An unusual case of aggressive systemic mastocytosis mimicking hepatic cirrhosis

Xiao-Yang Zhang, Wei-Hua Zhang

1Department of Pathology, Second Hospital of Tianjin Medical University, Tianjin 300211, China;

2Department of Dermatology, Traditional Chinese Medical Hospital of Rizhao, Rizhao 276000, China

An unusual case of aggressive systemic mastocytosis mimicking hepatic cirrhosis

Xiao-Yang Zhang1, Wei-Hua Zhang2

1Department of Pathology, Second Hospital of Tianjin Medical University, Tianjin 300211, China;

2Department of Dermatology, Traditional Chinese Medical Hospital of Rizhao, Rizhao 276000, China

Hepatic involvement in aggressive systemic mastocytosis (ASM) is relatively common, and the main clinical features of this disease include hepatomegaly, portal hypertension, ascites, and fi brosis. Cirrhosis is a rare ASM symptom. We report an ASM case that initially mimicked cirrhosis based on clinical and radiographic analyses.e portal tract was expanded by mononuclear in fl ammatory cells, and an increase in collagen amount was observed in routine histological sections of the biopsied liver. A diagnosis of systemic mastocytosis (SM) was made aer ancillary tests for mast cells using bone marrow aspirates. Extensive involvement of the liver and gastrointestinal tract was observed. Clinicians and pathologists need to consider ASM as a diagnosis or di ff erential diagnosis in a clinical case of cirrhosis with unknown etiology.e diagnosis can be con fi rmed or disregarded by immunohistochemical staining and molecular analysis.

Aggressive systemic mastocytosis (ASM); hepatomegaly; hepatic fi brosis; hepatic cirrhosis

Introduction

Systemic mastocytosis (SM) is characterized by the presence of a heterogeneous group of disorders. These disorders involve the growth and accumulation of morphologically and immunophenotypically abnormal mast cells in at least one extracutaneous organ with or without skin lesions. Aggressive systemic mastocytosis (ASM) is a subtype of SM. An SM diagnosis needs to fulfill the WHO1diagnostic criteria, which include one major and one minor criterion or at least three minor criteria.e major criterion is the presence of multifocal dense infiltrates of mast cells in aggregates of 15 cells or more. Such aggregation can be con fi rmed using immunohistochemical stains for either c-kit or tryptase in sections of bone marrow and/or other extracutaneous tissue(s). Minor criteria include the following: (1) more than 25% of the total number of mast cells are immature or show atypical morphology; (2) mast cellsaberrantly express CD2 and/or CD25 (normal mast cells are typically negative for these lymphocyte markers); (3) serum/ plasma tryptase level persistently exceeds 20 ng/mL; and (4) the presence of a codon 816 of KIT mutation in the peripheral blood, bone marrow, or lesional tissue. Moreover, the diagnosis of ASM can be made when one or more “C” fi ndings are present.“C” fi ndings include the following: (1) anemia (Hb ＜10 g/dL), thrombocytopenia (＜ 100,000/mm3), and neutropenia; (2) hepatopathy with ascites or portal hypertension; (3) splenomegaly with hypersplenism; (4) malabsorption with weight loss; and (5) osteolysis with pathological bone fractures.

ASM exhibits highly variable clinical characteristics, and skin lesions are often absent. Overlapping symptoms and heterogeneous clinical scenarios make early and accurate diagnosis extremely di ffi cult. Patients are frequently undiagnosed or misdiagnosed. The primary symptom of ASM is the pathological accumulation of mast cells in various tissues. The liver is frequently involved, but only a minor percentage of ASM patients develop portal hypertension and ascites. Cirrhosis symptoms are rarer. The liver is rarely biopsied and examined unless significant organ dysfunction has developed. In this paper, we report a rare case of ASM without skin lesions. Only hepatic and gastrointestinal tract symptoms were observed in thepatient.is report prompts pathologists and gastroenterologists to consider ASM as a differential diagnosis in patients with hepatic and gastrointestinal tract diseases of unknown etiology.e study was approved by the institutional ethics commiee.

