Growing teratoma syndrome in mixed hepatoblastoma with teratoid features

Abstract

Mixed epithelial mesenchymal (MEM) hepatoblastoma with teratoid features is rare histological variant of hepatoblastoma and described in case reports. Growing teratoma syndrome (GTS) is a rare and often unrecognised phenomenon generally associated with less than 5% of germ cell tumour. It is defined by enlarging tumour mass which is generally mature teratoma with normal or significantly decreasing tumour markers during chemotherapy. The treatment outcomes in GTS are dependent on early recognition and complete surgical excision. We describe a rare case of MEM hepatoblastoma with teratoid features with GTS in an infant who had a delay in definitive management due to late diagnosis of GTS.

Background

Hepatoblastoma (HB) is the most common primary malignant neoplasm in children less than 5 years of age. It comprises less than 1% of all paediatric cancers. It is a heterogeneous tumour composed of various epithelial and mesenchymal elements. It is classified into four epithelial and two mixed subtypes based on these elements.¹ Mixed epithelial mesenchymal (MEM) HB with teratoid features is rare and seen in 4% of HB.² It is described in isolated case reports.^3–6

Growing teratoma syndrome (GTS) is a rare and often unrecognised phenomenon generally associated with less than 5% of Germ cell tumour (GCT). It is defined by enlarging tumour mass which is generally mature teratoma with normal or significantly decreasing tumour markers during chemotherapy. The complications due to GTS arise due to mass effect. The treatment outcomes in GTS are dependent on early recognition and complete surgical excision of this rare entity.⁷

We describe a rare case of MEM HB with teratoid features with GTS in an infant who had a delay in definitive management due to late diagnosis of GTS.

Case presentation

An 8-month-old female infant initially presented to a tertiary care hospital with progressively increasing right-sided abdominal lump, noticed by parents, for 1 month. There were no associated complaints. She had tachypnoea while the other vital signs were stable. She weighed 8 Kg (−2Z) and length was 68 cm (−1Z). She did not have any dysmorphic features. Abdominal examination revealed 10×10 cm hard, immobile, non-ballot able, non-tender mass with lobulated surface and ill-defined margins in right hypochondrium and right lumbar region.

Investigations revealed normal complete blood count, normal renal and liver function tests (LFT) except aspartate transaminase (AST) of 219 U/L (Normal value 5–40). Her lactate dehydrogenase- 995 U/L (normal value 46–116), serum alpha feto protein (AFP)—998 U/mL (normal value for age 0.8–87) and ß-human chorionic gonadotropin- 1.36 U/L (normal value <2.9). Ultrasonography (USG) of abdomen revealed ill-defined mass in right lobe of liver involving segment V, VI with punctuate calcification. Contrast-enhanced CT (CECT) scan of chest and abdomen revealed a 10×8×14 cm heterogeneous mass involving segment V, VI, VII with chunky classification with no intravascular involvement with minimal perihepatic fluid and no significant lymphadenopathy (PRETEXT stage II)(figure 1A, B). No lung metastasis was noted. Trucut biopsy of lesion revealed features of MEM HB with epithelial component (fetal and embryonic pattern) comprising more than 90% morphology. No teratoid component was reported.

Figure 1.

Serial CT scan of abdomen showing (A, B) Coronal section and cut section revealing heterogeneous lobulated lesion in segment V, VI and VII of liver with calcification. (C) Increase in size of lesion with increase in cystic spaces and coarse calcification after four courses of chemotherapy. (D, E) Further increase in size of lesion with increase in cystic spaces occupying whole of abdomen after fifth course of chemotherapy.

She was managed as standard risk HB and started on neoadjuvant chemotherapy (NACT) with single agent cisplatin as per International Society of Pediatric Oncology Epithelial Liver tumor study Group (SIOPEL) protocol.⁸ She was given four cycles of NACT at 15 days interval. Tumour size and AFP were not monitored during NACT. After fourth cycle of NACT, she was noted to have increase in abdominal girth. CECT abdomen revealed increase in the size of mass (10.6×13×15.8) and additional involvement of segment IV and VIII with an increase in number and size of cystic spaces and coarse calcification (figure 1C). In view of progressive and extensive disease, surgical resection was not feasible. She was referred to our centre for second line chemotherapy and possible liver transplantation.

