Myofibroblastoma in the Liver: A Case Report and Review of Literature

Abstract

Myofibroblastoma is a rare benign mesenchymal tumor first described in the breast. It is also known as mammary-type myofibroblastoma outside of the breast, more frequently located along the embryonic milk line. Exceptionally, myofibroblastoma can occur at visceral locations. We present a case of myofibroblastoma detected incidentally in the liver. A well-circumscribed mass, grossly measuring 6.2 cm in the liver parenchyma, was found on imaging studies. Histologically, the lesion is characterized by benign spindle cells in a hyalinized collagenous stroma, with positive staining for SMA and ER, focal positivity for CD34, negative for desmin, and loss of RB1. This rare tumor at such an unusual location makes it diagnostically challenging, especially on core biopsy of the lesion. To our knowledge, this is the second case of myofibroblastoma in the liver reported in the English literature and the first such case with a detailed pathology description.

Introduction

Myofibroblastoma is a rare benign spindle cell tumor with fibroblastic and myofibroblastic differentiation, and usually occurs in the breast. Most commonly, it presents as a slow-growing painless breast mass, which on imaging, appears as a well-circumscribed, lobulated mass. Infrequently, it occurs outside of the breast along the embryonic milk line and is also known as mammary-type myofibroblastoma. Myofibroblastoma was first described in 2001 in a series of 9 cases. ¹ The most common locations are the inguinal region, perineum, scrotum, and vulva. Myofibroblastoma is exceedingly rare in the liver, and currently, only one such case has been reported in the English literature. ²

When occurring in the liver, myofibroblastoma may pose diagnostic challenges due to its non-specific clinical and radiological features. On histology, it overlaps with other bland spindle cell lesions. Herein we describe a case of myofibroblastoma in the liver of a 52-year-old woman, with detailed histological and immunohistochemical analyses.

Case Report

A 52-year-old woman presented with symptoms of urinary tract infection and subsequently underwent computed tomography (CT) urogram examination to rule out anatomic abnormalities. Incidentally, she was found to have a 5.4 cm lesion in the right liver (Figure 1). Subsequent magnetic resonance imaging (MRI) of the abdomen demonstrated a mass with avid uniform arterial phase enhancement without washout on delayed portal venous phase. The gallbladder, bile ducts, adjacent hepatic parenchyma, and hepatic vasculature were unremarkable. The overall imaging findings were indeterminate, as imaging features were not characteristic of benign hepatocellular lesions (eg, focal nodular hyperplasia or adenoma). Percutaneous biopsy was thus performed under ultrasound imaging guidance. Histology demonstrated a hypocellular spindle cell neoplasm with bland, oval to spindle cells embedded in the hyalinized collagen bundles (Figure 2). There were no mitoses or necrosis. A broad panel of immunohistochemical stains showed a unique combination of positive estrogen receptor (ER), CD34 (focal), and muscle markers (SMA and caldesmon) consistent with myofibroblastoma.

Figure 1.

Computerized tomography (CT) urogram protocol, axial images during (A) non-contrast, (B) nephrographic, and (C) excretory phases. Imaging finding is notable for a hypo/isoattenuating liver mass in segment 8 with homogeneous enhancement on portal venous phase and delayed washout.

Figure 2.

Morphological features of the tumor on liver biopsy. (A) H&E (100×) section shows a bland spindle cell proliferation with low cellularity in the background of the collagenous stroma. There is no significant atypia or mitosis. Immunohistochemical stains show the tumor cells are positive for SMA (B), focally positive for CD34 (C), and ER (D) (200×original magnification).

She subsequently underwent partial hepatectomy. A gross examination of the liver revealed a solitary, white-tan, firm, well-circumscribed, homogeneous mass measuring 6.2 × 4.9 × 3.8 cm. The cut surface of the mass was smooth, firm, and whorled, with a focal area of hemorrhage consistent with the prior biopsy site (Figure 3A). The mass was 0.1 cm away from the inked resection margin. Hematoxylin and eosin-stained (H&E) sections from the liver tumor demonstrated a distinct well-demarcated spindle cell proliferation with uniform oval to spindle cells arranged haphazardly and in short fascicles in a background of collagenous stroma (Figure 3B), similar to prior biopsy. High risk features such as cytological atypia, mitotic activity, or necrosis were absent. The hepatic parenchymal resection margin was negative for tumor, and the background liver parenchyma did not show any significant inflammation, fibrosis, or steatosis.

Figure 3.

