Keywords
colorectal cancer - KRAS mutation - lung adenocarcinoma - multiple primary tumors
- synchronous malignancy
Introduction
Multiple primary malignant tumors (MPMT), first described by Billroth in 1889 and
later detailed by Warren and Gates in 1932, refer to the occurrence of two or more
distinct malignancies in the same patient. Synchronous MPMT refers to a second malignancy
developing within 6 months of the original tumor, while metachronous MPMT occurs when
a second tumor develops more than 6 months after the primary tumor.[1] The development of multiple primary malignancies (MPMs) is not fully understood
and is likely multifactorial, with identified risk factors including prior cancer
treatment, smoking, diet, and genetic mutations.[2] Here, we present a case of a 75-year-old male patient presenting with synchronous
double primary lung and colon cancer, incidentally discovered during staging, highlighting
rare concurrent malignancies with distinct pathological and molecular profiles. Ruling
out metastatic lung lesions originating from the colon is essential, as they account
for 20% of cases.[3] The findings underscore the importance of comprehensive imaging, histopathology,
and molecular diagnostics in guiding the management of patients with dual primary
malignancies.
Case Report
A 75-year-old male patient with a notable smoking history, no known comorbidities,
and no family history of malignancy presented with Grade II dyspnea on exertion and
an ECOG performance status of 2. Physical examination revealed bilateral crepitations
with reduced air entry, while chest CT showed multiple right lung lesions; PET-CT
further identified abnormalities including a 4.1 cm × 1.6 cm rectosigmoid junction
mass (SUVmax 19.2), a 4.8 cm × 4.9 cm right lung mass (SUVmax 7.7) involving the pleura
with moderate to massive pleural effusion, enlarged lymph nodes (SUVmax up to 7.5),
and a small hypoenhancing liver lesion in segment VIII (SUVmax 6.2).
A CT-guided biopsy of a pleural nodule confirmed metastatic adenocarcinoma of lung
origin, with immunohistochemistry showing CK7 and TTF-1 positivity with CK20 and CDX2
negativity. In light of the rectosigmoid mass detected on imaging, a colonoscopy was
conducted, and it revealed a rectal neoplasm, colonic polyps, and cecal diverticuli,
with biopsy confirming rectosigmoid adenocarcinoma; immunohistochemistry showed CK20
and CDX2 positivity.
A comprehensive panel of next-generation sequencing (NGS) was performed to evaluate
SNVs, CNVs, and indels spanning over 15,000 loci for 1,080 tumor-specific genes in
both the lung and rectosigmoid tumor tissue-derived DNA and RNA. The genomic analysis
of the lung adenocarcinoma revealed mutations in KRAS (p.G12V, Exon 2; variant allele
frequency [VAF] 11%), ERCC2 (p.E300, Exon 10), SMO (p.G288D, Exon 4), and NF1 (p.Y1689F,
Exon 37). PD-L1 testing using the Dako 22C3 assay showed a tumor proportion score
(TPS) of 70%, while, NGS of the rectosigmoid adenocarcinoma identified mutations in
KRAS (p.G12V, Exon 2; VAF 11%), TP53 (p.E286D, Exon 8), PIK3CA (p.E542K, Exon 10),
and APC (p.R499*, Exon 12 and p.Q223, Exon 7). PD-L1 testing for this site revealed
a TPS of 2%.
Given the patient's age, ECOG performance status, and disease status, oral metronomic
chemotherapy with capecitabine (1,000 mg) and cyclophosphamide (50 mg) was initiated,
along with low-dose nivolumab administered biweekly. The patient has demonstrated
good tolerability to the regimen, and on subsequent clinical follow-up, continues
to demonstrate clinical stability with sustained therapeutic benefit.
Discussion
The widespread adoption of comprehensive screening strategies, along with advancements
in cancer therapies that have extended survival, has led to an increasing frequency
of MPM in a single patient, a phenomenon first recognized over a century ago.[4] MPM can be synchronous or metachronous, with the latter occurring over 6 months
after the first; SEER database analysis reports MPM incidence ranging from 1% in liver
cancer to 16% in bladder cancer,[5] with a 2.5% occurrence in lung cancer patients.[6] Liu et al reported that the most common tumors associated with lung cancer were
in the aerodigestive tract (larynx, nasopharynx, esophagus, oral cavity, and hypopharynx),
followed by colorectal and cervical cancers.[7] Double primary malignancy is more prevalent in cases of colorectal cancer (CRC).
