Case Report

Noduläre regeneratorische Hyperplasie mit metastasenartigen Eigenschaften in CEUS Introduction !

Liver nodules detected by ultrasound may arise on the basis of neoplastic, degenerative and infectious diseases. Characterization may be facilitated by contrast enhancement (CEUS) as these conditions have distinct vascular features (M. Claudon et al. Ultraschall Med 2013; 34: 11 – 29). Nodular regenerative hyperplasia (NRH), a combination of liver atrophy and adjacent hyperplastic nodules, may be caused by vascular liver lesions from drugs or herbal substances. Here a challenging case of liver nodules in the follow-up care of colonic cancer is presented. The contrast enhancement mimicked hypervascular metastases; detailed pathological workup revealed NRH. However, morphological features partially resembling focal nodular hyperplasia (FNH) were also present, which is another vascular damage-related condition.

Case presentation !

A 46-year-old male presented with a mucinous adenocarcinoma of the right colonic flexure 6 years ago (ICD-O M8480/3 C18.2 pT3 pN1b(2/29) cM0 G3 R0). The postoperative recovery after right hemicolectomy was excellent. Adjuvant oxaliplatin-based chemotherapy was applied (FOLFOX4 regimen: Folinic acid, 5-Fluorouracil and oxaliplatin) and well tolerated. Subsequently the patient was in good health without evidence of recurrent disease. Due to the high-risk situation (2 lymph node metastases up to 4 cm in size) and the patient’s young age, ultrasound examinations including CEUS of the liver were scheduled every 6 months. All follow-up US investigations were performed in a standardized way by the same physician. In the 6th year, 3 new echopoor lesions were detected that showed hyperperfusion in the arterial " Fig. 1, 2). The sizes of phase of CEUS (● these lesions were 5 – 8 mm only. One

nodule in segment II showed early arterial enhancement and a wash-out phenomenon in the late phase, as known from " Fig. 1b, c). Another nodule metastases (● in segment V had a prominent feeding artery and early and prolonged contrast enhancement, features typically seen in " Fig. 2b). The echoes of the liver FNH (● parenchyma were enhanced reminiscent of 1st grade fatty liver disease. Blood counts and liver enzymes were normal. Carcinoembryonic antigen (CEA) was not elevated. Portal hypertension was ruled

Histopathology !

The nodules were investigated by frozen sections intraoperatively. Macroscopical-

Fig. 1 Nodular lesion in liver segment II six years after colonic carcinoma. a Transcutaneous ultrasound. b, c Contrast enhancement shows early enhancement b and latephase wash-out c (Logiq E9 with 9 L and C1 – 5 probes). Abb. 1 Knotige Veränderung in Lebersegment II, sechs Jahre nach Kolonkarzinom. a Transkutaner Ultraschall. b, c Contrast Enhancement zeigt Anreicherung b früher arterieller Phase und Wash-Out in später arterieller Phase (Logiq E9 mit 9 L und C1 – 5 Schallköpfen).

Höpfner* M et al. Unusual Nodular Regenerative … Ultraschall in Med · DOI http://dx.doi.org/10.1055/s-0033-1355907

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Unusual Nodular Regenerative Hyperplasia Mimicking Liver Metastases in CEUS

out. Magnetic resonance imaging (MRI) and computed tomography (CT) did not show any of these lesions, even with fusion imaging (GE, LOGIC E9; Volume Navigation, C1 – 5 and 9 L probe). It was decided to combine open laparotomy with intraoperative ultrasound including CEUS to reevaluate the number of lesions and perform frozen sections. The nodules " Fig. 2a) and two more were confirmed (● 3-mm lesions were detected. All five lesions were resected under US control. The immediate histological result confirmed R0 resection yet did not reveal malignancy. The patient recovered well and six months after the resection, no signs of further nodules were detected in follow-up CEUS.

Fig. 2 Nodules in liver segment V. a Intraoperative presentation. b One of the nodules shows early and prolonged contrast enhancement and prominent feeding vessels as well as draining veins . Abb. 2 Knotige Veränderungen in Lebersegment V. a Intraoperative Darstellung. b Einer der Knoten zeigte frühe und verlängerte Kontrastanreicherung und prominente, zuführende Blutgefäße, sowie drainierende Venen.

ly the foci were difficult to recognize as they were just slightly brighter compared to the adjacent liver tissue. Malignancy was ruled out. In hematoxylin-eosin stainings after paraffin-embedding the nodules were of subtle appearance. Reticulin stainings revealed sinusoidal dilation in the nodular areas. The hepatocytes were slightly enlarged and formed " Fig. 3), inditwo-cell-broad cell plates (● cative of nodular regenerative hyperplasia (NRH). Immunohistochemistry (IHC) for the endothelial marker CD31 demonstrated neovascularization of the nodules " Fig. 3c). Elastica-van-Gieson stainings (● showed signs of damage to portal vein branches in the adjacent liver parenchyma: mild periportal fibrosis, slit-like and " Fig. 4a). obliterated portal veins (● Also, minor lymphocytic infiltration was noticed around the one nodule in seg" Fig. 4b) as well as slender ment V (● fibrotic strands with mesh-like pattern" Fig. 4c). Cytokeratin7-IHC reing (● vealed proliferated bile ducts within the " Fig. 4 d). These findfibrotic strands (● ings are typical for focal nodular hyperplasia (FNH).

Discussion !

