Fanconi Anemia in a 31-Year-Old Patient with Multiple Malignant Tumor Foci, Including Appendiceal Cancer, and Multiple Coexisting Pathologies

Introduction

Fanconi anemia (FA) is a genetic disorder that leads to disruptions in bone marrow function and predisposes individuals to aplastic anemia. Fanconi anemia occurs in approximately 1 in 200 000 newborns worldwide [1]. In Europe, the disease is diagnosed in approximately 4-7 people per million live births [2].

FA is caused by mutations in genes responsible for DNA repair. Although FA itself is not a form of cancer, individuals with this condition have an increased risk of developing various neoplasms. DNA damage caused by genetic mutations makes normal cells more susceptible to tumorigenic transformation [3]. The most commonly observed cancers in FA patients are squamous cell carcinoma of the head and neck region or the upper part of the esophagus, as well as tumors in the genital organs and perineal tissues [4].

In the literature, cases of a rarer pathology have been previously described in patients with FA. These include Coats’ disease reported in teenager with FA [5], a rare, Complex pathology of the wrist [6], medulloblastoma as the initial manifestation of FA [7], and FA with cataract [8]. Maxwell et al described a case of multiple malignant tumor foci without bone marrow failure [9].

Our literature review did not find any description of a case involving a patient with FA, malignant appendiceal tumor, and other concomitant pathologies. In general, primary appendiceal cancer is relatively rare and is often discovered incidentally during surgical removal of the appendix for acute appendicitis. The appendix can give rise to various subtypes of cancer, differing in both histology and biology. There is a classification that divides appendiceal cancer into 4 subgroups: neuroendocrine and mucinous tumors, adenocarcinoma, goblet cell carcinoid, and neuroendocrine neoplasia [10].

In the present article, we describe the case of a 31-year-old man with Fanconi anemia who underwent bone marrow transplantation at the age of 5 years and later underwent surgery for lower lip cancer. He was hospitalized due to elevated levels of the carcinoembryonic antigen (CEA). The case is notable for the atypical tumor localization and a series of other anomalies in the patient.

The case report may increase understanding of the variability in the manifestation of Fanconi syndrome and determining optimal diagnostic and treatment strategies in similar cases in the future.

Case Report

A 31-year-old man with previously confirmed Fanconi anemia was admitted to the General Surgery Department for diagnosis and treatment due to elevated levels of the CEA marker. At the age of 5 years, he underwent bone marrow transplantation as a treatment for Fanconi anemia. The blood type before transplantation was B Rh (+), CcDEe K(−). The donor for the transplant was the patient’s younger brother. Testing of HLAI class phenotype and HI AII class genotype showed compatibility of both HLA haplotypes with the donor (allogeneic transplantation, HLA-matched family transplantation).

Before bone marrow transplantation, the patient exhibited the following abnormalities:Chromosomal abnormalities: Increased percentage of cells with chromosomal breaks and a significant increase in the number of chromosomal breaks per cell.Bone marrow: Bone marrow hypoplasia (requiring blood product transfusions every 4 weeks), with a total of 20 units of erythrocyte concentrate and 15 units of platelet concentrate transfused.Urinary system: Right kidney agenesis, duplication of the pelvicalyceal system in the left kidney.Skeletal system: Absence of the thumb (Figure 1) and first metacarpal bone in both hands, skeletal age delay.

In the post-transplantation period, the patient developed a skin rash typical of graft-versus-host disease (GVHD) (Figure 2), with diffuse erythematous micropapular lesions covering 80% of the skin, affecting the palms of the hands and soles of the feet, and pronounced facial erythema. No gastrointestinal tract abnormalities were observed.

The patient was an ethnic Pole, born from an uncomplicated first pregnancy. According to the patient’s mother, there was no family history of cancer.

The patient had a healthy younger brother. The patient was under the guardianship of his parents, had no permanent employment, and struggled to answer questions without the assistance of his mother. The patient did not use nicotine or any psychoactive substances and did not suffer from alcoholism.

The patient was hospitalized due to high levels of carcinoembryonic antigen (40 ng/ml). Upon admission, ne expressed no concerns about his well-being. No signs of intestinal obstruction or gastrointestinal bleeding were identified. There was no sudden weight loss or weight loss in general. He had normal appetite and regular bowel movements. Examination of the cardiovascular and respiratory systems revealed no abnormalities. Deep abdominal palpation also showed no significant deviations from the norm.

In addition to the aforementioned changes in the musculoskeletal system (absence of the thumb and first metacarpal bone in both hands, skeletal age delay), manifestations of hypogonadism were observed, such as underdeveloped external genitalia, high-pitched voice, and chronic graft-versus-host disease affecting the skin and oral cavity, papular lesions on the face, and discoloration of the torso and limbs.

At the age of 30, the patient underwent surgery to remove a lip neoplasm. Histopathological examination revealed squamous cell carcinoma. A few days before hospitalization, a neoplasm on the right eyelid was also removed. In addition, he had been diagnosed with the following chronic conditions: cholestatic liver disease, hypertension, and hypothyroidism.

