (1974) reported a nodular non-cirrhotic liver in a patient with rheumatoid arthritis; the liver was markedly reduced in size (592 g) and there was evidence of portal hypertension. The features in the liver were similar to those described by Blendis et al. (1974) in patients with Felty’s syndrome.

In this connexion the positive Rose Waaler and Latex tests in the present case may be significant ; the fibrous pericarditis would be consistent with a rheumatoid pro- cess. However, the nodules described in these c a m resembled NRH rather than PNT and arguments against NRH in the case reported here have already been mentioned. Although it is conceivable that these varieties of nodular lesions may well form part of a spectrum of liver disease found in rheumatoid disease, Blendis et al. stated that a causal relationship between NRH and Felty’s syndrome was not established. Simi- larly, Harris et a / . could not exclude a fortuitous association between NRH and rheumatoid arthritis in their case.

Focal nodular hyperplasia is usually a localized liver lesion composed of iiodular aggregates of cytologically normal hepatocytes with intranodular and internodular bile duct proliferation (Knowles & Wolff 1976); in occasional cases the lesion is

370 S. Variend

multiple. These nodules, usually measuring 1-7 cm in diameter, are nevertheless sufficiently distinctive in containing fibrous septa radiating from a central scar. Lastly, liver cell adenomas are smooth encapsulated masses of histologically normal appearing hepatocytes in which there are no bile ducts or central scars and should present no difficulty in diagnosis.

Many of the larger nodules in this case were delimited by compressed hepatocytes or incompletely by fibrosis. In addition there were scattered foci with the appearances of micronodular cirrhosis, but differed from true cirrhosis in that the latter condition is usually regarded as a diffuse lesion. Steiner (1959) speculated that the atrophic hepatocytes at the periphery of nodules in NRH could eventually disappear and that the resulting collapse of the reticulin framework would be replaced by fibrous tissue; thus, if the causative factors persisted, cirrhosis would finally develop, although he admits that NRH is not in itself a progressive lesion. None of his cases showed signi- ficant fibrosis. A similar pathogenesis for the areas of cirrhosis might be considered in the present case; this theory does not seem too unlikely in view of the compressed hepatocytes seen encircling many of the larger nodules. If this is so, then it is quite feasible that one is dealing here with a rather more advanced stage in the develop- ment of PNT.

PNT is difficult to diagnose on examination of a percutaneous needle liver biopsy (Sherlock et al. 1966); the cirrhotic areas in the case reported here might conceivably lead to an erroneous diagnosis of true cirrhosis on a needle biopsy.

Liver function in PNT is characteristically well-preserved and there is usually little evidence of a biochemical disturbance. In one of the cases reported by Sherlock et al. (1966) the alkaline phosphatase was slightly raised and a moderately raised level was reported in the case of Classen, Elster, Pesch & Demling (1970). The considerably raised level of alkaline phosphatase (1,241 IU/L) in the present case is unexplained although it might be related to the increased fibrosis in the cirrhotic areas. The raised gamma glutamyl transpeptidase would indicate that the alkaline phosphatase was of hepatic origin.

Boyer, Hales & Klatskin (1974) recently suggested that the cause of PNT was an intrahepatic portal vein thrombosis. These authors performed corrosion cast studies of the hepatic vasculature of cases of ‘idiopathic portal hypertension’. One of their cases showed features of partial nodular transformation; in this case there was marked reduction in the number and diameter of the peripheral branches on the portal veins. This led them to postulate that portal hypertension and partial nodular transformation were secondary to thrombotic occlusion of the intrahepatic portal vein branches. In support of this theory these authors referred to one of the cases originally reported by Sherlock et al. (1966) in which a spleno-portogram showed a sharp cut-off of the major branches and paucity of distal branches of the intrahepatic portal veins. In the case described by Connolly & O’Brien (1977) the intra-hepatic portal vein thrombosis seemed a recent event and was more likely a complication rather than a primary factor. A large number of sections of the liver examined in this case showed no evidence of past or recent portal vein thrombosis.

Dick & Gresham (1972) were impressed by a conspicuous intimal fibro-elastic thickening of the portal veins in the region of the nodules, a feature that was not found

Nodular transformation of liver 37 I

in the present case. They stated that the intimal thickening was not found elsewhere in the liver, a point which led them to suggest that the nodules were responsible for local pressure on the portal veins and portal hypertension.

Although the nodular morphology of the liver in the case described here was simi- lar to that described in PNT, there were some unusual features. Until more is known about the nature of this condition and its precise relation to NRH it is intended to regard the present case as one of atypical PNT in which some of the changes have advanced to fibrosis and appearances of cirrhosis.

Without more information I should tend to agree with Sherlock et al. (1966) that the portal hypertension in PNT is probably related to lack of central veins as well as to the nodules impinging on intrahepatic portal veins. Steiner (1959) thought that the nodules in NRH might represent disordered liver cell regeneration secondary to liver cell injury. Blendis et al. (1974) considered that disturbed hepatic blood flow due to increased splenic blood flow might be a factor in the abnormal liver histology in their cases of Felty’s syndrome. The aetiology of the nodules in PNT must, however, for the present remain speculative. The finding of a plasmacytoma in the lung of the same patient would appear to be fortuitous.

Acknowledgements

I wish to thank Professor P.J. Scheuer for his opinion on the liver sections and Dr I.D. Ansell for valuable advice.

References

BLENDIS L.M., PARKINSON M.C., SHILKIN K.B. & WILLIAMS R. (1974) Nodular regenerative hyper- plasia of the liver in Felty’s syndrome. Quarterly Journal of Medicine 18,zs-p

BOYER J.L., HALES M.R. & KLATSKIN G . (1974) ‘Idiopathic’ portal hypertension due to occlusion of intrahepatic portal veins by organised thrombi. Medicine 53, 77-91

CLASSEN M., ELSTER K. , PESCH H.J. & DEMLING L. (1970) Portal hypertension caused by partial nodular transformation of the liver. Gut 11, 245-249

CONNOLLY C.E. & O’BRIEN M.J. (1977) Nodular transformation of the liver: Report of a case. Human Pathology 8, 350-352

DICK A.P. & GRESHAM G.A. (1972) Partial nodular transformation of the liver presenting with ascites. Gut 13, 289-292

HARRIS M., RASH R.M. & DYM~CK I.W. (1974) Nodular, non-cirrhotic liver associated with portal hypertension in a patient with rheumatoid arthritis. Journal of Clinical Pathology 27, 963-966

KNOWLES D.M. & WOLFF M. (1976) Focal nodular hyperplasia of the liver. A clinicopathological study and review of the literature. Human Pathology 7, 533-545

SHERLOCK S., FELDMAN C.A., MORAN B. & SCHEUER P.J. (1966) Partial nodular transformation of the liver with portal hypertension. American Journal of Medicine 40, 195-203

STEINER P.E. (1959) Nodular regenerative hyperplasia of the liver. American Jorrrrialo/%thology 35, 943-953