Demystifying Fetus-in-fetu: A Systematic Review of Its Clinical and Pathological Attributes

ABSTRACT

Background:

Fetus-in-fetu (FIF) is an exceedingly rare condition, characterized by a fetal-like or fetiform mass with a calcified vertebral axis surrounded by other organs or limbs. This systematic review was conducted to comprehensively analyze the clinicopathological attributes, management strategies, and prognosis of FIF to consolidate existing knowledge on FIF.

Methodology:

Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a comprehensive search was performed across various electronic databases, using the keywords “fetus-in-fetu,” “fetus-ex-fetus,” “homunculus,” or “fetiform teratoma” to look for published articles until December 2023. Data extraction and analysis were carried out for cases meeting the defined criteria for FIF diagnosis, that is “presence of both/either the vertebral column and/or long bones of extremities” and “absence of immature elements.”

Results:

A total of 249 case reports/case series comprising 241 single FIF cases and 33 multiple FIF cases were included for analysis. The majority of single FIF cases presented within the 1^st year of life, with a slight male predominance. Retroperitoneal location was most common, and imaging modalities played a crucial role in preoperative diagnosis. Complete surgical removal of the mass with detailed histopathological examination is the cornerstone of treatment for FIF, with favorable outcomes in the majority of cases. Both mature and immature teratoma can rarely be found in association with FIF.

Conclusion:

This comprehensive systematic review enhances understanding of FIF, emphasizing the importance of accurate diagnosis by diligent histopathological examination, appropriate management, and vigilant postoperative monitoring for favorable outcomes.

INTRODUCTION

Fetus-in-fetu (FIF) is very rare and mostly occurs in neonates, with an incidence of about 1 in 500,000 live births.[1,2] As the name suggests, the mass is “fetal-like” or “fetiform,” that is, it resembles a normal fetus in several aspects. FIF was first defined by Willis, as a mass characterized by a calcified vertebral axis typically accompanied by other organs or limbs surrounding this central axis.[3] Since then, few authors have defined FIF in a more refined and elaborate manner, drawing from the foundational work of Nicholson (1929), Lord (1956), and Willis (1962) [Figure 1].[4,5] Conventionally, the recognition of vertebral segments, macroscopically or microscopically, has been crucial in defining FIF. However, a few cases documented in English literature have departed from this convention, presenting instances as FIF despite the absence of identifiable vertebral bodies. In such cases, authors have labeled them as FIF, due to the presence of limbs containing innervated muscles, as a piece of surrogate evidence for the presence of a rudimentary spine and spinal cord at variable levels of embryonic differentiation.[6] Hence, the defining criteria for the diagnosis of FIF remains unclear.

Figure 1.

Evolving concepts of fetus-in-fetu

Regarding its genesis, there are two prevailing theories, namely, the “teratoma theory” and the “identical twin theory.” The “teratoma theory” posits that FIF represents a specialized type of highly well-differentiated teratoma whereas the “identical twin theory” proposes that FIF arises from abnormalities in the twinning process. Under normal circumstances, twins develop symmetrically, but in cases of FIF, one twin remains underdeveloped and becomes encapsulated within the body of the other twin during gestation. This controversy warrants further investigation, as it is imperative to differentiate between a neoplastic process (teratoma) and an abnormality in embryonic development, from a management viewpoint. Furthermore, comprehensive clinicopathological data on FIF is not available as the current literature is limited to case reports and case series. Hence, with the research question “what are the clinical, pathological, and embryological characteristics of FIF that contribute to its differential diagnosis from teratomas, and what implications do these distinctions have for clinical management and treatment outcomes?,” we conducted a systematic analysis of reported cases of FIF to enhance our current understanding regarding its pathogenesis, associated clinical parameters, pathological findings, treatment approaches, associated complications, and prognosis, thereby guiding clinical management and future research endeavors in this rare and intriguing entity.