The common sites for the second primary malignancy in CRC include the stomach, urinary
system, liver, and lungs. The incidence of synchronous colorectal and lung cancer
is reported to range between 0.1 and 0.6%, with Evans et al identifying 801 cases
of primary lung cancer (0.6%) among 127,281 patients with CRC, underscoring the rarity
of this co-occurrence and its potential for underdiagnosis.[8]
[9]
The diagnosis and treatment of MPM remain contentious, as there is currently no established
method available to differentiate between multiple primary cancers and metastatic
disease. Timely detection of hidden secondary malignancies presents a significant
challenge in managing synchronous dual malignancies. Additionally, there are notable
variations in the driving genes across different tumors in patients with MPM. Identifying
the driving mutations in each lesion is critical for accurate pathological staging
and the formulation of effective treatment strategies. Combining this with immunohistochemistry
to trace the source may offer a more comprehensive approach.[10] In this case, the patient presents with cancers in two distinct organs—lung and
colon—each having a distinct immunohistochemical and NGS profile, which aids in differentiating
them as two primary malignancies.
The management of synchronous dual malignancies necessitates a personalized, multidisciplinary
approach, integrating considerations of tumor biology, disease stage, molecular profile,
and patient performance status.[11] NGS technology has enabled a genetic approach to defining multiple primary cancers,
and it was conducted on tumor samples from both the lung adenocarcinoma and rectosigmoid
adenocarcinoma to delineate their distinct genomic landscapes and inform therapeutic
decision-making. The lung adenocarcinoma harbored mutations in KRAS and other genes,
with a PD-L1 TPS of 70%, indicating a high likelihood of response to immune checkpoint
inhibitors. In contrast, the rectosigmoid adenocarcinoma also exhibited a KRAS mutation
along with other genomic alterations, but with a lower PD-L1 TPS of 2%. The shared
KRAS mutation, alongside unique mutation profiles, supports the classification of
these tumors as independent primary malignancies rather than metastatic disease. KRAS
mutations are established drivers in CRC and increasingly recognized in nonsmall cell
lung cancer. Their presence in both primary tumors raises the possibility of a clonal
relationship, potentially indicating a common progenitor cell or shared environmental
trigger. Identical KRAS mutations across synchronous malignancies have been reported,
supporting the hypothesis of clonal evolution rather than independent events. This
underscores the importance of comprehensive molecular profiling in distinguishing
metastatic disease from synchronous primary malignancies.[12] A potential central role of KRAS mutation exists in altering the tissue microenvironment.
Hence, in MPM, KRAS alteration also exhibits a unique immune signature characterized
by elevated PDL-1 expression and occasionally elevating tumor mutational burden beyond
its intrinsic pro-tumorigenic role. KRAS mutation shapes an immune suppressive microenvironment
by impeding effective T cell infiltration and recruiting suppressive immune cells,
including myeloid-derived suppressor cells, regulatory T cells, and cancer-associated
fibroblasts. This tumor microenvironment-modifying role of KRAS may affect multiple
organs simultaneously within the same individual, thus promoting MPM.[13] Should the presence of a KRAS mutation at presentation of a malignant neoplasm cause
alarm to screen other organs. This may be another topic of research.
In this case, surgical intervention was deferred due to the presence of multiple lesions
and the patient's overall disease burden. This decision aligns with established guidelines
that recommend nonsurgical management necessitating chemotherapy or other palliative
treatments as the primary therapeutic strategy. The decision to select a low-intensity
systemic treatment regimen was influenced by the patient's advanced age, ECOG performance
status, overall disease burden, and a TPS score exceeding 10%. This approach aimed
to optimize therapeutic efficacy while mitigating treatment-related toxicity through
the combination of OMCT and immunotherapy.
This case report highlights the importance of a multidisciplinary approach, integrating
imaging, histopathology, and molecular diagnostics to differentiate synchronous primary
malignancies from metastatic disease. A key strength is the comprehensive molecular
analysis, including NGS, which provided valuable insights into distinct tumor profiles.
Additionally, the case emphasizes individualized treatment strategies, particularly
in elderly patients with advanced disease. However, as a single-patient study, its
findings may not be broadly generalizable, and the lack of long-term follow-up limits
conclusions on treatment outcomes. The absence of a surgical perspective due to stage
IV disease further restricts discussions on curative interventions.
Conclusion
This case highlights the diagnostic challenge of synchronous dual primary malignancies,
emphasizing the role of comprehensive diagnostics, including immunohistochemistry
and NGS, in distinguishing independent tumors from metastatic disease. The patient's
favorable response to a low-intensity systemic regimen underscores the importance
of personalized treatment strategies in elderly patients with advanced disease.
