CLINICAL NOTE

 

Nodular regenerative hyperplasia of the liver and cutaneous T-cell lymphoma: An unreported association

Hiperplasia nodular regenerativa hepática y linfoma cutáneo de células T: una asociación no descrita

 

 

Verónica Ciria-Bru¹, Álvaro Giráldez-Gallego¹, Diego Pascual-Vaca-Gómez², Teresa Zulueta-Dorado² and Verónica Nacarino-Mejías³

¹Unit for Medical Management of Digestive Diseases. Section of Hepatology
²Department of Pathology
³Department of Radiology. Section of Vascular and Interventional Radiology.
Hospitales Universitarios Virgen del Rocío. Sevilla, Spain

Correspondence

 

 

---

ABSTRACT

Nodular regenerative hyperplasia of the liver -a type of non-cirrhotic portal hypertension- is a rare condition of unknown etiopathogenesis that has been associated with multiple disorders, including diverse types of hematologic disease. We report the case of a 36-year-old female patient diagnosed with cutaneous T-cell lymphoma of the mycosis fungoides variety, staged as T2N0M0B0, where a transjugular liver biopsy demonstrated the presence of nodular regenerative hyperplasia with a hepatic venous pressure gradient of 15 mm Hg. The study was triggered by the incidental radiologic finding of hepatomegaly with indirect evidence of portal hypertension. We are not aware of any previous reports on the association of nodular regenerative hyperplasia with mycosis fungoides in the medical literature.

Key words: Nodular regenerative hyperplasia. Cutaneous T-cell lymphoma. Vitamin A. Mycosis fungoides.

---

RESUMEN

La hiperplasia nodular regenerativa hepática -una modalidad de hipertensión portal no cirrótica- es una enfermedad poco frecuente de etiopatogenia desconocida que se ha asociado a multitud de trastornos diversos, incluyendo enfermedades hematológicas de distinta índole. Presentamos el caso de una paciente de 36 años diagnosticada de linfoma cutáneo de células T, tipo micosis fungoide, estadio T2N0M0B0, en la que una biopsia por vía transyugular demostró la existencia de una hiperplasia nodular regenerativa con gradiente de presión venosa hepática de 15 mm Hg; el detonante del estudio fue la aparición radiológica de una hepatomegalia incidental con datos indirectos de hipertensión portal.No nos consta que la asociación entre hiperplasia nodular regenerativa y micosis fungoide esté descrita en la literatura médica.

Palabras clave: Hiperplasia nodular regenerativa. Linfoma cutáneo de células T. Vitamina A. Micosis fungoide.

---

 

Introduction

Primary cutaneous lymphomas -whether B-cell or T-cell- are only second to gastrointestinal lymphomas as the most common extranodal non-Hodgkin type, with an annual incidence estimated around 1/100,000. Mycosis fungoides and Sézary syndrome are both the most common varieties of cutaneous T-cell lymphoma (CTCL). Their prognosis depends not only upon the type and extent of skin lesions but also on extracutaneous involvement, for which histologic confirmation is also recommended; hepatosplenic involvement is, however, an exception to this rule as it usually manifests as nodules in imaging studies, hence biopsy is not essential (1,2).

Nodular regenerative hyperplasia (NRH) is one of the categories included in the syndrome known as non-cirrhotic portal hypertension (NCPH), which requires absence of spleno-portal axis vein thrombosis and exclusion of an established cause of liver disease (3). In NRH, by definition, fibrosis is minimal or even absent. This is an uncommon condition in the Western world that has been associated with multiple disorders (infectious, genetic, autoimmune), various immune deficiency states, and exposure to a wide range of drugs and toxics. Occasionally, different potential etiologies are concurrently present in one patient. An association of NRH with a variety of hematological conditions is also well documented, and an underlying -ever so often manifest- thrombophilic status is posited in such cases as a key etiopathogenic factor (4). However, the description of an association between NRH and CTCL in the medical literature has never been made known to us.