METHODOLOGY

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA). A comprehensive electronic database search of PubMed, Scopus, Embase, Proquest, Cochrane database, and Google Scholar was conducted using the keywords “fetus-in-fetu,” “fetus-ex-fetus,” “homunculus” or “fetiform teratoma” to look for relevant published literature from inception to December 2023. A snowball principle involving the reference lists of highly cited papers and the citations to these papers, to find additional papers on the topic of interest was conducted, to find out any missing reports. Rayyan software was used for duplicate detection and preliminary screening through the entire search results. Two authors independently reviewed the titles and abstracts of the identified manuscripts, and disagreements between the authors were resolved through discussion. The data were further manually double-checked by two reviewers to avoid duplication. All original articles/case reports/series/letters to editors/clinical images/correspondence reporting cases of FIF were included. Case definition of FIF for inclusion was framed as “any mass showing radiologic/macroscopic/microscopic presence of complete/incomplete/rudimentary/dysplastic vertebral column with or without the presence of long bones of limbs OR any mass showing radiologic/macroscopic/microscopic presence of long bones of limbs in the absence of vertebral column AND absence of immature elements on microscopic examination of the mass,” deriving from various previously proposed definitions. Literature pertaining to isolated cases of fetiform teratoma, immature teratoma, and mature teratoma were excluded. From the included articles, data extraction was carried out independently by the authors. Microsoft Excel was used to compile data regarding the age and gender of the patient, gender of the fetiform mass, clinicopathological details, imaging findings, disease course, and treatment done. Cases not fitting the definition of FIF were excluded from the final statistical analysis. Descriptive statistics was used to calculate and analyze simple frequency, percentage, and proportions.

RESULTS

A total of 249 case reports/case series with a total of 241 cases of single FIF and 33 cases of multiple FIF were included for comprehensive analysis. The PRISMA workflow chart is presented in Figure 2.

Figure 2.

Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines flow diagram of the study. FIF: Fetus-in-fetu

Demographics and clinical attributes

In the cohort of 241 cases of single FIF, the age at presentation/diagnosis ranged from the 1^st day of life (i.e., at birth) to 47 years. In 43 cases, the mass was antenatally detected upon routine ultrasonography (USG) done for fetal well-being or at the time of the targeted anomaly scan. Although presentation within the 1^st year of life was common, a substantial number of cases (n = 57) presented beyond the infancy period [Table 1]. A slight preponderance of male gender was noted (M:F = 1.1:1). A family history of twin pregnancies was observed in 11 instances alone (172 cases did not report on family history). The examination of serum levels of tumor markers such as alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), and human chorionic gonadotropin (HCG) was conducted in a limited number of cases. Among the 30 cases tested for AFP, 10 showed an isolated increase in AFP, while 2 cases displayed a simultaneous increase in CEA levels as well. One case exhibited elevated levels of AFP, CEA, and HCG.

Table 1.

Age at presentation and gender distribution

	Number of cases	Mean (range)	Females	Males	Gender not mentioned
Antenatal detection of mass	43	-	12	21	10
Presentation at birth or during neonatal period (0–30 days)	63	5.8 days (0–28 days)	27	34	2
Presentation during 1–12 months’ period	78	4.36 months (1–11 months)	37	38	3
Presentation after 1 year period	57	12.8 years (1.1–47 years)	32	25	0

Conventional imaging modalities such as X-ray radiography, USG, computed tomography (CT), and magnetic resonance imaging (MRI) played an important role in preoperative diagnosis. The presence of one or more long bone(s) was detected in 131 instances (constituting 54.4% of cases), facilitating the preoperative diagnosis of FIF. In 25.3% of cases (n = 61), calcified regions lacking distinct bone structures were observed, while the remaining 20.3% (n = 49) showed no signs of calcification or bone formation in imaging. Among the antenatally detected cases of singleton FIF, only in 25% of cases, a preoperative diagnosis of FIF was considered by the radiologist, or the physician performing scan. In remaining cases (75%), FIF was not suspected on imaging and the presumptive diagnoses considered included hepatic cyst, retroperitoneal teratoma, meconium peritonitis or ileus, encysted fetal ascites, mesenteric or omental cyst, adrenal tumor, neuroblastoma, sacrococcygeal teratoma, hemangioma if the tumor was found in the abdominal cavity; lymphangioma, brachial cyst, teratoma in cases found in the region of head and neck; and epidermoid cyst in the third ventricle, intracranial tumor, or teratoma, if the mass was found intracranial. Majority of the cases (55%) were detected in the third trimester after 28 weeks of gestation and only a few cases were detected at the time of 18–22 weeks anomaly scan. Of all the reported cases, the earliest diagnosis was made at 14 weeks of gestation, however, parents opted for termination of pregnancy in this case.[7] In a total of 4 cases, parents opted for termination of pregnancy, after prenatal diagnosis. Two cases, both having intracranial FIF, had intrauterine fetal demise, in the late second trimester. In few mothers, complications such as preterm labor, prelabor rupture of membranes, and labor dystocia mandating cesarean section, were reported.