Upon hospitalization, basic laboratory and instrumental investigations were conducted to establish the diagnosis and initiate appropriate treatment. The complete blood count showed no significant deviations from the norm. The CEA level was 41.4 ng/ml. Gastroscopy, performed under general anesthesia, revealed signs of Barrett’s esophagus (C2M5). Numerous sessile polyps resembling Elster’s polyps were found in the cardia and body of the stomach. Tissue samples were taken from the esophageal polyps and the gastric fundus for histological evaluation. During colonoscopy, an opening of the appendix with reddened mucosa around its orifice was observed, so biopsy samples were taken and sent for histopathological examination. Additionally, a sessile polyp with a diameter of 6 mm was removed from the transverse colon by cold polypectomy. A computed tomography (CT) scan of the abdominal and pelvic organs revealed, among other things, a nodular formation measuring 4.5×5×5.5 cm in the right iliac region adjacent to the cecum, as well as right kidney agenesis. The left kidney was enlarged by 2-fold and had 2 ureters. A CT scan of the chest showed no significant pathological changes.

It was decided to perform laparoscopy. Trocars were placed in typical locations. Upon insertion of a camera, the abdominal cavity with metastases in the peritoneum and greater omentum was identified. A tumor measuring 5×6 cm protruding from the appendix was found (Figure 3). The base of the cecum with the tumor was resected using an endostapler. The tumor was placed in an endobag and removed from the abdominal cavity through an additional incision. Tissue samples for histopathological analysis were also taken from the greater omentum and peritoneum. No significant bleeding was observed during the intervention.

In the postoperative period, standard infusion therapy, pain management, and physiotherapy were employed. The histopathological examination yielded the following results:Fragments of peritoneal and omental tissue with several white formations up to 0.4 cm in diameter: mucinous carcinoma.Tissue specimen of the altered appendix: the tumor infiltrated the entire thickness of the appendix wall and extended into the subserosal tissue. The surface of the serosa of the appendix was uneven in some places, with areas of mucus containing cancer cells on the outer surface. Angioinvasion was present, but infiltration of nerve trunks was not detected. The tumor tissue was accompanied by sparse foci of lymphocytic inflammatory infiltrates.

Immunohistochemical testing of cancer cells showed: MSH-2 (+), MSH-6 (+), PMS-2 (+), MLH-1 (+).

Based on immunohistochemical findings, microsatellite instability was not detected. The final diagnosis was appendiceal carcinoma. The histological type was mucinous neoplasm, grade G3.

Additional diagnoses were Fanconi anemia status post-bone marrow transplantation in 1998, hypothyroidism, right kidney agenesis, Barrett’s esophagus, Ester’s polyps, transverse colon polyp, status post-radical surgery for lower lip cancer and tumor on the skin of the lower eyelid of the left eye, cholestatic liver disease, hypertension, absence of the thumb and first metacarpal bone in both hands, and skeletal age delay. Table 1 summarizes the medical history of the patient.

On the 14th day of hospitalization, the patient was discharged from the department with a referral for further palliative treatment at a specialized oncology center.

Discussion

In patients with FA, a correlation has been established between the expression levels of FA-associated genes (FANC genes) and the progression of colorectal cancer (CRC), as well as resistance to certain drugs. The FA pathway is considered a potential target for CRC treatment, and the characteristics of FANC genes may contribute to increased sensitivity of tumor cells to chemotherapy. FANC genes are also considered promising prognostic and predictive biomarkers for disease management and CRC treatment [11,12].

Earlier, an association was established between Fanconi anemia and a range of anomalies, including light-brown skin pigmentation, structural anomalies of the limbs such as absence or deformities of fingers and bones, anomalies of the head and face, hypogonadism, and urinary system pathology. Overall, the presence of such disorders is explained by genetic defects in FA, affecting various aspects of embryonic development and organ function [13–15].

Petryk et al noted that 8 out of 10 patients with FA have endocrine disorders. Further investigation into this issue has allowed them to develop recommendations aimed at screening and treating hormonal disorders in patients with FA. For instance, these recommendations include annual thyroid function assessment for timely diagnosis of hypothyroidism [16]. A review by Dufour et al discussed key aspects of the contemporary management of patients with aplastic anemia, which can be categorized into several points:Long-term monitoring and early detection of cancer;Use of hematopoietic stem cell transplantation (HSCT) for bone marrow function restoration (considering the increased risk of malignant tumors);Gene therapy, which remains experimental but is already demonstrating effectiveness in the early stages of bone marrow involvement [17].

The Fanconi Anemia Research Fund (FARF) has compiled current knowledge on FA and published more detailed recommendations for managing patients with FA. Consequently, studies suggest regular screening for cancers of the digestive organs, skin, and oral cavity, endocrine pathology, and other anomalies mentioned in the present case report [18].

The prognosis for Fanconi anemia can vary significantly depending on various factors, including the severity of the disease, the presence of associated complications, the patient’s age, and the availability of effective treatment. Aplastic anemia is a primary cause of death in children, while older patients are at risk of developing malignancies [14].

Conclusions

Our case represents the picture of a paraneoplastic process in a patient with FA, where radical removal of the tumor was not possible, emphasizing the importance of thorough and timely diagnosis of malignant neoplasms in FA patients. Effective case management requires a multidisciplinary approach involving oncologists, geneticists, and specialists from other medical fields.