COVID-19 Update - This is to inform you that the Government of India has announced a complete lockdown in India 22nd March 2020 to 3rd May 2020. As a result, our offices will now be closed till 3rd May 2020 and all our employees will be working from home. Office telephones will not be answered, and therefore you are requested to direct all your queries related to manuscript submission, review process, publication etc. at below mentioned details.,, Mob. 8826373757, 8826859373, 9910947804

Covid Alert

Print ISSN:-2394-6784

Online ISSN:-2394-6792


Current Issue

Year 2020

Volume: 7 , Issue: 2

  • Article highlights
  • Article tables
  • Article images

Article Access statistics

Viewed: 98

Emailed: 0

PDF Downloaded: 75

Sinha, Yadaraju, Adusumilli, Bora, and Rao: Conflicting immunohistochemistry and metabolic imaging parameters in adenocarcinoma lung showing elevated serum CA 19-9 with immunonegative TTF1 and Napsin A


Lung carcinoma is the most common and lethal cancer in men3, 2, 1 attributed to tobacco consumption. Non-small cell carcinomas (NSCLC) are more common and aggressive than small cell lung carcinomas. Most commonly lung cancers presentsat an advanced stage.4 Lung carcinomas are histologically and molecularly heterogeneous, hence rapid and meticulous work-up is often mandated. Immunohistochemistry and metabolic studies like 18F-FDG PET CT scan plays an important role in the initial assessment and diagnostic confirmation. The 2015 World Health Organization (WHO) classification is a better modified version, based on molecular marker study and genetic alterations in lung cancer. Molecular markers in case of lung carcinoma are EGFR mutation, KRAS mutation, ROS 1 gene rearrangement and Her2. The current guidelines recommend EGFR, ALK and ROS 1 testing. Targeted therapy can be initiated in cases of positive EGFR, ROS 1 or ALK genetic rearrangements.

Here in presenting a case report of TTF 1 and Napsin A negative lung adenocarcinoma with elevated serum CA19-9, imposing the necessity of pathologico-clinico-radiological correlation, especially in advanced cancers.

Case Report

A 56 year old male presented with multiple subcutaneous nodules of varying sizes all over the body. (Figure 1). Clinical examination revealed cachexic, anicteric and anaemic individual. Nodule size varied from 4 x 3 cms to 1 x 1 cm. Nodules were mobile, firm to hard in consistency and non-tender. Systemic examination revealed no organomegaly and no neurological deficit. Haematological investigaton revealed severe anaemia. Biochemical parameters were within normal limits. FNAC of subcutaneous nodules was suggesting metastatic adenocarcinoma deposits. (Figure 2). Incision biopsy of subcutaneous nodules was advised along with 18F-FDG PET CT scan. Incision biopsy of subcutaneous nodules was consistent with metastatic adenocarcinoma deposits. (Figure 4, Figure 3). 18F-FDG  PET CT revealed metabolically active right pleural based mass lesion (8.1 x 6.1 x 6.3 cm) in posterior aspect of right lower zone lung. (Figure 6, Figure 5). Multiple metabolically active pleural based nodular mass in right hemithorax, mediastinal lymphadenopathy and muscular deposits were also revealed.

Immunohistochemical study showed positivity for C k7, CA 19-9 and Ck19 and immunonegative for TTF 1, Napsin A, p40, Ck20, CDX-2, GATA-3 and Calretinin. (Figure 7). Possibility of adenocarcinoma of pancreatic origin was suggested on IHC of subcutaneous nodule.

18F-FDG PET CT scan and IHC were diverging/ dichotomous in the localisation of primary tumour. The dilemma existed between TTF 1 and Napsin A negative metastatic lung adenocarcinoma and CA 19-9 positive metastatic pancreatic adenocarcinoma. After review of all reports further tests were advised to aid in localisation of primary tumour. Serum CA 19-9 and EGFR mutation analysis by IHC, ROS 1 gene rearrangement by IHC and ALK by IHC were advised. Serum CA 19-9 was 4380 U/ml. EGFR mutation analysis by IHC showed Wild Type, ROS 1 gene rearrangement by IHC was positive and ALK (D5F3) by IHC was negative. Considering all the metabolic imaging, histopathological and IHC panel confirmation, final diagnosis was considered by exclusion and inclusion as lung adenocarcinoma and ROS 1 targeted therapy was started. Radiation therapy was not contemplated as the disease was already metastatic at the presentation and no pacemaker lesion that required palliation could be identified at that point of time. Treatment with Crizotinib was initiated.