Investigations and differential diagnosis

At our centre, repeat AFP was 283 U/mL. The trucut biopsy review revealed epithelial tumour (HB) arranged in cords, nests and trabeculae along with abundant osteoid (figure 2A), heterologous (teratoid component) seen in form of keratinised squamous epithelium (figure 2B), based on which diagnosis of MEM HB with teratoid component was established. Immunohistochemistry (IHC) highlighted hepatocytes (CK8/18 positivity) and revealed negative SALL 4 negating possibility of GCT. A possibility of GTS was considered in view of progressive disease despite NACT, predominantly cystic morphology with increase in calcification on reassessment CECT and decrease in AFP from baseline and surgical opinion was sought. Tumour was considered unresectable at this time by paediatric surgeons.

Figure 2.

Gross image of hepatectomy specimen along with photomicrographs of H&E and IHC (A) liver biopsy shows epithelial tumour (hepatoblastoma) arranged in cords, nests and trabeculae along with abundant osteoid (H&E stain, ×10). (B) heterologous (teratoid component) seen in form of Keratinised squamous epithelium (H&E stain, ×20). (C) gross image of cut surface of hepatectomy specimen showings near total effacement of normal architecture with presence of multiple solid and cystic areas. (D) sections from hepatectomy specimen shows effaced architecture by teratomatous components like osteoid, adipose tissue and glands (H&E stain, ×10). (E) osteoid with surrounding mesenchymal tissue (H&E stain, ×40).(F–H) CK 7 immunostain. (F) highlights the glandular lining (H&E stain, ×20); Hep Par-1 (G) and AFP (2 hours) immunostains highlight residual tumour (hepatoblastoma) cells (H&E stain, ×20). AFP, alpha feto protein; IHC, immunohistochemistry.

Treatment

In absence of intervening assessment of tumour size and serial AFP and surgery not being considered by surgeons, she was switched to high-risk chemotherapy with carboplatin/cisplatin and doxorubicin (super PLADO) as per SIOPEL protocol. After one cycle of chemotherapy the abdominal distension worsened (figure 3A, B) and there was further increase in tumour size (16×18×21 cm) (figure 1D, E) with decreasing trend of AFP (69 U/mL). She fulfilled criteria for GTS and was referred for paediatric surgeons for definitive surgery.

Figure 3.

Clinical photograph of index child showing grossly distended abdomen and distended collateral veins over anterior abdominal wall. (A) from top (B) from right side.

Abdomen was opened by transverse incision extending from right to left subcostal margin. The tumour was involving segments IVa, IVb, V, VI, VII and VIII, hence a decision for extended right hepatectomy was taken. Anatomy of abdomen was grossly deranged; all the abdominal organs were pushed to left. Inferior vena cava was very narrow with hardly any flow. Paediatric surgeons started with parenchyma first approach. Hepatic veins were identified and ligated as the surgery progressed (figure 4A, B). A 3.5 Kg tumour was removed. On surgical histopathology, gross examination showed a tumour involving the entire liver with multiple solid and cystic areas (figure 2C). Solid areas were hard and difficult to cut. HPE revealed a teratoma with varying proportion of ectodermal, mesodermal and endodermal components (figure 2D, E). IHC was done to demonstrate various components (figure 2F). Microscopic foci of residual HB component were identified, measuring less than 2% of total tumour area. These residual tumour cells were smaller than normal hepatocytes and arranged in thin cords and better highlighted by Hep Par-1 (figure 2G) and AFP (figure 2H) immunostains. Hepatic resection limit was free of tumour. On the basis of HPE report, a final diagnosis of MEM HB with teratoid features with GTS was given.

Figure 4.

(A) Intraoperative photograph from foot end showing the liver segment II, III (not involved with tumour) abd IV B (partially involved with tumour) as marked. Blue vascular sling is around portal vein and yellow vascular sling is around common bile duct. White arrowhead is pointing to solid calcified portion while white double arrow is pointing to cystic component of teratoma. (B) Photograph of cut section through recess of Rex showing remnants after completion of surgery. Liver segments are shown as marked with roman numerals. White arrowhead pointing to inferior vena cava, white double arrow pointing to left hepatic vein, blue arrow and yellow arrow pointing towards ligated middle hepatic vein and right hepatic vein.

Postoperatively, she had cholestasis (serum bilirubin 207 µmol/L, AST—40 U/L, alanine transaminase (ALT)−26 U/L) with massive bile stained ascites. She was managed conservatively. On postoperative day (POD)-10, a hepatobiliary iminodiacetic acid scan was done which did not show any uptake in liver, hence a diagnosis of small for size was made. For rapid liver regeneration splenic artery embolisation was done on POD-14. Five days later, she again started having bile leak, massive ascites and features of sepsis. She was started on antibiotics and supportive therapy. After failure of conservative management, she was taken up for re-exploration of abdomen on POD-30. Left hepatic duct was found accidentally ligated and there was bile leak from cut surface. A Kasai type roux en y hepatico enterostomy was done at the leak site. Postoperatively, she started passing cholic stools and her LFT normalised gradually.