 

Case report

A 36-year-old woman was referred from our dermatology and hematology clinics for the study of an incidental case of hepatomegaly on radiologic images. For approximately three years the patient had suffered from eczematous, erythematous, scaling, scarcely pruriginous, circular plaque-like skin lesions, some of them pigmented, on virtually all of the trunk and both upper and lower limbs. She had previously undergone two skin biopsies that yielded nonspecific findings (parakeratotic foci, minimal superficial perivascular lymphocytic infiltration with eosinophils, and mild epidermal hyperplasia), and the diagnoses of chronic eczema (perhaps due to contact atopy) versus atypical pityriasis rosea; she had received treatment mainly with various topic corticoids. Four months before our first encounter she was eventually diagnosed with CTCL of the mycosis fungoides variety. On this occasion a skin biopsy showed dense inflammatory infiltration of the superficial dermis with lymphocytes and exocytosis, that was minimal in the epidermis but well established in hair bulbs; the immunophenotype of the lymphocytic component was predominantly CD3/CD4 over CD8, with a scarce representation of CD20; the mitotic index (ki-67) was 25-30 %. An amplification of the VJ segment in the hypervariable region of the TCR-γ (T-cell receptor-gamma) gene was carried out by PCR with specific primers and successive fragment analyses, using the ABI Prism^® 3730 sequencer (Applied Biosystems, Foster City, CA, USA) and the commercially available MAD-003994TP-2/5^® kit (Master Diagnóstica, Granada, Spain). The sample had tumor cellularity in excess of 70 % with a DNA level of 21.2 ng/μl. A T lineage-specific monoclonal rearrangement was confirmed: the material analyzed showed an amplification fragment that was 156 base pairs in size.

At the time the diagnosis with CTCL was confirmed the patient was 26 weeks pregnant, which limited therapy options. As part of the staging process a CT scan with IV contrast was scheduled that also had to be delayed until after delivery, but that eventually identified a homogeneous hepatomegaly with no space-occupying lesions as sole significant finding. Stage at diagnosis was determined to be T2 (involvement greater than 10 % of body surface), N0, M0 (no lymphocytic infiltration in nodes or other organs), B0 (no changes in T-cells or CD4/CD8 ratio on cytofluorometry and normal peripheral blood smear). When our first interview took place the patient had completed a course of 24 phototherapy sessions with ultraviolet-B radiation (cumulative dosage of 19,804 MJ), which resulted in significant improvement. She was otherwise asymptomatic, with no palpable adenopathies or abdominal masses and no stigmata of chronic liver disease on inspection. Her body mass index was 20.6 kg/m². All three series in the blood panel were normal and routine parameters suggested a rigorously preserved liver function. Liver enzymes were normal. Serologies for hepatitis B and C viruses were negative, as also were liver disease-related autoantibodies. Neither iron overload nor changes in the proteinogram or immunoelectrophoresis were found.

At three months following light therapy completion the patient experienced a severe recurrence of skin lesions wherefore she underwent treatment with bexarotene (150 mg/m²: 225 mg daily, adjusted to body surface area [1.6 m²]), thyroxine (25 μg daily), fenofibrate (180 mg daily) and omega-3 triglycerides (1,000 mg daily) together with psoralen and ultraviolet-A radiation (PUVA). Concomitantly, a repeat CT scan with IV contrast was performed where previously absent radiographic portal hypertension (PHT) evidence was comparatively ascertained (increased portal vein caliber and splenomegaly); hepatomegaly persisted but now with a peripheral nutmeg liver pattern of enhancement that suggested potential veno-occlusive hepatic disease (Fig. 1). Here a transjugular liver biopsy was performed with simultaneous measurement of suprahepatic vein wedged (25 mm Hg) and free (10 mm Hg) pressures: The resulting hepatic venous pressure gradient (HVPG) was 15 mm Hg. No sedation was used for this procedure. Five liver tissue fragments with sizes between 5 and 10 mm were histologically studied: An architectural distortion could be seen that included a changed relationship between central veins and portal tracts and no fibrosis was present (Fig. 2).