The retroperitoneum (n = 174; 72.2%) was the most common location, followed by intraperitoneal sites (n = 14; 5.8%). Other less common locations included intrathoracic (n = 11; 4.7%), head-and-neck region including oral cavity (n = 10; 4.1%), sacrococcygeal/gluteal/perineal (n = 10; 4.1%), intracranial (n = 9; 3.7%), and within the gonads (n = 9; 3.7%). Few investigators have described cases of “fetus-ex-fetus” in which the fetiform mass is attached externally to the patient and satisfies the diagnostic criteria of FIF.[8,9] In another interesting instance, a 7-month-old female child presented with intracranial FIF with extra calvarial extension in the occipital-cervical region.[10] All cases underwent complete surgical removal of the mass. Intraoperatively, a definitive blood supply could be identified in 79 cases, with only 3 cases lacking any identifiable feeding vessel. However, it is to be noted that, in most of the instances (n = 159; 66%), the authors did not mention regarding presence or absence of a feeding vessel. The postoperative course was uneventful in the majority of the cases (n = 201; 83.4%). Only in 7 cases, the baby succumbed to postoperative complications. Following surgery, the levels of AFP, CEA, and HCG, if elevated, normalized in all cases.

The details of all the multiple FIF cases are enumerated in Table 2.[1,2,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38] The maximum number of FIF reported in a single host, till date, is eleven.[27] Similar to single FIF cases, retroperitoneal location and presentation during infancy were most common. In two instances, the baby was diagnosed with mature teratoma, 1–2 years postsurgery.[21,22]

Table 2.

Key clinicopathological attributes of multiple fetus-in-fetu reported till December 2023

