ACROMEGALY AND A GIANT RETROPERITONEAL LIPOSARCOMA PRODUCING IGF-1

Abstract

Objective:

Liposarcoma is the most common histotype of retroperitoneal sarcomas, representing up to 45% of all cases. We report a rare combination of acromegaly and liposarcoma in the same individual.

Methods:

Laboratory and imaging studies including an oral glucose tolerance test, measurements of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), and a computed tomography scan were performed.

Results:

The patient was a 60-year-old male with a history of acromegaly diagnosed on the basis of elevated IGF-1 at 1,373 ng/mL (age-appropriate reference range is 87 to 225 ng/mL) and macroadenoma treated with transsphenoidal surgery. He presented 8 years later with a history of abdominal distension and weight loss. Physical examination was notable for a right-sided abdominal mass that was tense and non-fluctuant. Two years earlier, he had a post oral glucose tolerance test GH level <0.25 ng/mL and IGF-1 level of 256 ng/mL (age-appropriate reference range is 55 to 206 ng/mL). Pituitary magnetic resonance imaging reported a 3.7 × 2.0-mm left-sided parasagittal lesion. Computed tomography scan showed a 25.0 × 22.0 × 32.3-cm heterogeneous giant mass in the right abdomen corresponding to a liposarcoma causing displacement of kidney, liver, and bowel loops. The patient was treated with a complete en bloc resection of the liposarcoma with the right kidney (45 × 33 × 17 cm) and tumor (9,400 g). Immunohistochemical examination revealed positive IGF-1 and GH staining. The patient suffered postoperative gastrointestinal bleeding that resulted in hemorrhagic shock and died on the 29th postoperative day after a cardiorespiratory arrest.

Conclusion:

Acromegalic patients are at increased risk of developing various types of neoplasms. This is the first documented coexistence of liposarcoma and history of acromegaly.

INTRODUCTION

The most common type of soft tissue sarcoma is liposarcoma that occurs primarily in the extremities and followed by the retroperitoneum (1). It is usually asymptomatic and when symptomatic, it is characterized as a nonspecific abdominal pain and a diffuse abdominal enlargement. Radical surgery offers the best chance of disease control (2). Prognosis is poor despite complete removal of the tumor; nearly 85% of the cases are malignant with a 5-year survival rate of 20% (3).

Approximately 15% of the mortality of the acromegaly is most commonly due to malignant breast, colon, prostate, and hematological cancers (4). Other documented tumors presenting in acromegaly include bone, adrenal, and skin tumors (5). To our knowledge, this is the first reported case of liposarcoma occurring in a surgery-treated, acromegalic elderly male.

CASE REPORT

In June 2010, a 60-year-old Latino presented clinical manifestations of acromegaly that was diagnosed on the basis of insulin-like growth factor-1 (IGF-1) of 1,373 ng/mL (age-appropriate reference range is 87 to 225 ng/mL) and magnetic resonance imaging that revealed macroadenoma (11 × 8 × 5 mm) with posterior displacement of the infundibular stalk. Analysis of growth hormone (GH) response during an oral glucose tolerance test (OGTT) was not carried out at diagnosis.

Transsphenoidal pituitary resection was performed. Histologic examination revealed a sparsely granulated adenoma that stained positive for GH. Radiotherapy was proposed but was rejected by the patient. Postoperative magnetic resonance imaging revealed a left-sided tumor remnant measuring 4.7 × 3.6 mm. An OGTT revealed GH at 0.3 ng/mL (reference range is 0 to 3 ng/mL) and IGF-1 of 189 ng/mL. A regular follow-up visit was uneventful.

In January 2016, a routine biochemical test reported serum levels of IGF-1 of 290 ng/mL and GH of 0.48 ng/mL. At that time, residual acromegalic features were present including diastema, prognathism, and soft tissue hypertrophy of the hands and feet. The post-OGTT GH nadir was <0.25 ng/mL. At a later follow-up visit, serum levels of IGF-1 remained higher than the reference range and a second post-OGTT GH nadir was <0.32 ng/mL. Testosterone and dehydroepiandrosterone sulfate levels were within normal range. Pituitary magnetic resonance imaging reported a 3.7 × 2.0-mm, left-sided parasagittal lesion.

Cabergoline treatment was started. In spite of the treatment, a normal level of IGF-1 was not achieved. In June of 2019, he reported 6-month history of abdominal distension and weight loss. Physical examination was remarkable for a right-sided abdominal mass that was tense and non-fluctuant. Computed tomography demonstrated a 25.0 × 22.0 × 32.3-cm, heterogeneous giant mass in the right abdomen causing caudal and contralateral displacement of the kidney, liver, and bowel loops (Fig. 1). Fine-needle percutaneous biopsy of the abdominal mass was performed and revealed a well-differentiated liposarcoma with sclerotic regions. IGF-1 level was 256 ng/mL and insulin-like growth factor-binding protein-3 (IGFBP-3) level was 1.6 μg/mL (reference range is 3.4 to 6.9 μg/mL).

Fig. 1.

(A) Contrast-enhanced, axial abdominal computed tomography scan showing a large heterogeneous left-sided retroperitoneal mass. The mass has a low-fat attenuation and septum in its interior (arrow). Note the anterior and medial displacement of the right kidney (arrow head). (B) Coronal view showing a 25 × 22 × 32-cm mass occupying the entire left retroperitoneal space. Note the inferior vena cava (white arrows) and portion of the colon displacement (red arrow). (C) Sagittal view showing adjacent structures being compressed and displaced by the large retroperitoneal mass including the liver (red arrow), right kidney (white arrow), and colon (blue arrow).

