Signet ring cell carcinoma of the rectum: atypical metastatic presentation

Abstract

Colorectal cancer is the third most common cancer in the world and the fourth most common cause of death related to cancer. Signet ring cell carcinoma represents an uncommon histological type for rectal cancer with less than 1% of all rectal neoplasms. It usually behaves aggressively and has an inferior prognosis. We present the case of a young man diagnosed with signet ring cell rectal carcinoma. He underwent neoadjuvant therapy with partial response, had surgery with curative intent and showed local recurrence after only 3 months. Disease progression happened only weeks after recurrence with metastasis to vertebrae, extraocular muscles, bone marrow and skin. He is currently receiving palliative chemotherapy.

Background

Colorectal cancer (CRC) is the third most common cancer in the world, with most cases detected in Western countries.¹ In our country, according to the National Institute of Public Health, and the latest data published by GLOBOCAN in 2018, CRC is the fourth most frequent cancer, responsible for 7084 deaths in 2018 with an age-standardised mortality rate of 5.2/100 000.

Usually, CRC presents in people over 50 years and commonly arises from a polypoid lesion that follows the classic adenoma–carcinoma progression.² Ninety percent of tumours correspond to adenocarcinomas, but there are some other histological variants such as mucinous, signet ring cell, medullary, adenosquamous, micropapillary, spindle cell and undifferentiated.³

Colorectal signet ring cell carcinoma is a rare histological type of tumour with an incidence ranging between 0.1% and 2.6% of all cases according to literature.⁴ It appears as a rigid lesion, associated with thickening of the bowel wall similar to the gastric malignancy linitis plastica and is defined by more than 50% of signet ring cells, characterised by prominent intracytoplasmic mucin vacuoles.

Tumour behaviour is usually very aggressive and has a poor prognosis. Differently, to adenocarcinoma, the median age of presentation is under 40 years. Most series report a predominance in males, with ratios of 2:1, and is usually found in the right colon or the rectum.⁵

Case presentation

A 39-year-old man, with no previous medical history, started his complaint with sudden intermittent bloody stools, weight loss and diarrhoea. He did not seek medical attention elsewhere until 6 months later when he was referred to our centre for evaluation. We initially found him with stable vital signs, with physical exam revealing him to be severely emaciated, with generalised skin and conjunctival pallor, and a palpable indurated tumour on a rectal exam that was fixated and partially obstructed the rectal lumen.

Investigations

A colonoscopy was performed, revealing an irregular hard tumour in the lower third of the rectum, that obstructed 30% of the lumen, along with oedema and ulceration of the mucosa. Several biopsies were taken during the procedure. Histology was reported as signet ring carcinoma.

The staging approach revealed carcinoembrionary antigen levels of 2.36 IU/L (normal range 0–2.5 IU/L). Thoracoabdominal CT scan showed no evidence of metastatic lesions, and pelvic MRI disclosed a T3c anorectal tumour with invasion to mesorectal fascia and a fistulous tract comprising the anal verge and the pre-coccygeal fat (figure 1).

Figure 1.

Pelvic CT scan (A). Axial cut is displaying localised thickening and enhancement of the rectal wall compatible with neoplastic lesion (yellow circle). MRI T1 weighted sequence (B) and (C) displaying tumorous thickening (yellow circle) in the lower third of the rectal posterolateral wall.

No lymph node invasion was observed.

The patient underwent a diverting loop colostomy and port-catheter placement for the administration of neoadjuvant therapy.

Differential diagnosis

As differential diagnosis, adenocarcinoma was considered as well as mucinous, medullary, adenosquamous, micropapillary, spindle cell and undifferentiated carcinomas of the rectum.

Treatment

Considering the absence of an international consensus for the treatment of signet ring rectal carcinoma, nor a recommendation to adopt the treatment of rectal cancer to histological types,⁶ we decided to follow the latest algorithm of the National Comprehensive Cancer Network (NCCN) regarding locally advanced rectal cancer,⁷ and proposed our institutional neoadjuvant protocol to the patient.

He was started on chemoradiotherapy, receiving five sessions of 5 FU and a total dose of 54Gy, which were divided into 30 sessions. During the restaging workup (suggested by NCCN before surgery), MRI revealed partial response, so a new scheme of six cycles of FOLFOX4 were administered. Following this treatment cycle, MRI showed a reduction in the size of the lesion (from 21 to 17 mm). After multidisciplinary consensus, abdominoperineal resection was agreed along with reconstruction of pelvic floor with a rectus abdominus pedunculated flap.

