A case of a 60 years old female who was admitted in the hospital with work up of possible COVID 19.

Patient had controlled type 2 DM and breast lumpectomy 2 years ago without knowledge of official
result (done in the province). Apparently well until…. patient developed cyclical fever, progressive
cough, sense of anosmia and anorexia, and lethargy. Xray showed pleural effusion. Diagnostic
thoracentesis was done. 230ml dark brown and turbid fluid submitted to the laboratory. Smears and cell
block were prepared. Two days after, without knowledge of the pleural effusion result a chest CT scan
was done which revealed a suspicious lesions in both lung lobes. CT – Guided FNAB was done.

Source: Houston, K. A., Henley, S. J., Li, J., White, M. C., & Richards, T. B. (2014). Patterns in
lung cancer incidence rates and trends by histologic type in the United States, 2004–2009.
Lung Cancer, 86(1), 22–28. doi:10.1016/j.lungcan.2014.08.001 

New Treatments
Surgical resection continues to be the most effective treatment for localized tumors although this
relies on lung cancer being diagnosed at an early stage and at present, only a small proportion of
lung cancers meet this criterion.154 Some recent advances have been made in the management of
early stage non-small cell lung cancer involving novel, minimally invasive surgical and
radiotherapy approaches, while the introduction of platinum-based chemotherapy has been
shown to provide a survival benefit for metastatic non-small cell lung cancer.155 In addition,
genetic testing, which screens actionable genetic alterations including EGFR mutations for
targeted therapy,156 will likely provide important information about the treatment and prognosis
of lung cancer although the treatment only affects a small minority of lung cancer patients
overall. Beyond the approved therapies for EGFR, including tyrosine kinase inhibitors such as
gefitinib, erlotinib and afatinib,157 many small molecules are in various phase trials to target
EGFR. The majority of the mutations, fusions or amplifications are being tested in Phase I, II, or
III clinical trials. Guidelines for selecting which lung cancer patients should have molecular
testing were summarized in 2013 by Lindeman et al.158 The final recommendations, which are
summarized and graded based on the evidence in the literature, suggest that all advanced stage
lung cancer patients, regardless of age, gender, smoking exposure or other clinical factors,
should have molecular testing with tissue priority given to EFGR and ALK testing. From 2013 to
today, the rates of testing across the globe remain variable. For example, in China, survey data
showed that only 9.6% of non-small cell lung cancer cases were tested for EGFR
mutation,159 while in Sweden, 49% of cases received testing. With the ever growing list of
actionable mutations, improved sampling and analysis of scarce tissue with ever-advancing high-
throughput technologies, e.g., next-generation sequencing,160 will be required to support the use
of these tests to direct the development of new agents and improved clinical care and
outcomes.73,157
Further, immunotherapy appears set to offer new modes of treatment for non-small cell lung
cancer, even for patients with advanced disease, building on progress in the understanding of
anti-tumour immune responses.161 Corresponding gains are yet to be realized in the treatment of
small cell lung cancer, with limited options because of barriers in the development molecular
profiling leading to the use of targeted agents; work in this field is continuing.162,163
The main treatments for lung cancer include surgery, chemotherapy, and radiotherapy.
In the present study, although the surgical rate showed slight fluctuations over time, it
remained relatively stable at about 25%. The radiotherapy rate experienced a general
downward trend, but showed an increasing trend from 2007 (35.3%) to 2015 (38.8%).
However, treatment with chemotherapy rose over the past decades, increasing from
14.9% in 1973 to 39.2% in 2015 (Figure 4).

Figure 4 The rates of surgery, chemotherapy, and radiotherapy for lung cancer over

the years.

Abbreviation: APC, annual percentage change.

The present study revealed that the surgical rates for NSCLC were much higher than
those for SCLC (Figure 5A). From 1973 to 2015, the highest average surgical rate was
seen in ADC patients (36.6%), followed by SCC (31.2%), LCC (26.4%), and SCLC
patients (5.9%). The surgical rates for ADC, SCC, and SCLC decreased over time, but
the rate for LCC significantly increased from the late 1980s. As shown in Figure 5B,
most patients with localized stage lung cancer underwent surgical treatment (an
average of 61.6%). However, the surgical rate significantly decreased from 1988 to
2015. The average surgical rate for regional stage lung cancer was 38.2%, ranking
second, while only 5.1% of patients with distant stage lung cancer underwent surgery,
and this rate declined from 1988 to 2015. For unstaged tumor, the average surgical
rate was 3.6%, and showed a decreased trend from 1973 t

While the treatment of lung cancer follows the same principles around the world, the differences in the
epidemiology of lung cancer and the genetic variations in the patients lead to some variations in the
exact treatments received by patients. As a result, since an increased proportion of patients in Asia have
activating EGFR mutations,23 there is an increased prevalence in the use of EGFR tyrosine kinase
inhibitors in these countries

Thus in this era of large global studies, attention must be paid to possible genetic differences in
populations before generalizing therapy for all patients. Stratification based on country of origin may
help improve our understanding of these issues.