At surgical intervention, the tumoral lesion was found to be adhered to the right kidney and it was resected en bloc (Fig. 2). Gross examination of the surgical specimen revealed a 45 × 33 × 17-cm giant mass adhered to the right kidney. The tumor weighed 9,400 g. Histopathology examination revealed adipocytes that included nuclear pleomorphism and hyperchromasia (Fig. 3). A high-power examination showed adipocytes with irregular nuclei and intranu-clear vacuoles suggesting lipoblasts. Immunohistochemical analyses for GH and IGF-1 were carried out, revealing focal positivity in the cytoplasm of atypical stromal cells (Fig. 4). Positivity was even more evident in the cytoplasm of the lipoblasts of the neoplasm which was completely negative in the non-neoplastic tissue. Staining for insulin-like growth factor-2 and IGFBP-3 was negative.

Fig. 2.

(A) Gross photograph of the removed retroperitoneal liposarcoma adhered to the right kidney. (B) Through-cut section of the surgical specimen showing a bright yellow and multiloculated surface.

Fig. 3.

Histology of the removed retroperitoneal mass. (A) Low-power magnification of the cylindrical core biopsy showed the tumor is comprised of alternating fat and fibrous tissue (hematoxylin and eosin stain; ×4). (B) Section showing abundant fat tissue separated by thick bands of sclerotic collagen (hematoxylin and eosin stain; ×4) and (C) higher magnification of the same tissue (×10) showing adipocytes with irregular nuclei and intranuclear vacuoles as well as the presence of lipoblasts (circle).

Fig. 4.

Immunohistochemistry images showing (A) a control panel next to positive staining for both (B) growth hormone and (C) insulin-like growth factor-1.

The patient suffered postoperative complications including pneumonia and gastrointestinal bleeding that resulted in hemorrhagic shock. Emergency surgery was performed, however ongoing bleeding was documented. The patient's relatives refused further treatment or cardio-pulmonary resuscitation. The patient died on the 29th postoperative day after cardiorespiratory arrest.

DISCUSSION

The clinical features of acromegaly are almost always the result from excessive GH secretion from a pituitary adenoma. Transsephenoidal surgery is the benchmark treatment, but even in the hand of the most skilled neurosurgeons cure is achieved in only 50 to 70% of the cases (6,7). Cure is defined as normal IGF-1 (by age and sex), random GH <1 ng/mL, and a post-OGTT GH nadir <0.4 ng/mL (8).

However, its interpretation is not always simple with an incidence of discordant data reported up to 39% (9). The most common discordance seen is elevated IGF-1 levels with normal GH suppression as in our patient (10). In this case, his 8-month postsurgical treatment IGF-1 value was 189 ng/mL (age-appropriate reference range is 50 to 317 ng/mL). Discordant results of GH and IGF-1 levels started 4 years after surgery. As recommended (11), repeated testing of IGF-1 and GH levels were carried out documenting persistent elevated IGF-1. Two GH suppression tests were performed due to the persistently elevated IGF-1 level, and they did not confirm recurrence of disease.

Both testosterone and dehydroepiandrosterone sulfate have been shown to increase IGF-1 during GH replacement (12). Furthermore, GH and IGF-1 discordance is also attributed to radiation and somatostatin receptor ligand treatment (13). Our patient, however, had normal levels of testosterone and dehydroepiandrosterone sulfate and he did not receive treatment with somatostatin receptor ligands or radiotherapy. Our multidisciplinary team agreed to treat the patient as a recurrent acromegaly with cabergoline and radiotherapy. The latter was refused by the patient.

The insulin-like growth factor system plays a pivotal role many cellular processes and, essentially, is comprised of 3 ligands (IGF-1, insulin-like growth factor-2, and insulin), 2 receptors (IGF-1 receptor and insulin receptor), and 6 insulin-like growth factor-binding proteins (numbered 1 through 6) (14). IGF-1 is mainly produced by the liver and it is characterized by being a circulating hormone and a tissue growth factor (15,16). IGFBP-3 is the main circulating IGFBP and is largely attached to IGF-1, modulating its bioavailability (17). Increased expression of insulin-like growth factors and IGF-1 receptor have been measured in a variety of bone and soft tissue sarcomas, including liposarcoma. It is hypothesized that their overexpression promotes proliferation compared to normal adjacent tissues (18). In acromegalic states, excess GH increases levels of both IGF-1 and IGFBP-3 (19) however their activities are oppositional as IGFBP-3 promotes apoptosis (20). Our case's level of IGFBP-3 was low and his IGF-1 to IGFBP-3 ratio was 185 (296 ng/mL to 1.6 μg/mL), suggesting his tissue levels and circulating bioavailability of IGF-1 was increased.

CONCLUSION

We describe a rare case of coexistence of a history of acromegaly and a giant liposarcoma. As the elevated IGF-1 could not be attributed to GH stimulation in our patient, it is very possible that persistent elevation of IGF-1 was caused by liposarcoma that was confused as a recurrent acromegaly disease.

Abbreviations

GH

growth hormone

IGF-1

insulin-like growth factor-1

IGFBP-3

insulin-like growth factor-binding protein-3

OGTT

oral glucose tolerance test