The surgical procedure was carried out uneventfully and the patient was discharged on postoperative day 7. Surgical margins came back negative.

Three months after surgery, during the patients follow-up, nodular lesions were noticed all over the flap’s cutaneous tissue. MRI demonstrated local recurrence in the rectus abdominis flap along with enlargement of right inguinal lymph nodes concluding recurrence of the disease.

Outcome and follow-up

Two weeks later, the patient was admitted to the emergency room secondary to an episode of intestinal obstruction of multifactorial aetiology. During this admission, a CT was ordered as part of the workup, disclosing generalised enteritis, peritoneal carcinomatosis and adhesions (with a transition zone in the distal ileum), as well as metastatic deposits in lumbosacral vertebrae (figure 2).

Figure 2.

Thoracoabdominal CT scan. Coronal (A) and saggital (B) cuts displaying metastatic lumbosacral lesions in the vertebra of the patient (yellow circle).

The patient did not respond to a conservative approach with nil per os, nasogastric tube placement, intravenous hydration and administration of hydrosoluble contrast media, and required a surgical intervention during which adhesiolysis was attempted via laparotomy.

Peritoneal carcinomatosis was documented during the procedure, along with a sealed pelvis due to extensive metastatic disease and adhesions Thus, a defunctioning loop ileostomy was fashioned. Metastatic tissue was sent for histological assessment, and histology was reported once again as ring cell carcinoma (figure 3).

Figure 3.

H&E histological samples of the omentum (A), 10x and (B) 20x; and peritoneal implants (C), 20x. Notice abundant fibroadipose tissue with carcinoma infiltration and signet ring cells (B) and (C).

A week after surgery, the patient developed abdominal pain, fever and an increase in creatinine levels; bilateral hydronephrosis was documented. Placement of ureteral catheters was unsuccessful and percutaneous bilateral nephrostomies were placed.

During the same hospitalisation, all haematological cell lines started decreasing and bone marrow biopsy was compatible with myelophthisis (figure 4).

Figure 4.

H&E histological images of bone marrow biopsies. Notice intertrabecular spaces showing carcinoma infiltration (10x) (A) and abundant infiltration by signet ring cells (20x). (B). Immunohistochemistry is showing positive MUC2, CDX2, MUC5 and CK20 (C).

The patient also reported blurred vision, diplopia and right ocular pain, which was accentuated by lateral movement of the eye. Three days later, the pain became unbearable and associated with paralysis of cranial nerves III, IV and VI.

A cranial CT scan revealed a nodular lesion with thickening of the lateral rectus muscle of the eye and loss of fatty tissue, compatible with a metastatic implant (figure 5). Palliative radiotherapy to the orbit was offered, but the patient declined this option. He was discharged after stabilisation with analgesia and started on chemotherapy with FOLFIRI scheme plus FEC X7 (folinic acid, irinotecan and 5-FU).

Figure 5.

Head CT scan with intravenous contrast. Sagittal cuts from lateral to medial showing notice metastatic nodules to lateral rectus muscle of the right eye.

During subsequent follow-up, the patient developed multiple cyst type lesions in the face, abdomen and legs, the biggest one with a 5-cm diameter (figure 6). A biopsy was performed, and the result was consistent with cutaneous metastases. Four months later, the patient received palliative care.

Figure 6.

H&E histological images of the skin. Notice metastasic signet ring cell carcinoma in reticular and deep dermis (10x) (A) and (40x) (B).

Discussion

Here, the presented case demonstrates two interesting aspects: the uncommon pathways of metastatic spread and the comparatively rare signet ring histology.

At the time of diagnosis, about 20% of patients with colorectal adenocarcinoma will present distant metastases, and another 30% will develop them during follow-up. The most common sites of metastasis for adenocarcinoma include liver (77%), peritoneum (25%) and lungs (22%).⁸

Before the concept of total mesorectal excision was introduced in 1988, as much as 40% of patients that undergo surgery with curative intent developed local recurrence during their lifetime.

Although this rate has dropped to 5%–10%,⁹ local recurrence continues to be significant in the prognosis of these patients.