Outcome and follow-up

After 1 month of discharge, she is on complete oral feeds, gaining weight, AFP—1.7 U/mL with normal serum bilirubin and liver enzymes. She is planned for monthly follow-up with USG abdomen, radiograph chest, AFP and LFT.

Discussion

HB is a rare malignant neoplasm of liver seen in children less than 5 years of age. International paediatric liver cancer pathological classification subclassifies MEM HB depending on presence of teratoid feature. MEM with heterogeneous epithelial or endothelial component apart from mesenchymal elements are labelled to have teratoid features.^{1 9} MEM with teratoid features is a rare entity first described in 1986 as ‘teratoid HB’.¹⁰ Subsequently, few other case reports have described it as a rare hepatic tumour which frequently leads to diagnostic dilemma with malignant GCT.^3–6

GTS is a rare phenomenon which has been described in GCT until. It should be suspected when the tumour size is increasing in serial images despite chemotherapy with normalisation of tumour markers. Diagnosis is confirmed when surgical pathology report reveals presence of predominantly mature teratoma and absence of malignant component. Postulated mechanisms for GTS are: (1) destruction of malignant component by chemotherapy and sparing of mature teratomatous elements, (2)transformation of totipotent malignant cells to benign mature teratoma and (3)spontaneous and inherent differentiation of malignant to benign tissues.^11–13 Good treatment outcomes in GTS are dependent on awareness of this entity, frequent monitoring of tumour size and tumour markers during chemotherapy, early diagnosis by picking up paradoxical response to chemotherapy and lastly complete and prompt surgical excision. The earlier diagnosis of GTS also avoids unnecessary chemotherapy which may be counterproductive and worsen the tumour. Therefore, frequent monitoring of tumour size and tumour markers during chemotherapy of a malignant tumour with teratoid component is must.

All the reports of MEM with teratoid component^{3–6 10} had progression of tumour during chemotherapy and were fatal in immediate post op period except case described by Moll et al, where the tumour progression was picked up very early during first course of chemotherapy and a complete and prompt surgical excision achieved favourable outcome.⁵ However, GTS as an entity has not been described in abovementioned case reports.

Our case reflects association of GTS in tumour other than conventionally described GCT. Our case like other case reports emphasises on frequent monitoring of size and tumour markers during NACT, early diagnosis and complete surgical excision. Index child had delayed diagnosis due to missing of teratoid component in HPE report, probable unawareness of GTS at referring hospital and not monitoring size and tumour markers during NACT. We could establish a definitive diagnosis and achieve a complete surgical excision at our centre but with associated morbidity which could have been averted had GTS been diagnosed early in an HB which was restricted initially (PRETEXT II).

Parent’s perspective.

Our daughter had progressive abdominal distention for a month and was diagnosed with a liver tumour. She was started on chemotherapy. She was tolerating the therapy well. After 3–4 cycles of chemotherapy we noticed that the distension of abdomen has again started increasing. After repeat scans, doctors said that the tumour is probably not responding to chemotherapy and has increased in size. We were told that our daughter may require liver transplantation and we were referred to a new hospital. Here after reviewing reports we were told that there is a possibility of ‘growing teratoma’, and a high risk surgery is the only hope. After a long surgery, we were informed that a 3.5 Kg tumour which is almost half the weight of our child has been removed. We were also counselled about chances of liver failure since hardly 20% of the liver was left behind. Post op period was stressful and she required multiple surgical procedures. We were losing hope but doctors were trying their best. Miraculously, she recovered and we were discharged after a prolonged hospital stay. Presently, she is playful, feeding well and gaining weight. During follow-up, as per doctors, her liver functions are normal and there is no recurrence of tumour. We just hope that she continues to be healthy.

Learning points.

• Mixed epithelial mesenchymal hepatoblastoma with teratoid features is a rare histological subtype of hepatoblastoma.

• Growing teratoma syndrome (GTS) should be suspected while managing tumours with teratoid components, when there is a paradoxical increase in tumour despite chemotherapy with normalisation or significant decrease of tumour markers; and further chemotherapy should be avoided.

• Favourable outcomes in GTS are dependent on awareness of this entity, frequent monitoring of tumour size and tumour markers during chemotherapy, early diagnosis and complete and prompt surgical excision.