 

 

No gastroesophageal varices or other PHT manifestations were documented by oral endoscopy. An abdominal sonogram revealed no evidence of steatosis. Liver stiffness as measured by transient elastometry (TE) was 6.1 kilopascals (kPa) with an interquartile range of 0.8 kPa. Baseline urinary Na/K excretion was 132/141 mmol/24 hours. No changes worth mentioning were found in a complete hypercoagulability study including antithrombin III, proteins C and S, homocysteine, antiphospholipid antibodies and both prothrombin and factor V Leiden gene mutations. No complications have arisen after six months following her diagnosis with NRH.

 

Discussion

Hepatic distortion in NRH results from diffuse parenchymal transformation into regeneration nodules (single-acinus, smaller than 3 mm) with central hyperplasia alternating with tissue atrophy areas; typically, in contrast with cirrhosis, nodules are not separated by fibrosis (5). The most commonly accepted hypothesis regarding their genesis considers NRH a consequence of generalized tissue adaptation (hyperplastic liver cells and/or atrophy) to a disruption or heterogeneous distribution of blood flow secondary to the obliteration, luminal narrowing and destruction of smaller portal veins (up to 0.2 mm in diameter). Regardless of the underlying disorder, the unifying histology of NRH is therefore obliterating portal vein disease (6), without significant septal fibrosis, probably associated with a baseline prothrombotic status (7). These changes, however, are not pathognomonic and also develop in other NRH-related conditions (8). The clinical behaviour of NRH is usually silent with long symptom-free periods lacking specific laboratory or radiologic changes. Nevertheless, most patients (50-70 %) eventually develop irreversible PHT signs or complications. Ascites is peculiarly uncommon and prognosis is never as poor as for liver cirrhosis, likely because liver function is usually preserved until end-stage disease. Otherwise, recommendations regarding the prophylaxis and management of PHT clinical manifestations are similar to those established for patients with cirrhosis (3). Consequently, a high level of suspicion is necessary in routine clinical practice regarding this condition, where histological confirmation is considered crucial. However, telling NRH from liver cirrhosis may be challenging in clinical practice when using conventionally obtained liver biopsy samples (5). In our case neither the size nor the number of nodules in the sample could be established as needle rather than wedge specimens were provided. On the other hand, the liver parenchyma analyzed had no lymphocytic infiltrates, hence no TCR-γ rearrangement testing was ordered; this technique allows a diagnosis of up to 95 % of T-cell lymphoproliferative disorders (9).

The typical hemodynamic pattern seen in patients with NRH is predominantly presinusoidal, with a normal or slightly elevated HVPG, in contrast to patients with cirrhosis and PHT, who usually exhibit a high HVPG. Bissonnette et al. (10) demonstrated that HVPG was lower than 10 mm Hg (threshold for clinically significant PHT) in 15 of 21 patients with NRH -with also varices or ascites- undergoing free and wedged hepatic vein pressure measurements. However, they found a portal vein pressure above 12 mm Hg in 100 % of all 12 patients undergoing this direct measurement. The presinusoidal component (from obliterating vein disease) is not the only explanation for PHT in patients with NRH: direct sinusoidal compression by regeneration nodules may as well develop. Some authors (11) posit a mixed (presinusoidal and sinusoidal) component for NCPH, and the result may depend on the measuring of pressures for the predominant mechanism in each individual case, and/or disease progression stage: 6 of 21 (28.6 %) patients in the study by Bissonnette et al. had a HVPG higher than 10 mm Hg, some of them with no esophageal varices, as in our case. Recently, promising evidence has emerged on the capacity of TE to discriminate between liver cirrhosis and NCPH (12): Seijo et al., using HVPG measurements and TE, studied a cohort of 27 patients with NCPH (7.1 ± 3.1 mm Hg and 8.4 ± 3.3 kPa, respectively) and compared their findings with those from a cohort of cirrhotics with PHT (17.0 ± 3.0 mm Hg and 40.9 ± 20.5 kPa, respectively) finding statistically significant differences in both cases. Only 5/27 (18.5 %) patients with NCPH had an HVPG above 10 mm Hg and only two patients had a liver stiffness value greater than 13.6 kPa. Therefore, in patients with unequivocal PHT evidence, HVPG and/or liver stiffness values below those considered significant for cirrhosis should raise suspicion for a condition within the NCPH syndrome complex.