In the context of colorectal adenocarcinoma, spreading is possible by lymphatic, haematogenous and direct extension. Batson plexus, a network of valveless veins that connect the deep pelvic and thoracic veins to the internal vertebral venous plexuses, seem to play an important role in allowing the migration of tumour cells towards the vertebra, as it forms several anastomoses within the bone marrow and the epidural venous channels.¹⁰ Also, an alternative pathway may follow the haemorrhoidal veins, all the way up through either the vena cava or the portal circulation through the pulmonary vasculature and finally to the systemic circulation through the aortic branches; explaining the involvement of atypical sites such as the eye and extraocular structures.

The metastatic sequence of signet cell rectal carcinoma seems to be entirely different and is nonpredictable. This phenomenon appears to be secondary to the presence of anaplastic and undifferentiated cells with the capacity to cause diffuse infiltration followed by rapid dissemination from all the structures adjacent to the tumours primary site.¹¹

Wu et al performed a retrospective review of patients with signet cell carcinomas of multiple origins, identifying different sites of metastases in their sample depending on the primary location.¹²

Most series stand out that these patients present with peritoneal carcinomatosis, suggesting that the predominant component of dissemination occurs via the peritoneum, in comparison with adenocarcinoma, where the haematogenous pattern seems to prevail.⁴

The haematogenous and lymphatic pathways may as well play an important role in metastatic signet ring cell carcinoma, specially in the context of atypical patterns of spread.

Myelophthisis corresponds to the destruction of the bone marrow precursor cells from the invasion of metastatic cells; it occurs in less than 10% of patients with metastatic cancer, commonly from solid tumours.¹³ In a study performed by Lindemann et al, micrometastases from rectal cancer were found into the bone marrow of 42% of patients even when they had gone through radical resection,¹⁴ and the characteristics of such micrometastasis had a substantial impact in prognosis.¹⁵

When colorectal neoplasms present cutaneous metastasis, they usually start in the abdomen and spread to the extremities and perineum; This might involve two of the three pathways of dissemination, including direct invasion through the umbilical stump, and haematogenous spread with seeding to the abdominal wall vasculature through a portosystemic shunt via the paraumbilical veins in patients with portal hypertension; This being facilitated by the infiltrative nature of signet ring cell carcinoma. Patients with skin lesions have a survival rate of 3 months after its detection.

Ocular and orbital metastases of CRC are extraordinarily uncommon.

The choroid is the most affected site, accounting for more than 80% of cases reported in the literature.¹⁶ This pattern of spread is thought to be secondary to haematogenous dissemination, and also presents other systemic lesions in the majority of cases.¹⁷

In our particular case, the metastatic pattern of spread to the extra ocular muscles, appears to have involved the extrahepatic circulation, as suggested by the abscece of liver involvement at any point of the disease. This is exceptionally interesting as similar cases do not seem to spare the liver in both adenocarcinoma and signet ring cell carcinoma of the rectum.

Visual abnormalities are the presenting symptom in patients with ocular metastases.

Regarding the preferred treatment, several alternatives have been documented as individual reports, including radiotherapy, enucleation, systemic chemotherapy and even the application of intravitreous bevacizumab with mixed results.^{17 18 19}

Khawaja et al ¹⁶ published a literature review in 2015 including all reports of colorectal neoplasms with metastases to the eye and orbit gathering a total of eight cases. The survival of these patients was poor but variable, ranging from 1 to 32 months after diagnosis, and related to the extent of the systemic disease at presentation.

However, none of these cases was primary signet ring cell rectal carcinoma, with most being adenocarcinomas and other uncommon neoplasms, making our case the first report of this exceptional presentation to our knowledge.

In conclusion, there is little information about signet ring cell carcinoma in colon and rectum, but the natural course of this type of tumour seems to be difficult, with a short life expectancy and quick dissemination despite proper administration of aggressive and optimal treatment.

Our case stands for an extremely aggressive presentation of metastatic disease in an unusual histological type of rectal cancer with a different dissemination pattern than those previously reported in literature.

Learning points.

• Signet ring rectal carcinoma is extremely rare and includes. About 1%–2.6% of all colorectal neoplasms worldwide.⁴

• Tumour behaviour is usually very aggressive and has a poor prognosis. The median age of presentation is under 40 years and predominates in men.

• Metastatic spread is unpredictable, with the predominant component being through local invasion of the peritoneum and the haematogenous pathway.