Figure 1

Patient with subcutaneous nodule

Figure 2

Microphotograph of FNAC from subcutaneous nodule showing metastatic adenocarcioma deposits

Figure 3

Microphotograph of histopathology from subcutaneous nodule showing metastatic adenocarcinoma deposits

Figure 4

Microphotograph of histopathology from subcutaneous nodule showing metastatic adenocarcinoma deposits

Figure 5

PET scan showing metabolically active right pleural based mass lesion.

Figure 6

PET CT scan showing no lesion in pancreas (white arrow) and metabolically active subcutaneous nodule (blue arrow).

Figure 7

Microphotograph of Immunohistochemistry from subcutaneous nodule showing Ck 7 positive, CA 19-9 positive, Ck19 positive, TTF 1 negative, Ck 20 negative and CDX2 negative.


Lung cancer is the most common cancer in men and third most common cancer in women.1 It is one of the common lethal diseases afflicting the global population.2 Cigarrete and other forms of tobacco consumption attributes to most of the cases of lung cancer. Lung carcinomas were classified broadly into small cell carcinoma and non-small cell lung carcinoma (NSCLC) till WHO 2004 classification. Non-small cell carcinomas are more common and aggressive as compared to small cell carcinoma of lung.5, 3 Prior to WHO 2004 classification, NSCLCs tumors were not classified further in small tissue samples because of therapeutic options paucity. WHO 2004 classified NSCLCs into squamous cell carcinoma (SqCC), adenocarcinoma (ADC) and others. WHO 2015 further classified NSCLCs. It emphasised the use of immunohistochemistry and genetic studies. Integration of molecular testing helped to personalize treatment strategies, especially for advanced lung cancer patients.6

Platinum based chemotherapy is the standard of care for NSCLC with Permetrexed being used in adenocarcinoma. According to WHO current guidelines testing for EGFR, ALK and ROS 1 is essential for all lung adenocarcinomas.

Most lung cancers present at an advanced stage with aggressiveness and metastatic potential.4 Cytology and histopathology plays an important role in the initial assessment of these tumours especially those at advanced stage with metastatic deposits.7 After the initial assessment, localization of primary tumour is mandatory for initiation and planning therapy. Immunohistochemistry, radiology and metabolic imaging plays crucial role in diagnosis and localization of primary tumours.

The emerging immunohistochemical markers preferred as classifier of NSCLC include TTF 1 and Napsin A (for ADC) and p40, p63 and CK5/CK6 (for SqCC). Sensitivity and specificity of TTF 1 and Napsin A ranges from 80%-90% in cases of adenocarcinoma lung. Sensitivity of Napsin A is higher as compared to TTF 1.8 The positivity of both TTF 1 and Napsin A decreases with increasing tumour grade.7 Similar decrease in positivity in metastatic lung ADC were seen in study done by Gurda et al,7 where TTF1 expressed the sensitivity and specificity of 84.5% and 96.4% in cases of primary lung ADCs, and 86.9% and 87.5% in metastatic lung ADCs. Napsin A expressed sensitivity and specificity of 92.0% and 100% in the primary lung ADCs, and 67.8% and 100% in cases of metastatic lung ADCs.

NSCLC should be tested for epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS 1 (ROS 1) gene rearrangement. The presence of these mutations predicts the responsiveness to tyrosine kinase inhibitors (TKIs) and Crizotinib.

