Goblet Cell Adenocarcinoma With Heterotopic Ossification: A Rare Case Report and Review of Literature

Heterotopic bone formation is a rare phenomenon when associated with gastrointestinal neoplasms. Here we present a rare case of heterotopic ossification associated with goblet cell adenocarcinoma of the appendix, and a literature review of such cases associated with neoplasms within and out of the gastrointestinal tracts. We reviewed the clinical data and when available, immunohistochemical markers of osteoblastic differentiation. Our review shows similar findings to prior reports of apparent high association of heterotopic bone formation with neoplasms with mucinous features. Two, previously proposed main hypotheses of the mechanisms are reviewed. The unique feature about this case is that goblet cell adenocarcinoma was not reported previously in the setting of bone formation.


Introduction
Heterotopic ossification is defined as the formation of lamellar ectopic bone in the soft tissue [1]. It is commonly seen in various anatomic locations including muscles and joints. It can be associated with clinical scenarios such as burns, prolonged bedridden states secondary to brain injuries, and certain orthopedic surgeries [1]. Males tend to have a higher incidence possibly due to differences in muscle mass, mechanism of injury, and hormonal status that affects osteogenesis [1][2]. Here, we report a case of heterotopic ossification associated with goblet cell adenocarcinoma of appendiceal origin. Studying the upregulation of chondrogenic and osteogenic genes in the injured soft tissue as well as the tumor cells/microenvironment has been previously performed by other investigators and may help us understand the pathogenesis of this phenomenon.

Clinical history
A 57-year-old female patient, presented with severe, intermittent abdominal pain, worsening in intensity. Abdominopelvic CT scan was performed and revealed a large pelvic mass in addition to small intestinal thickening ( Figure 1). The patient was taken to the OR for total abdominal hysterectomy, bilateral salpingo-oophorectomy with tumor debulking. On intraoperative frozen section consultation, the ovary was involved by a malignant neoplasm. Histologic examination on paraffin-embedded sections showed an adenocarcinoma with signet ring cell features involving pelvic organs and omentum. Immunohistochemical studies were 1 2 2 2 performed and showed immunoreactivity for CK20 and CDX2, consistent with a gastrointestinal primary. The gastrointestinal origin of this tumor was not suspected at the time of the surgery, hence the appendix was not resected. The oncology service started the patient on FOLFOX regimen (Folinic acid, Fluorouracil, Oxaliplatin). The patient completed a total of 12 cycles of FOLFOX with hyperthermic intraperitoneal chemotherapy (HIPEC) and underwent a right hemicolectomy after the eighth cycle of FOLFOX.

Surgical intervention and gross examination
The patient underwent an exploratory laparotomy, right hemicolectomy with en bloc omentectomy, cholecystectomy, and intraperitoneal tumor resection for her surgical management. The main specimen was received as a 30.5 cm segment of large bowel and terminal ileum with an attached appendix and a moderate amount of attached fibrofatty tissue. The appendix was adherent to the surrounding fibrofatty tissue and measured 5.0 cm in length x 1.2 cm in diameter. No tumor was grossly identified on the large bowel or ileal mucosa, or at the appendiceal orifice. Sectioning through the appendix revealed an obliterated lumen and a nodule that appeared to be contiguous with the appendiceal surface and wall. The nodule was markedly calcified and measured 2.5 cm in length x 0.9 cm in diameter and appeared to extend into the periappendiceal fat ( Figure 2).

Discussion
Heterotopic bone formation is reported in association with tumors; some of which are summarized in Table 1. We present here the first reported case of heterotopic ossification in association with goblet cell adenocarcinoma of the appendix. The six case reports, in addition to our case of appendiceal tumors with mucin production and heterotopic ossification are summarized in Table 2. Various hypotheses have been put forth to explain heterotopic ossification in tumors. Huang et al. showed that the formation of bone in neoplastic settings results from pluripotent stromal cells undergoing osseous differentiation as highlighted by differential expression of morphogenic markers between the stroma and tumor cells [3].   BMP9: bone morphogenetic protein 9, ALK1: anaplastic lymphoma kinase 1

Conclusions
As more cases are reported, a probable mechanism for heterotopic ossification associated with neoplasia is gaining better understanding. Further studies to assess the clinical significance of bone formation in these tumors, and possible correlation with tumor behavior are warranted. One of the limitations of this case report is the lack of morphoproteomic analysis via immunohistochemistry due to financial reasons.

Additional Information Disclosures
Human subjects: Consent was obtained by all participants in this study.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.