Metastasis of cutaneous squamous cell carcinoma to the stomach: a rare entity

Abstract

Metastatic spread of cutaneous squamous cell carcinoma (cSCC) to the gastrointestinal tract is a rare entity. A 63-year-old woman with a history of poorly controlled HIV and a recurrent cSCC on the right temple presented with functional decline, ascites and shortness of breath. A CT scan showed widespread metastatic malignancy involving lung, pleura, heart, stomach, liver, retroperitoneum and soft-tissue. In the case presented here, an upper endoscopy revealed a submucosal lesion in the stomach. Biopsies described the lesion as a poorly differentiated SCC. Comprehensive genomic profiling yielded striking molecular similarities between the gastric tumour and the patient’s prior cSCC. It confirmed the origin of the disease and excluded spread from an occult primary. This case adds to the limited literature on gastrointestinal metastases of cSCC and serves as a reminder that non-AIDS-defining cancers are on the rise in the HIV-population.

Background

The HIV positive population is at higher risk of developing malignancy.¹ Kaposi sarcoma (KS) and non-Hodgkin’s lymphoma (NHL) are AIDS-defining malignancies.² The incidence of these conditions has fallen dramatically since the introduction of antiretroviral therapy (ART), arguably altering the natural history of HIV.² Given improved life-expectancy, non-AIDS-defining cancers (NADC) are on the rise.² Among the NADC, non-melanoma skin cancers (NMSC) defined as basal cell carcinoma and squamous cell carcinoma (SCC) are of increasing incidence. In individuals with a history of HIV/AIDS, SCC appears to predominate, is more aggressive and metastasizes more often than the general population.^{3 4} The most common sites of distant SCC spread are the lungs, brain, skin and bones.⁵ This case outlines an example of an HIV-positive patient treated with ART who was diagnosed with a metastatic cutaneous SCC (cSCC) to the stomach.

Case presentation

The patient was a 63-year-old woman diagnosed with HIV in 2003 and treated with ART. The treatment was complicated by medication non-adherence. Her latest regimen combined abacavir, lamivudine and raltegravir. In June 2019, the patient’s CD4 count was 108 and her viral load was undetectable. The patient was diagnosed with a cSCC involving the right temple in 2016. She was initially treated with surgical excision followed by adjuvant radiation therapy. Local recurrence of the cSCC was documented in 2017. An excision was completed and the biopsy results confirmed an invasive poorly differentiated cSCC.

Investigations

The patient was admitted to the hospital in November 2019 with functional decline, increased ascites and shortness of breath. Two months earlier, she was diagnosed with anaemia in an infectious disease clinic. As part of the workup, a CT-scan of the chest, abdomen and pelvis was ordered to rule out malignancy. It showed several findings including a soft-tissue lesion within the left atrium, multiple right-sided lung nodules with a pleural effusion, nodules throughout the liver, a portal vein thrombosis, a retroperitoneal soft-tissue mass, and a polypoid mass arising from the gastric antrum (figure 1). These findings favoured metastatic disease of unknown primary although a lymphoproliferative disorder could not be excluded. An oesophagogastroduodenoscopy was performed to obtain tissue sampling to clarify the diagnosis. The endoscopic evaluation detected a 2×2 cm submucosal ulcerated lesion in the gastric antrum and a 5 mm raised lesion in the duodenum (figure 2). The pathology yielded a diagnosis of poorly differentiated SCC in the antral mass and the duodenal nodule.

Figure 1.

Contrast-enhanced CT scan image of a mural-based lobulated intraluminal soft-tissue lesion arising from the gastric antrum measuring 2.2×3.6x1.3 cm (marked by arrow).

Figure 2.

Upper gastrointestinal endoscopy views. (A) Submucosal mass with ulcerated overlying mucosa in the gastric antrum; (B) 5 mm erythematous lesion in the duodenum.

Comprehensive genomic profiling was performed on the patient’s prior right temple cSCC and the metastatic SCC of the stomach (figure 3). It yielded strikingly similar mutational profiles, confirming the temple tumour as the site of origin of the stomach metastasis (table 1). The tumours had two identical pathogenic nonsense (stop-gain) mutations in TP53 and identical variants of unknown significance (VUS) in ATR, PALB2, MSH6 and CDKN2B (table 1). Tumour mutation burden was also similar, and very high, for the two tumours, at 67.4 and 73.5 per megabase (Mb) for the primary and metastatic tumour, respectively. The CC >TT dinucleotide substitution, a hallmark of ultraviolet light-mediated DNA damage, was also found several times in both tumours.⁶ The stomach tumour had acquired a pathogenic nonsense mutation in MPL that was not found in the primary, likely representing tumour evolution.

Figure 3.

The right temple cSCC and the gastric SCC underwent comprehensive genomic profiling using the Illumina TSO500 next-generation sequencing DNA panel. The panel interrogates all exons of 523 cancer-related genes. Sequencing was performed on a NextSeq500 according to manufacturer’s specifications and data were processed using an in-house bioinformatics analysis pipeline. (A) Sections from the patient’s right temple skin lesion show invasive squamous cell carcinoma, with nests of malignant squamous cells infiltrating the dermis beneath squamous cell carcinoma in situ (H&E, ×40). (B) Gastric biopsies show antral mucosa infiltrated by subjacent nests of malignant squamous cells (H&E, ×100), as confirmed by positive immunohistochemical expression of p40 (inset; p40, ×100). cSCC, cutaneous squamous cell carcinoma.