Case report

A 62-year-old female patient was referred to the digestive system department of our hospital because of progressive abdominal distension for 1.5 years and edema of bilateral lower limbs for one month.e patient presented with the following symptoms upon admission: malaise, weight loss (10 kg), intermient upper abdominal pain, watery diarrhea (three to four times daily), oliguria (500 mL/day), and transient skin fl ushes.e patient’s blood pressure declined from 120/90 mmHg to 100/70 mmHg. She did not receive any therapy before admission. Her medical history revealed that she had tuberculosis for 40 years and other unremarkable symptoms.

Results of the laboratory examination performed at admission revealed a white blood cell count of 5.4×109/L with a normal differential count, hemoglobin level of 107 g/L, and platelet count of 249×109/L. The patient had a serum sodium level of 126 mmol/L (normal: 137-150 mmol/L), albumin level of 31.6 g/L (normal: 37-53 g/L), aspartate aminotransferase level of 12.9 U/L (normal: 0-40 U/L), alanine aminotransferase level of 13.2 U/L (normal: 0-40 U/L), gamma-glutamyltransferase level of 93 U/L (normal: 0-50 U/L), alkaline phosphatase level of 148 U/L (normal: 42-128 U/L), total bilirubin level of 6.5 μmol/L (normal: 0-20 μmol/L), direct bilirubin level of 1.4 μmol/L (normal: 1.7-6.8 μmol/L), and prothrombin time of 24.3 s (normal: 12-16 s).e tumor marker CA125 was present at a level of 207.6 U/mL (normal: ＜35 U/mL). Serological testing for hepatitis A, B, and C and HIV showed negative results. Autoimmune markers, other tumor markers, and blood and fecal cultures were negative.

A preliminary diagnosis based on clinical symptoms and laboratory examination results of the patient was made by the physician as follows: “hepatic cirrhosis, decompensated phase, however, etiology was not clear. In addition, given the tumor marker CA125 was in high level, exclude other abdominal or gynecological tumor was necessary.”

The patient underwent upper and lower gastrointestinal endoscopy three times during hospitalization because of persistent and intermient diarrhea. She also underwent a liver biopsy. Subsequently, the patient developed anemia (hemoglobin level of 98 g/L). Bone marrow aspiration was performed, and results show an abundance of atypical hypogranulated round or spindle-shaped cells. The abundance of such cells con fi rmed the presence of mast cell differentiation. Further immunohistochemical staining was performed on cells. Di ff use CD25 and CD117 in tryptase-positive mast cells in fi ltrated the gastric and colonic mucosa. Sheets of mast cells were present in the portal tract of the liver.

Figure 1 Microscopic images of the liver. (A) Liver biopsy highlighted an extinction area comprising a large amount of spindled mast cells, fi brous tissue, entrapped hepatocytes, ductular reactions, and a portal spanning the width of the needle’s core (H&E ×40); (B) mast cells were strongly positive for CD117 (IHC ×100).

A diffuse hyperemia with superficial erosions was present.e mucosa showed a slightly raised appearance, which mimicsthe proliferative polyp found by upper and lower gastrointestinal endoscopy (Figure 2A).e results of histological analysis were as follows. Mucosal erosion and gland expansion and distortion were observed. Diffuse spindled mast cell infiltration in the gastric and colonic lamina propria was characterized by cells with small, elongated, and baculiform nuclei, inconspicuous nucleoli, and pale cytoplasm (Figure 2B). These cells were admixed with some lymphocytes and plasma cells.e tumor cells were positive for CD117 (Figure 2C), and showed abnormal surface molecular expression of CD25. However, tumor cells were negative for CD30.

These fi ndings were fully consistent with ASM according to the WHO criteria, and a diagnosis of ASM with extensive involvement of the liver and gastrointestinal tract was made. The patient received H1and H2histamine antagonists with improvement in diarrhea.e patient was discharged upon the demand of her family and the patient herself. The patient died aer one month.

Discussion

Hepatic involvement in SM is common. Evidence of hepatic involvement includes hepatomegaly, portal hypertension, ascites, fibrosis, cirrhosis, liver failure secondary to SM, and abnormal liver test results. The main characteristics of SM patients with hepatic involvement according to the literature are summarizedin Table 12-12. SM patients frequently showed the following gastrointestinal and hepatic symptoms: hepatomegaly (90%), splenomegaly (79%), diarrhea (54%), abdominal pain (50%), and ascites (37%).