Molecular diagnostics for personalized treatment for lung cancer

INTRO “Lung malignancy is a leading cause of cancer related morbidity and mortality worldwide [1]. The
majority (85%) of cases are histologically proven non-small cell lung carcinomas (NSCLC)
(adenocarcinomas, squamous cell carcinomas and large cell carcinomas) with an overall pooled 5-year
survival rate of 16% in USA and less than 10% in the UK [2]. New therapeutic modalities have emerged;
however if these treatments are applied to the whole NSCLC population they exhibit limited clinical
effectiveness and are associated with an increased overall cost [3]. Therefore, new approaches are
required to identify eligible patient subgroups for targeted therapies, by utilizing biomarkers that will
characterize appropriate subgroups [4].” Source: Sampsonas, F., Ryan, D., McPhillips, D., & Breen,
D. (2015). Molecular Testing and Personalized Treatment of Lung Cancer. Current Molecular
Pharmacology, 7(1), 22–32. doi:10.2174/187446720701150105171219 

Sub Intro “More than 55% of lung carcinomas harbor at least one genetic alteration, most of them being
histologic subtype specific [5]. Molecular characterization improves the subtyping of lung cancer,
prognostic assessment, and treatment outcomes [6, 7]. In particular, the discovery of acquired
alterations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genes in a
subset of patients with adenocarcinoma and its association with significant response to therapeutic
agents targeting these receptors has revolutionized the way these tumors are managed [8].

Source: Sampsonas, F., Ryan, D., McPhillips, D., & Breen, D. (2015). Molecular Testing and
Personalized Treatment of Lung Cancer. Current Molecular Pharmacology, 7(1), 22–
32. doi:10.2174/187446720701150105171219 
Body Molecular Diagnostic Techniques

“A variety of methods can be used to genetic aberrations including immunohistochemistry, fluorescent

in situ hybridization (FISH), allele-specific polymerase chain reaction (PCR), quantitative real-time PCR
(qRT-PCR), sanger sequencing and next generation sequencing (NGS). Each method has its merits and
demerits thus molecular pathologists should consider the available approaches and the advantages and
disadvantages of each method including turnaround time and analytical sensitivity [31].”
(Mention what are available in the PH)

Emerging Technologies for Molecular Diagnostics: Liquid biopsy: Circulating tumor cells available at Lung
center of the philippines https://lcp.gov.ph/images/Brochures/CTC_Count_Brochure_2017.pdf

In the treatment of lung cancer, one of the great advances is personalized medicine which is based on
the concept of tailoring therapeutic decisions based on the histologic and genetic characteristics of the
patient’s tumor. (WHO TUMOR CLASSSIFICATION) Although in our case, the patient was not tested for
the specific gene that caused the cancer, a study (McIntyre, A. & Ganti, A.K. 2017) mentions that there is
an increased proportion of patients in Asia to have activating EGFR mutations.

PCR

“Allele-specific PCR is also known as an amplification-refractory mutation system. Allelespecific PCR has
the advantage of mutant enrichment, resulting in high sensitivity, which is essential for mutation
detection in samples with a low tumor cell percentage. It is based on the principle that extension is
efficient when the 3′ terminal base of a primer matches its target, whereas extension is inefficient or
nonexistent when the terminal base is mismatched [38]. Furthermore, combining allele-specific PCR
with qRT-PCR techniques allows monitoring template amplification, resulting into improved
interpretation of PCR results [39]” KUMAR

SANGER

Sanger sequencing or chain terminating sequencing is considered the gold standard for mutation
analysis. Sanger sequencing is performed on PCR products and requires sequencing primers spanning
the region of interest, DNA polymerase, nucleotides bases and a low concentration of modified
nucleotide (also known as dideoxyNTP). All four dideoxy nucleotides (cytosine, guanine, adenosine and
thymine) are labelled with a different flourophore. In Sanger sequencing, DNA fragments of different
lengths are generated, which are then separated out with capillary gel electrophoresis [36]. It is one of
the preferred methods to detect mutations of clinically relevant genes, such as the EGFR hot-spot
mutations. Sanger sequencing can detect all known and novel base substitutions, small insertions and
deletions. However, direct DNA sequencing requires a high ratio of tumor cells to normal cells (more
than 50%) for reliable results. Furthermore, it is unable to analyze multiple gene hot-spots
simultaneously. To overcome these problems, multiplexed approaches for molecular testing, particularly
for gene mutation analysis have been developed [12, 36]. The limited sensitivity of Sanger sequencing
has created a need for alternative techniques to detect common mutations, such as well RT- PCR based
assays, pyrosequencing and NGS

NGS

NGS is high-throughput method, which allows massive parallel sequencing that affords maximal tumor
genomic assessment. NGS approach is utilizes to sequence both DNA and RNA.  DNA sequencing
includes whole genome, whole exome, epigenome and targeted sequencing. RNA sequencing allows
whole transcriptome analysis which provide information of alternative spliced transcripts, gene fusion,
mutations, SNPs, small and long non-coding RNAs and changes in gene expression [42]. NGS is rapidly
changing the paradigm of lung cancer research and patient

McIntyre, A., & Ganti, A. K. (2017). Lung cancer-A global perspective. Journal of Surgical
Oncology, 115(5), 550–554. doi:10.1002/jso.24532 

Source: WHO
One of the great advances in the past decade in lung
cancer diagnosis and treatment is the concept of personalized
medicine, where therapeutic decisions are based on the specific
histologic and genetic characteristics of the patient’s tumor.

Discovery that epidermal growth factor

(EGFR) mutations and anaplastic lymphoma kinase (ALK)
rearrangements are effective targets for EGFR tyrosine kinase
inhibitors or ALK inhibitors in patients with advanced lung adenocarcinoma
has not only revolutionized therapeutic strategies,
but transformed clinical practice for pathologists.