Follow-up care with CEUS revealed five suspicious hepatic nodules six years after adjuvant chemotherapy for colonic cancer. The nodules showed early arterialphase enhancement. One nodule in segment II showed late phase wash-out and was suspicious for malignancy. The lesions were not detected by CT and MRI. A possible reason for the discordance is the different behavior of the respective contrast agents (S Wilson et al. Am J Roentgenol 2007; 189: W7-W12). Using intraoperative high-frequency ultrasound they could be excised in sano. Histopathology revealed nodular regenerative hyperplasia (NRH) with some features of focal nodular hyperplasia (FNH) and vascular damage of portal vein branches. Data on the literature describe an ‘atoll sign’ in NRH, i. e. ringshaped B-mode appearance. This was not present in our case. Possibly the echointense border was masked by the echorich chemotherapy-induced steatotic parenchyma (E. Caturelli et al. Br J Radiol 2011; 84: e129 – 34). Oxaliplatin as part of the FOLFOX chemotherapy is a known vasculature damaging agent. Damage of portal vein branches by

oxaliplatin has been described to trigger NRH while damage of the central vein may cause the more acute sinusoidal obstruction syndrome (SOS) (D.E. Kleiner, Practical Hepatic Pathology, Chapter 24; Saunders 2011). Here, diffuse damage of portal vein branches could be directly observed in histopathology. Since other risk factors or exposures are absent, it appears that the FOLFOX treatment is causative of the hepatic microcirculation disturbance and resulting nodular hyperplasia. Neovascularization demonstrated by CD31IHC seems to be the correlate of the early contrast enhancement in CEUS. The morphological appearance of four of the nodules was typical for NRH but one nodule in segment V showed contrast enhancement and morphology comparable to FNH. Besides “classic” FNH, so-called FNH-like lesions are histopathologically recognized and have been described in vascular disorders of various causes. Oxaliplatin-induced portal vein damage has so far not been linked to the formation of FNH-like lesions. On the other hand, it is plausible for a vasculature-damaging agent to cause any form of resulting hepatic reaction. Liver damage is a common side-effect of oxaliplatin but usually causes only mild increases in liver enzymes and does not lead to clinical consequences (L. Rubbia-Brandt et al. Histopathology 2010; 56: 430 – 439). Thus, NRH and also FNHlike lesions may often remain undiscovered and might be more common than is reflected by published reports. Here, detailed follow-up including CEUS demonstrated two variants of NRH presumably caused by adjuvant FOLFOX six years earlier. One nodule resembled the contrast enhancement pattern of metastases. The case exemplifies that the evaluation of vascularized lesions remains a challenge in CEUS.

Acknowledgement !

We would like to thank David E. Kleiner, M.D., Ph.D., National Cancer Institut, Bethesda, USA, for critical review of the case and fruitful discussion. M. Höpfner*, A.H. Scheel*, M. Braun, J. Rüschoff, C. Löser, Kassel *Authors contributed equally.

Höpfner* M et al. Unusual Nodular Regenerative … Ultraschall in Med · DOI http://dx.doi.org/10.1055/s-0033-1355907

Downloaded by: University of Pittsburgh. Copyrighted material.

Case Report

Downloaded by: University of Pittsburgh. Copyrighted material.

Case Report

Fig. 3 Histopathological presentation of the nodules in segments II and V. a In Hematoxylin-Eosin (HE) stainings the nodules are of subtle appearance best seen at low-power magnification (10x). b Reticulin stainings show sinusoidal dilation within the nodules and highlight broadened hepatocytes. c Immunohistochemistry for endothelial marker CD31 shows a multitude of small arterial vessels within both nodules. Abb. 3 Histopathologische Darstellung der Knoten in den Lebersegmenten II und V. a In der Hämatoxylin-Eosin(HE)-Färbung heben sich die Knoten kaum vom angrenzenden Parenchym ab und sind nur bei geringer Vergrößerung (10x) sichtbar. b In der Retikulin-Färbung zeigt sich sinusoidale Dilatation im Bereich der Knoten und verbreiterte Hepatozyten. c Immunhistochemische Färbung des endothelialen Markers CD31 demonstriert eine Vielzahl kleiner arterieller Blutgefäße in den Knoten.

Höpfner* M et al. Unusual Nodular Regenerative … Ultraschall in Med · DOI http://dx.doi.org/10.1055/s-0033-1355907

Fig. 4 a: Elastica-van-Gieson (EvG) steinings and high power magnification of the adjacent liver parenchyma demonstrates portal fields with mild fibrosis and obliterated portal veins (200x). b, c: The nodule in segment V showed minor lymphocytic infiltration (b, HE) and mesh-like fibrotic strands (c, EvG, d: Immunohistochemistry for cytokeratin 7 reveals proliferated bile ducts within the strands. Abb. 4 a: In der Elastica-van-Gieson (EvG) zeigen sich bei starker Vergrößerung leichte periportale Fibrose sowie obliterierte Portalvenenäste (200x) im Leberparenchym außerhalb der Knoten. b, c: Der Knoten in Segment V zeigt leichtgradiges lymphozytäres entzündliches Infiltrat (b, HE) und netzartige fibrotische Gewebsstränge (c, EvG). d: Immunhistochemisch zeigt der Marker Cytokeratin 7 Gallengangsproliferate innerhalb dieser Gewebsstränge.

Höpfner* M et al. Unusual Nodular Regenerative … Ultraschall in Med · DOI http://dx.doi.org/10.1055/s-0033-1355907

Downloaded by: University of Pittsburgh. Copyrighted material.

Case Report

Unusual Nodular Regenerative Hyperplasia Mimicking Liver Metastases in CEUS.

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