Authors; year of publication	Age at presentation	Family history of twinning	Gender	Number of FIF/location	Blood supply	Sac-like covering/UC-like structure	Postoperative course	Remarks
Kimmel DL et al., 1950[11]	At birth	Absent	Female	5; intra-cranial	NM	Present/present (see remarks*)	Autopsy after death on 19 days	Hydrocephalus at birth One had sac-like covering, two had UC-like structure*
Gross RE and Clatworthy HW, 1951[12]	2 days	Absent	Female	2 in single sac with membrane separation; retroperitoneum	Superior mesenteric artery	Present/present	Uneventful
Lee EY, 1965[13]	2 month	NM	Male	3 in single sac; retroperitoneum	Sacral artery	Present/present	Uneventful	-
Chi J et al., 1984[14]	8 week	NM	Male	2 in single sac; retroperitoneum	Mesenteric vessels	Present/present	Uneventful	-
Eng HL et al., 1989[15]	1.6 years	Absent	Female	2 in same sac but without membrane separation; retroperitoneal	Mesenteric vessels	Present/absent	Uneventful
Gurses N et al., 1990[16]	4 month	Absent	Male	2 in single sac with membrane separation; retroperitoneum	Superior mesenteric artery	Present/present	Uneventful	-
Martine Zurrutia MJ et al., 1990[17]	At birth	NM	Female	2 in single sac; retroperitoneum	Celiac trunk	Present/present	Uneventful	-
Luzzato C et al., 1994[18]	9 days	NM	Male	2 in single sac; retroperitoneum	NM	Present/absent	Uneventful	-
Bhat BV et al., 1998[19]	At birth	NM	Female	2; intra-abdominal	Abdominal aorta, mesenteric arteries	Present/absent	Died, reason unknown	-
Magnus KG et al., 1999[20]	5 days	NM	Female	Multiple FIF within a single sac; intrahepatic	Intrahepatic portal vein	Present/absent	Uneventful	Showed a co-existing benign teratoma within the same sac
Mills P et al., 2001[21]	PD	NM	Female	2, retroperitoneum	Superior mesenteric artery	Present/present	At 2 years of age: Retroperitoneal mature cystic teratoma	-
Gilbert-Barness E et al., 2003[22]	PD	NM	Female	2; retroperitoneum	Superior mesenteric artery	Present/present	At 1 year of age: Retroperitoneal benign cystic teratoma	By DNA analysis the infant, the fetuses-in-fetu, and the teratoma were identical
Iyer KV et al., 2003[23]	PD	NM	NM	2; retroperitoneum	Renal artery	Present/NM	NM	Larger fetus demonstrated male external genitalia
Wada K et al., 2005[24]	4 months	Absent	Female	2 in single sac with membrane separation; retroperitoneum	Lumbar artery	Present/absent	Uneventful	PCR analysis: Presence of X chromosome, with absence of Y chromosome in the fetuses None of the tumor marker levels (HCG, NSE, AFP, UVMA) were elevated
Miura S et al., 2006; case 1[25]	PD	NM	Male	2, retroperitoneum	Abdominal aorta	Present/present	NM	Genotype analysis of host and fetiform masses revealed identical genotypes were all identical
Miura S et al., 2006; case 2[25]	PD	NM	Male	One intracranial FIF and 6 fetiform masses elsewhere	NM	NM	Terminationumber of pregnancy at 21 weeks of gestation	Genotype analysis of host and fetiform masses revealed identical genotypes were all identical
Saito et al., 2007; case 1[26]	PD	NM	Male	2 in same sac but no membrane separation; retroperitoneal	Abdominal aorta	Present/present	complicated by temporary heart failure, but recovered	Cytogenetic studies of host and the fetiform masses revealed 46, XY karyotype STR marker analysis: Host and tumor were genetically identical
Saito et al., 2007; case 2[26]	PD	NM	NM	6; intracranial	NM	Present/absent	Terminationumber of pregnancy at 21 weeks of gestation	Co-existent immature teratoma Associated with marked hydrocephalus
Gerber RE et al., 2008[27]	At birth	Present	Female	11; intraperitoneal (9) and retroperitoneal (2)	NM	Present/present	Died of multisystem organ failure on day 34	Co-existing benign ovarian teratoma Co-existing atretic bowel loops with malrotation and hypoplastic kidneys Cytogenetic studies of host and the fetiform masses revealed 46, XX karyotype
Pourang H et al., 2009[28]	3 days	NM	Female	2 in same sac but no membrane separation; retroperitoneum	Abdominal aorta	Present/absent	Uneventful	Showed a co-existing immature teratoma within the same sac No tumor markers were evaluated prior to the surgery
Daga BV et al., 2009[29]	20 years	NM	NM	2; retroperitoneum	NM	Present/NM	Uneventful	Positive history of a palpable abdominal lump since childhood
Wobenjo A and Osawa F, 2010[30]	3 months	Present	Female	2 in same sac intra-abdominal	NM	Present/absent	Uneventful	-
Gangopadhyay AN et al., 2010[2]	2.5 months	Absent	Male	2 in same sac but no membrane separation; retroperitoneum	Abdominal aorta	Present/present	Uneventful	Normal AFP levels
Rai R et al., 2011[31]	6 weeks	NM	NM	2; retroperitoneum	Abdominal aorta	Present/absent	Uneventful	-
Huddle LN et al., 2012[32]	PD	Absent	Female	2; intracranial	NM	Present/absent	Complicated by seizures, but recovered	Cytogenetic studies of host and the fetiform masses revealed 46, XX karyotype SNP patterns of host and the fetiform masses showed identical genotypes, which is a finding consistent with monozygosity
Pang KK et al., 2015[33]	At birth	NM	Female	2; retroperitoneum	Abdominal aorta, renal artery	Present/present	Uneventful	Each fetiform mass had an UC like structure connecting to a single placenta-like mass
Traisrisilp K et al., 2018[34]	PD	Absent	Female	3; intracranial	NM	Present/present	Died due to cardiac arrest intra-operatively	Gene mappings of the host and fetiform masses revealed exactly the same genes in 16 loci confirming monozygotic twins
Xiaowen M et al., 2021; case 2[1]	PD	NM	Male	2; retroperitoneum	NM	Present/absent	Complicated by ascites but recovered	Raised AFP preoperatively
Xiaowen M et al., 2021; case 3[1]	PD	NM	Female	2, retroperitoneum	NM	Present/absent	Uneventful	Raised AFP and HCG preoperatively
Sanders M et al., 2023[35]	PD	NM	Female	2; retroperitoneum	Abdominal aorta	NM/present	Uneventful	-
Nandan R et al., 2023[36]	7 days	NM	Male	3; retroperitoneum	Superior mesenteric artery	Present/absent	Uneventful	Genetic mapping of the child and FIFs were similar
Hong SS et al., 2002[37]	2 days	NM	Male	2; retroperitoneum	Renal artery	Present/absent	Uneventful	*****
Peng W et al., 2023[38]	PD	NM	Male	2; retroperitoneum	Abdominal aorta	Present/present	Uneventful	Microscopy showed immature teratoma-like characteristics