Figure 2 (A) Endoscopic image of the stomach showing erythema, superficial erosions, and nodularity without ulceration; (B) microscopic appearance of the gastric mucosa showing erosion, dilated and distorted gland architecture, increase in mast cells with chronic in fl ammation, and cell in fi ltration in the lamina propria (H&E ×20); (C) mast cells were highlighted by positive CD117 (IHC ×100).

Table 1 Main characteristics of patients suffering from SM with hepatic involvement. Data were collected from the current study and previous studies

Liver biopsy is rarely performed unless significant organ dysfunction has developed. Thus, information on liver histopathological features of SM patients is limited. The main sign of hepatic involvement in SM is the pathological accumulation of mast cells in the liver. Mast cells aggregate predominantly in portal areas. The most common symptoms are portal fibrosis and eosinophilic infiltration. Portal fibrosis was observed in 51% of the total number of cases. Mican et al.4observed a direct correlation between mast cell in fi ltration and fibrosis. Eosinophilic infiltration was observed in 61% of the total number of cases (Table 1), and may be correlated with hepatic mast cell burden13.e occurrence of portal cirrhosis was relatively rare (7%) (Table 1). Kyriakou et al.9described three patients with liver biopsy characteristics that were consistent with autoimmune cholangitis. They concluded that SM rarely causes non-cirrhotic portal hypertension, often simulating autoimmune cholangitis and leading to an erroneous diagnosis of liver cirrhosis. Other reported pathological fi ndings included the following symptoms: a dense aggregation of mast cells in fi ltrating the central veins, thereby increasing the thickness of the walls and obliterating luminal structures; muscular hypertrophy around the occluded vessel; subendothelial collagen deposition; and sinusoidal dilatation, centrilobular necrosis, cholestasis, and cholangitis2-9,13,14.

Despite significant hepatic involvement, normal values are obtained by the usual liver tests (except for the alkaline phosphatase test) in SM patients13. Furthermore, hepatic lesion severity is not correlated with the size of the liver or the results of liver function tests13. Mican et al.4demonstrated that fi ve patients who showed symptoms of ascites or portal hypertension died of complications secondary to SM. However, mild impairment of liver function was observed in these patients. Thus, the development of ascites or portal hypertension is an adverse prognostic marker. The lack of skin involvement also results in negative prognosis for an SM patient.

In the present case, the patient was initially diagnosed with cirrhosis based on the CT and clinical results. Microscopic examination of liver biopsy showed disturbed architecture with portal fibrosis and spindled mononuclear cell infiltration. Common eosinophils were absent.e histological examination results were inconclusive.e abnormal mast cells were di ffi cult to identify, particularly in the presence of other cells, such as lymphocytes, macrophages, and eosinophils.e mixture of cells simulated changes in chronic active hepatitis.us, a special stain was necessary to distinguish the cells. Normal mast cells typically expressed two characteristic surface markers, namely, the CD117 antigen and IgE. However, these markers were not speci fi c. CD25 and/or CD2 are invariably expressed in neoplastic mast cells from SM patients10. More recent data suggested that most neoplastic mast cells in indolent SM cases are usually negative for CD30. By contrast, CD30 is expressed abundantly in the cytoplasm of most mast cells in patients with advanced SM, such as ASM and mast cell leukemia11. Some authors considered that CD30 expression may help in con fi rming the diagnosis of advanced SM and excluding other potential neoplasms15. Unexpectedly, CD30 was not expressed in the current case.

Conclusion

SM diagnosis can be challenging especially in the absence of typical skin manifestations. Diagnosis is di ffi cult even if a patient shows symptoms of aggressive disease, impaired liver function, hepatomegaly, ascites, and cirrhosis. A diagnosis of SM must be considered during routine clinical practice.is diagnosis can be con fi rmed or disregarded using immunohistochemical markers, such as tryptase, CD117, and CD25, in combination with molecular analysis (KITD816V) and laboratory parameters (i.e., serum tryptase).

Con fl ict of interest statement

No potential con fl icts of interest are disclosed.

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Cite this article as: Zhang XY, Zhang WH. An unusual case of aggressive systemic mastocytosis mimicking hepatic cirrhosis. Cancer Biol Med 2014;11:134-138. doi: 10.7497/j.issn.2095-3941.2014.02.009

Xiao-Yang Zhang

E-mail: xiaoyangsys@126.com

Received April 18, 2014; accepted June 2, 2014. Available at www.cancerbiomed.org

Copyright © 2014 by Cancer Biology & Medicine