Gross and microscopic images of liver resection. (A) Gross examination shows a well-circumscribed mass with a homogeneous white-tan, firm, whorled cut surface and a focal area of hemorrhage corresponding to prior biopsy site. (B) H&E section (200×) demonstrates a distinct spindle cell proliferation with uniform oval to spindle cells arranged haphazardly and in short fascicles in a background of collagenous stroma, similar to prior biopsy. (C) Immunohistochemical staining for RB1 shows partial loss of expression (400×). (D) Single-color FISH shows normal cell (two signals, right yellow circle), heterozygous deletion (single signal, middle red circle), and homozygous deletion (no signal, left green circle) of RB1 locus (1000×).

Additional immunohistochemical stains were performed on the resected tumor. The tumor cells were positive for progesterone receptor (PR), and androgen receptor (AR). The tumor cells were negative for KIT, DOG1, desmin, EMA, S100, and STAT6. The immunohistochemical staining for RB1 was partially lost (Figure 3C). A fluorescent in-situ hybridization (FISH) assay using Vysis single-color probe kit was performed to detect 13q14 (RB1) locus alteration. Among 151 tumor cells, there was monoploid RB1 signal in 49% of cells consistent with monosomy or heterozygous deletion, and complete loss of RB1 signal in 41% of tumor cells indicative of homozygous deletion (Figure 3D). ³ These findings confirmed a diagnosis of myofibroblastoma.

The patient was well nine months after surgery, except for minor postsurgical discomfort. There was no residual or recurrent disease.

Discussion

Myofibroblast is modulated fibroblast with the ability to contract and hence functionally resembles smooth muscle. ⁴ In 1987 Wargotz et al coined the term myofibroblastoma for a distinct benign stromal tumor of the breast in which the tumor cells showed immunophenotypic and ultrastructural features of myofibroblasts. ⁵ It usually affects older men and postmenopausal women. ⁶ A similar mesenchymal tumor resembling mammary myofibroblastoma occurs at a location other than the breast is known as extramammary or mammary-type myofibroblastoma. ¹ They usually occur along the milk line and primarily affect adults ⁷ ; however, there have been occasional cases reported in children. ⁸ The histogenesis of extramammary myofibroblastoma remains enigmatic. The proposed theory is that these tumors originate from tissue along the embryonic milk line that extends from the axilla to the medial groin. The alternative theory proposed for the lesions outside the embryonic milk line is the presence of ectopic breast tissue. ¹

In the largest series of 143 extramammary myofibroblastomas, the tumors were distributed in the inguinal (45%), chest wall/axilla (5%), trunk (12%), lower extremity (13%), upper extremity (1%), and intraabdominal/retroperitoneal organs (10%). ⁹ The exact breakdown of intraabdominal tumors with respect to visceral involvement was unavailable. The mean age in the series was 54 years, with a male predominance (66%) and a mean tumor size of 6.6 cm. Most patients were asymptomatic, with few presenting with a painful mass. ⁹ Other reported unusual locations outside of the milk line included the popliteal fossa, ⁶ liver, ² orbits,^10,11 head and neck, ¹² thigh, buttock, ¹³ prostate, ¹⁴ para testicular region, ¹⁵ meningeal, ¹⁶ seminal vesicle, ¹⁷ scrotum, ¹⁸ and perianal area. ¹⁹ Wei et al described a collision tumor in the vulva composed of extramammary myofibroblastoma and eccrine adenocarcinoma. ²⁰ Most patients had a good prognosis despite positive surgical margins, except for one case that recurred 20 years later. ⁹ Among the 160 cases of myofibroblastoma reported in the literature in various locations, ¹¹ there was only one instance in the liver. ² Radiologic features of these rare tumors are not well characterized; nonetheless, MRI typically shows a well-circumscribed mass with an intralesional fat component. ¹¹

Histologically, myofibroblastomas are well-circumscribed mesenchymal tumors composed of bland spindle cells arranged in a fascicular pattern in a background of collagenous stroma.^5,21 Individual cells have short elongated nuclei and eosinophilic cytoplasm with indistinct cell borders. The tumor may have a varied proportion of intralesional fat. ⁹ Less common morphologic features such as nuclear atypia, epithelioid tumor cell morphology, and neurilemmoma-type nuclear palisading were also described. ⁹ Recognizing the histological diversity, the World Health Organization (WHO) classification of breast tumors describes five variants, ie, lipomatous, myxoid, fibrous/collagenized, epithelioid/deciduoid, and palisading/Schwannian-like myofibroblastomas. ²² Our case was fibrous predominant with no intralesional adipocyte component.