AFP: Serum alpha-fetoprotein, HCG: Serum human chorionic gonadotropin, NM: Not mentioned in the article, NSE: Serum neuron-specific enolase, PD: Prenatal detection, SNP: Single nucleotide polymorphism, STR: Short tandem repeat, UC: Umbilical cord, UVMA: Urinary vanillylmandelic acid

Pathological attributes

In 163 cases (67.6%) of single FIF, the fetiform mass was enveloped within a fluid-filled sac-like covering, reminiscent of a typical chorioamniotic membrane enclosing a normal fetus and amniotic fluid, out of which 10 were histomorphologically consistent with chorioamnion. Conversely, this covering or sac-like structure was not present in 36 cases (14.9%). In addition, one case with an intrathoracic location was enveloped by parietal pleura.[39] The umbilical cord-like structure was documented in 53 cases, with two cases exhibiting a small amount of placental tissue as well.[7,40] In 5 cases, microscopic analysis of the umbilical cord was performed and all revealed two vascular profiles, an artery, and a vein (single umbilical artery). In the 33 reported cases of multiple FIF, 31 cases documented the presence of a sac-like covering.

The excised mass in single FIF cases showed wide variation in size, ranging from 2 cm to 30 cm, with a mean size of 11.5 cm. In terms of weight, it ranged from 6 g to 3890 g, averaging at 679.15 g. Among the 241 cases, vertebral column and long bone(s) of at least one limb were present in 155 cases (64.3%). Only a vertebral column was seen in 27 cases (11.2%) whereas 59 cases (24.5%) showed the presence of limb bone(s) alone without any evidence of a vertebral column. Besides the vertebral column and long bones of limbs, other bones such as portions of the skull (n = 45), mandible/maxilla (n = 7), scapula (n = 7), ribs (n = 8), and ilio-sacral/pelvic bones (n = 6) were also observed in some cases. Grossly visible tooth and hair tufts, common features of well-differentiated teratomas, were detected in only 10 (4.2%) and 64 (26.5%) cases, respectively. Microscopically, derivatives of all the three germ cells layers were noticed in varying proportions, akin to well-differentiated teratomas [Table 3]. Among the internal organ systems, gastrointestinal tissue was the most prevalent type, found in 104 (43%) cases, followed by glial tissue (n = 82; 34%). Notably, grossly identifiable external genitals or microscopically identifiable gonadal tissue were reported in 44 (18.3%) cases (undifferentiated/ambiguous = 10; male genitals/testicular tissue = 13; ovarian tissue = 8; and not specified = 13). Genetic analysis for determining the gender of the fetiform mass was conducted in 39 cases of single FIF and 9 cases of multiple FIF, and in all cases, the gender was identical to that of the host/patient. The presence of co-existing teratoma within the same cystic sac was reported in four cases (n = 4/33; 12.1%) of multiple FIF, of which, three were of immature type.[20,26,28,38]

Table 3.