In summary, NRH (as other forms of NCPH) is a condition that entails a serious prognosis, likely remains underdiagnosed and may be easily mistaken for liver cirrhosis. Diagnostic tools available to us include biopsy, liver hemodynamics, and -of late- TE, but the disease may manifest with a wide range of nonspecific data that, on occasion, may even look conflicting. Describing the association of NRH with other conditions (e.g., with CTCL, as in our patient) may foster understanding for this still puzzling disease on whose etiopathogenesis all theories remain merely guesswork. Its treatment currently consists of the generic management of PHT, but the hypothesis that anticoagulation therapy may be beneficial is overtly appealing (3).

 

References

1. Willemze R, Dreyling M; ESMO Guidelines Working Group. Primary cutaneous lymphoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009;20:115-8.         [ Links ]

2. Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: A consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol 2011;29:2598-607.         [ Links ]

3. Schouten JN, Garcia-Pagan JC, Valla DC, Janssen HL. Idiopathic noncirrhotic portal hypertension. Hepatology 2011;54:1071-81.         [ Links ]

4. Wanless IR, Godwin TA, Allen F, Feder A. Nodular regenerative hyperplasia of the liver in hematologic disorders: a possible response to obliterative portal venopathy. A morphometric study of nine cases with an hypothesis on the pathogenesis. Medicine (Baltimore) 1980;59:367-79.         [ Links ]

5. Steiner PE. Nodular regenerative hyperplasia of the liver. Am J Pathol 1959;35:943-53.         [ Links ]

6. Cazals-Hatem D, Hillaire S, Rudler M, Plessier A, Paradis V, Condat B, et al. Obliterative portal venopathy: Portal hypertension is not always present at diagnosis. J Hepatol 2011;54:455-61.         [ Links ]

7. Bayan K, Tüzün Y, Yilmaz S, Canoruc N, Dursun M. Analysis of inherited thrombophilic mutations and natural anticoagulant deficiency in patients with idiopathic portal hypertension. J Thromb Thrombolysis 2009;28:57-62.         [ Links ]

8. Verheij J, Schouten JN, Komuta M, Nevens F, Hansen BE, Janssen HL, et al. Histological features in western patients with idiopathic non-cirrhotic portal hypertension. Histopathology 2013;62:1083-91.         [ Links ]

9. Yang H, Xu C, Tang Y, Wan C, Liu W, Wang L. The significance of multiplex PCR/heteroduplex analysis-based TCR-gamma gene rearrangement combined with laser-capture microdissection in the diagnosis of early mycosis fungoides. L Cutan Pathol 2012;39:337-46.         [ Links ]

10. Bissonnette J, Généreux A, Côté J, Nguyen B, Perrealt P, Bouchard L, et al. Hepatic hemodynamics in 24 patients with nodular regenerative hyperplasia and symptomatic portal hypertension. J Gastroenterol 2012;27:1336-40.         [ Links ]

11. Duseja A, Chawla Y. Portal hypertension in nodular regenerative hyperplasia: A mixed bag! J Gastroenterol Hepatol 2012;27:1260-2.         [ Links ]

12. Seijo S, Reverter E, Miquel R, Berzigotti A, Abraldes JG, Bosch J, et al. Role of hepatic vein catheterisation and transient elastography in the diagnosis of idiopathic portal hypertension. Dig Liver Dis 2012;44:855-60.         [ Links ]

 

 

Correspondence:
Álvaro Giráldez Gallego
Unit for Medical Management of Digestive Diseases
Section of Hepatology
Hospitales Universitarios Virgen del Rocío
Avda. Manuel Siurot, s/n
41013 Sevilla, Spain
e-mail: giraldezg@hotmail.com

Received 31-10-2013
Accepted 27-01-2014