Immunohistochemically and ultrastructurally, myofibroblastomas prove to be of smooth muscle differentiation. Lee et al reported that these lesions are diffusely positive for desmin, compared to focal positivity as originally reported by Wargotz et al.^5,23 They are variably positive for CD34, AR (androgen receptor), and ER. Actin positivity may be seen in one-third of the tumors.^24,25 Howitt et al found CD34 positivity in 89% and desmin positivity in 91% of the tumors; however, both markers were negative in 4 cases (3%). In addition, RB1 expression was lost in 92% of tumors. ⁹ In our case, the tumor was positive for SMA, caldesmon and ER, focally positive for CD34, and negative for desmin, with partial loss of RB1 expression. Pathologists must be aware of the variable expression of immunohistochemical markers in order to arrive at a correct diagnosis. As shown in our case, RB1 FISH assay is available to confirm the diagnosis if the immunohistochemical staining pattern is equivocal or shows partial loss of expression.

The differential diagnosis includes benign tumors such as spindle cell lipoma, cellular angiofibroma, angiomyofibroblastoma, solitary fibrous tumor, perineurioma, and malignant lesions such as gastrointestinal stromal tumor (GIST) and low-grade malignant nerve sheath tumor.

Spindle cell lipoma is a well-circumscribed, thinly encapsulated, lobulated mass common in the head and neck area. This lesion is composed of an admixture of mature adipocytes and undifferentiated spindle cells with short stubby nuclei and pale, poorly defined cytoplasm with rare mitoses. They are set in a variably fibromyxoid stroma notable for the presence of brightly eosinophilic, hyaline collagen fibers and numerous mast cells. ²¹ Myofibroblastoma contains less fat and more prominent collagen-rich stroma, and it is usually positive for desmin compared to spindle cell lipoma (<2% cases are positive). ¹ Both are genetically related neoplasms and share partial loss of genetic material from the chromosome 13q14 region.

In the inguinal region, cellular angiofibromas and angiomyofibroblastomas also enter into the differential diagnoses for extramammary myofibroblastoma. Angiomyofibroblastoma, more commonly seen in females, is well-circumscribed with prominent small vessels and desmin-positive perivascular cells. In postmenopausal women, they show hyalinized stroma and a more spindled appearance resembling myofibroblastoma. ¹ Cellular angiofibromas in females are small and circumscribed, while in males these tumors are larger and less circumscribed. Histologically, they exhibit relatively uniform spindle cells with scant eosinophilic cytoplasm, indistinct cell border, and short, blunt to wavy nuclei arranged in short fascicles associated with wispy collagen bundles. The striking hyalinized vessels are distinct for these lesions and do not occur in myofibroblastoma. Immunohistochemically cellular angiofibromas are positive for CD34 but commonly negative for desmin and SMA, which helps to differentiate from myofibroblastoma. ¹

The tumor suppressor gene RB1 is located on chromosome 13q14, and deletion of this region has been reported in genetically related tumors, including spindle cell lipoma, myofibroblastoma, and cellular angiofibromas.^18,26–28 Magro et al suggested the term “benign stromal/mesenchymal tumors with 13q14 deletion” as a unifying concept, as all three share the same genetic alteration and a subset of spindle cell lipomas and cellular angiofibroma showed histologic similarity to myofibroblastoma. ²⁸

Solitary fibrous tumor (SFT) is another differential diagnosis to be considered while dealing with a bland spindle cell lesion in the liver. It comprises short stubby spindle cells in a patternless pattern with intervening hyalinized collagen, characteristic branching hemangiopericytoma-like vascular pattern, and perivascular hyalinization. SFTs occurring outside of the pleura rarely exhibit mitoses and necrosis. The tumor cells are typically positive for CD34 and STAT6 and negative for S100, actin, desmin, and keratin. A subset of tumors show nuclear positivity for beta-catenin, ²¹ and positivity for desmin is infrequent and focal. ¹

Gastrointestinal stromal tumor (GIST) is a common mesenchymal tumor in the gastrointestinal tract which may involve the liver. It may contain variable amount of collagen-like stroma; however, GIST is typically positive for KIT and DOG1. ²⁹ Malignant peripheral nerve sheath tumors (MPNST) consists of spindle cells with tapering or buckled nuclei and show perivascular whirling appearance. Usually desmin is negative in MPNSTs except for those with rhabdomyogenic differentiation (Triton tumor), and S100 is positive in 50% of MPNSTs. ¹ Loss of H3K27me3 is a typical finding in MPNST which can help establish the diagnosis.

In summary, myofibroblastoma in the liver is a rare tumor composed of cytologically bland spindle cells in a hyalinized collagenous stroma. The spindle cells show variable expression of CD34 and desmin. Usually, they are positive for SMA and ER in addition to the loss of RB1 as demonstrated by immunohistochemistry and FISH. With its histological heterogeneity and characteristic immunohistochemical profile, awareness of this uncommon entity is essential to arrive at the correct diagnosis, especially in small biopsies.