Proportions of various tissue types documented in published cases of singleton fetus-in-fetu

Macro- or microscopically evident organs/tissue	Number of cases (%)
Epidermal tissue including adnexal structure	188 (78)
Gastro-intestinal tract/tissue	104 (43)
Glial tissue	82 (34)
External genitals/gonadal tissue	44 (18.3)
Respiratory epithelium	37 (15.4)
Adrenal tissue	18 (7.5)
Hepatic tissue	12 (5)
Pancreatic tissue	10 (4.1)
Heart/cardiac tissue	9 (3.7)
Meninges	8 (3.3)
Renal tissue	7 (2.9)

DISCUSSION

This systematic review encompassing a total of 274 cases (241 cases of singular and 33 cases of multiple FIF), represents the most extensive and comprehensive analysis of FIF conducted thus far. Earlier, Hoeffel et al. and Prescher et al. reviewed 87 and 95 published FIF cases, respectively, and reported comparable findings with of ours, such as slight male predominance, presentation within the first few months of life, and retroperitoneal location.[41,42] In context with rare locations, Neto et al. documented a rare case of intrapulmonary FIF in a 12-year-old girl undergoing treatment for pulmonary tuberculosis, while Magnus et al. reported a unique instance of multiple FIF within the liver.[20,43] The most frequently encountered tissue type in FIF is gastrointestinal tissue followed by that of the central nervous system. Notably, we found that the presence of heart tissue was exceptionally rare in FIF cases, consistent with the observations of Hoeffel et al. and Prescher et al. Interestingly, Hoeffel et al. also noted that the lower limbs tended to be more developed than the upper limbs. Corroborating with this observation, we found that 31 cases exhibited one to two well-developed or rudimentary lower limb(s) alone compared to only 4 cases with just one to two upper limbs, that is caudal portion of FIF is usually better developed than the cephalic portion. We also observed that 140 cases displayed all four limbs at varying stages of development, with occurrences of more than four limbs being uncommonly encountered as well.[44] In the working definition of FIF, the authors have considered the presence of vertebral column and/or limb bones and have not taken into account the other components of axial (such as skull and facial bones, ribcage, and sternum) and appendicular skeleton (such as shoulder and pelvic girdle). The presence of skull and facial bones and ribs was more often noted than the presence of scapula and pelvic bone. Although small parts of the skull and glial tissue were documented in 45 and 82 cases, respectively, none of the cases demonstrated a complete/nearly complete cerebral hemisphere or skull structure, thereby reaffirming that FIF is consistently anencephalic.

Numerous theories have been proposed to explain the origin of FIF. It is crucial to differentiate them from highly differentiated teratomas. Teratomas, despite containing well-organized structures, are neoplasms originating from embryonic pluripotent cells, exhibiting the potential to behave in a malignant fashion. On the contrary, FIF, as the name suggests, refers to a parasitic twin within its host. The most likely explanation is that it is a monozygotic twin of its host. It is suggested that FIF is a monochorionic-diamniotic monozygotic twin that becomes incorporated into the body of the host after anastomosis of the vitelline circulation.[44] On thorough assessment of published literature, the authors uncovered supporting pieces of evidence in support of both the theories of FIF etiopathogenesis. In favor of the “teratoma theory,” it was noted that few cases of both single as well as multiple FIF, presented with synchronous mature or immature teratoma.[26,27,28,45] In addition, in a few instances, the patient was diagnosed with teratoma a few years after surgical removal of the FIF mass, indicating a potential association between FIF and teratomas, occurring either simultaneously or subsequently.[21,22] Moreover, “retroperitoneum,” the most common location of FIF, and less common locations such as intrathoracic and intracranial, are well-established sites for the occurrence of teratoma as well. Conversely, reports of twin FIF cases have described the presence of two FIF with a single cystic covering, with a distinct separating membrane between the two FIF, akin to monochorionic diamniotic twinning. The presence of placental villi was noticed in two cases, a feature that has not been documented in connection with teratomas to date.[7,40] Furthermore, cytogenetic studies have confirmed identical sex of host and mass, thereby providing strong supportive evidence to the “twinning theory.” However, it is difficult to explain how the fetiform mass gets “absorbed” within the host body to become a “parasite.” Late presentations in certain cases and the co-existence of teratoma in a few instances are also difficult to explain by this “twinning theory.” Furthermore, a positive family history of twinning was analyzed, considering its association with twinning in subsequent pregnancies.[46] Notably, a case involving multiple FIFs, consisting of nine intraperitoneal and two retroperitoneal FIFs within the same infant, was associated with a history of monozygotic twinning on both maternal and paternal sides.[27] However, a family history of twinning could not be established as a potential risk factor for FIF due to the lack of this history in the majority of published case reports.