Table 1.

Mutational profiles of temple cSCC and gastric SCC

	Temple cSCC	Gastric SCC	Pathogenic?*
Shared mutations	TP53 c.949C>T, p.Gln317† TP53 c.1024C>T, p.Arg342† ATR c.3424A>G, p.Ser1142Gly PALB2 c.559C>T, p.Pro187Ser MSH6 c.663A>C, p.Glu221Asp CDKN2B c.256G>A, p.Asp86Asn		Y Y VUS VUS VUS VUS
Unique mutation		MPL c. 1194G>A, p.Trp398†	Y
Tumour mutation burden	67.4/Mb	73.5/Mb	–
CC >TT mutations†	7	9	–

*Only mutations determined to be pathogenic or VUS in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/) are included.

†Includes GG>AA mutations, which may occur through CC>TT mutations on the complementary strand.

VUS, variant of unknown significance; cSCC, cutaneous squamous cell carcinoma.

Outcome and follow-up

Given the disease extent and the poor performance status of the patient, after discussions with the patient and her family, a palliative approach was pursued. The patient died approximately 3 weeks after her admission.

Discussion

The burden of AIDS-defining malignancy has decreased significantly since the emergence of ART.⁷ However, these diseases should still be considered in the differential diagnosis of gastric submucosal lesions in a HIV-infected patient. KS remains the most frequent malignancy diagnosed worldwide in the HIV population.⁸ It can involve visceral sites in the absence of cutaneous disease.⁹ The gastrointestinal (GI) tract is affected in 40% of individuals.⁹ Similarly, NHL can occur in the GI tract in up to 28% of HIV-infected individuals.¹⁰ Contrary to KS, NHL in the GI tract is often symptomatic.¹⁰

The HIV population exhibits an increased incidence for a broad range of age-related cancers such as cSCC. cSCC has the potential to spread to regional lymph nodes and to distant organs, with the incidence of systemic metastases ranging from 1% to 7%.¹¹ Distant metastases are most commonly found in the lungs, brain, skin and bones.⁵ Many risk factors have been identified for the development of regional and systemic metastases, including tumour location, size, depth, histological differentiation, immunosuppression and recurrence of primary tumour.⁵ According to a meta-analysis conducted at the Mayo Clinic, location in the temple and poor differentiation have a respective relative risk ratio of 2.95 and 4.98, for the spread of the disease.¹²

A history of HIV confers a 2.6-fold increased incidence rate for the development of cSCC.¹³ Immunosuppression is a known risk factor for more aggressive cSCC and inferior outcomes in individuals with established malignancy. Burgi et al have demonstrated that the use of ART is beneficial in protecting against the development of NADC.¹ The study by Zhao et al further supports this correlation in NMSC specifically.¹⁴ In addition, there is evidence to suggest increased recurrence of SCC in HIV-infected individuals with a low CD4 and a high viral load.³ One retrospective study showed HIV-infected individuals are at higher risk of death due to cSCC compared with patients with hematopoietic malignancies and organ and stem cell transplants.⁴

Systemic therapies are indicated in patients with metastatic cSCC who are not candidates for curative surgery or radiotherapy, due to the extensive spread of their disease.¹⁵ The management modalities used are platinum-based chemotherapy, epidermal growth factor receptor (EGFR) inhibitors and immune checkpoint inhibitors.¹⁵ Currently, no consensus exists in regards to a standard therapeutic approach.¹⁵ The efficacy of chemotherapy appears superior to EGFR inhibitors, whereas EGFR inhibitors offer a more favourable side effect profile.¹⁵ Immune checkpoint inhibitors, in particular anti-PD-1 antibodies such as cemiplimab are expected to become the preferred modality, as they have shown a response rate as high as 50%, a duration of response superior to both other systemic therapies and a safety profile favourable to chemotherapy agents.¹⁵ CGP is an area of great promise as it has the ability to assess the clonal relationship between neoplastic lesions.¹⁶ In addition, it enables the detection of clinically relevant genetic alterations.¹⁶ This technology can guide decision making for treatment strategies and potentially improve patient outcomes.¹⁶ In the current case, it confirmed that the patient’s gastric tumour was a metastasis of her earlier cSCC, thereby eliminating the possibility of another site of origin such as the lungs.

Primary gastric SCC is a rare clinical entity with an unknown pathogenesis. Less than 100 cases have been reported in the literature. The worldwide incidence of this disease is estimated to constitute 0.04%–0.07% of all gastric cancers.¹⁷ The stomach is a rare metastatic site for SCC of all primary sites. The occurrence of gastric metastasis has been reported in a few case reports involving individuals with lung and uterine cervix SCC. In the literature, there is limited evidence of GI involvement with cSCC. A case report presented an immunocompetent patient with cSCC and a sigmoid colon metastasis as the sole site of his metastatic disease.¹⁸ A second case report described a jejunal perforation secondary to disseminated metastases throughout the peritoneum of a patient on long-term immunosuppressive medication for renal transplant.¹⁹ To our knowledge, we present the first case of cSCC gastric metastasis.

Learning points.

• Non-AIDS-defining cancers must be included in the differential diagnosis of malignancies in the HIV population as their incidence is increasing in the ART era.

• HIV-infected individuals are at a higher risk of developing cutaneous squamous cell carcinoma with an aggressive behaviour.

• Comprehensive genomic profiling is a valuable tool for the diagnosis of cancers.