As a part of preoperative investigations, a few investigators checked for serum levels of tumor makers such as AFP, CEA, and beta-HCG, and found them to be elevated. However, a positive association could not be established. Elevated or normal serum levels of tumor markers do not rule in or out the diagnosis of FIF, respectively. Imaging, on the other hand, plays a diagnostic tool and most cases of FIF were detected prenatally or before surgery. Demonstration of discernible vertebral column and/or tubular limb bones within a solid-cystic mass clinches the diagnosis of FIF. CT or MRI with three-dimensional reconstruction enables the complete visualization of the axial bone system within the FIF, facilitating accurate and reliable imaging diagnosis for clinicians, and can be considered in older patients whereas ultrasound examinations are safe and commonly used for prenatal assessments.[47] It has to be borne in mind that FIF can be misdiagnosed as teratoma due to similar sonographic features of both these entities.[1,48,49] Furthermore, depending on the age of the mass, only foci of calcification may be seen rather than well-formed bones.[48,49]

Surgical excision is the gold standard treatment modality and complete removal of sac is recommended. Leaving behind any part of the mass or even the membranous covering in the host might cause local recurrence or even metastatic spread.[1,2,21] In addition, detailed gross examination and adequate tissue sampling of the excised mass, followed by diligent microscopic analysis is vital in ruling out any foci of immature elements. Hopkins KL, way back in 1997, reported a case of FIF with malignant recurrence in an infant.[50] However, we opine that the case was mislabeled as FIF and was a case of immature teratoma or fetiform teratoma instead, as histopathological examination of the fetiform mass had revealed the presence of immature elements. In a more recently published case, a 13-year-old girl with an ovarian FIF presented with malignant recurrence (immature teratoma) 9 months postsurgery.[51] In this scenario as well, the possibility of initial misdiagnosis cannot be ruled out due to teenage presentation, gonadal location, and lack of molecular analysis to confirm the initial diagnosis of FIF.[51] Furthermore, two cases of multiple FIFs, were diagnosed with retroperitoneal teratoma (? recurrence/? de novo primary tumor) after 1–2 years postsurgery.[21,22] There are no existing guidelines or follow-up protocols for operated cases of FIF. Despite excellent prognosis postsurgery and only rare instances of disease recurrence, we recommend monitoring the patient, every 6 months or annually, at least for 2–3 years postsurgery. Measurement of serum AFP levels in conjunction with imaging assessment may be performed for detection of malignant recurrence, if any.[1,47,52] The highlights of this review are presented in Figure 3.

Figure 3.

Key findings of the study and general recommendations

The limitation of this review is that it primarily relies on retrospective analyses of reported cases or case series, lacking original research articles and controlled studies that could provide more robust evidence on the etiopathogenesis, clinical management, and outcomes of FIF. In addition, the inconsistency in the diagnostic criteria for FIF across different studies poses a challenge for standardizing data and drawing definitive conclusions. In few case reports, histopathological examination was not done, or not described in detail and it was assumed that there was absence of immature elements. In addition, many case reports lack detailed information on family history of twinning and long-term follow-up data. The absence of this information limits the ability to identify potential risk factors and assess long-term outcomes, including the risk of recurrence or malignant transformation.

CONCLUSION

FIF remains an intriguing entity, necessitating further exploration to clarify its etiology and refine diagnostic criteria. This systematic review, encompassing the largest cohort of FIF cases to date, sheds light on its varied clinical presentations, imaging characteristics, and histopathological attributes. Complete surgical excision followed by vigilant histopathological examination, with or without cytogenetic studies, remains the cornerstone of management. Despite the generally favorable prognosis, long-term follow-up, including serum tumor marker assessment and imaging, is advised.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.