Carbohydrate antigen 19-9 (CA 19-9) is isolated from a human colorectal cancer cell line.9, 7 Although applied in the diagnosis of pancreatico- biliary adenocarcinoma, it can be positive in advanced lung adenocarcinoma (ALADC) also.10 CA 19-9 is extremely elevated in advanced lung adenocarcinoma. This spurious and deceptive high value of CA 19-9 can cause diagnostic dilemma in cases of non-pancreatic adenocarcinoma. Similar elevation of CA 19-9 was seen in the present case of advanced lung adenocarcinoma.

Metabolic imaging combined with radiological imaging is rapidly progressing modality of choice, especially in oncology set-ups. The metabolic uptake of the glucose analog 18F-FDG is studied in Positron emission tomography (PET) scan. Combination of PET with computerised tomography (CT) scan increases the sensitivity and specificity to 85% - 95%.12, 11 Being economical tool in the evaluation of lung cancer, 18F-FDG PET stands ahead in diagnosing, staging, and evaluating response to treatment.10

The present case is lung carcinoma with multiple metastatic deposits. Initial assessment of metatstatic adenocarcinoma by cytology and histopathology was supported by IHC which showed negativity for TTF 1 and Napsin A and positivity for CA 19-9 and Ck 19, suggesting adenocarcinoma of pancreatico-biliary origin. 18F-FDG PET CT scan revealed metabolically active right pleural based mass lesion (8.1 x 6.1 x 6.3 cm) in posterior aspect of right lower zone lung with multiple pleural nodular mass in right hemithorax, mediastinal lymphadenopathy and muscular deposits. Immunohistochemistry of subcutaneous nodule was negative for TTF 1 and Napsin A and immunoreactive for CA 19-9 with markedly elevated serum CA 19-9. Working as a team of pathologist, oncologist and radiologist we could diagnose the case of TTF 1 and Napsin A negative lung adenocarcinoma with elevated CA 19-9.


Advanced tumours requests vigilant and meticulous investigations to be carried out. CA 19-9 elevation can be seen in non-pancreatic ADC,10 such as lung ADC in the present case. Its elevation is a bad prognostic marker. Napsin A and TTF 1 positivity decreases with increasing tumor grade of Lung ADC. A physician/ pathologist should not be biased, especially in advanced stage cancers. Clinico-pathologico-radiological correlation is mandatory. Multidisciplinary approach and team work of pathologist, oncologist and radiologist helps in concluding diagnostic dilemmas, especially in case of advanced carcinomas.

Source of funding


Conflict of interest




W D Travis Pathology of lung cancerClin Chest Med201132669692


C Zappa S A Mousa Non-small cell lung cancer: current treatment and future advancesTransl Lung Cancer Res201653288300


K Inamura Update on Immunohistochemistry for the Diagnosis of Lung CancerCancers201810215


R E Shackelford M Vora K Mayhall J Cotelingam ALK-rearrangements and testing methods in non-small cell lung cancer: a & Cancer


P P Luk C I Selinger A Mahar W A Cooper Biomarkers for ALK and ROS1 in Lung CancerArch Pathol Lab Med2018142922928


W D Travis The 2015 World Health Organization Classification of Lung Tumors. Impact of Genetic, Clinical and Radiologic Advances Since the 2004 ClassificationJ Thorac Oncol20151012431260


Grzegorz T Gurda Lei Zhang Yuting Wang Li Chen Susan Geddes William C Cho Utility of five commonly used immunohistochemical markers TTF-1, Napsin A, CK7, CK5/6 and P63 in primary and metastatic adenocarcinoma and squamous cell carcinoma of the lung: a retrospective study of 246 fine needle aspiration casesClin Transl Med2015416113


J Rosai J Rosai J (ed.) Rosai and Ackerman's Surgical Pathology. USA . Special Techniques in Surgical Pathology20113773


Yuki Sato Daichi Fujimoto Keiichiro Uehara Ryoko Shimizu Jiro Ito Mariko Kogo The prognostic value of serum CA 19-9 for patients with advanced lung adenocarcinomaBMC Cancer201616890


S J Wong C M Hong H P Wang T Y Cheng High serum value of CA 19-9 not always related to the pancreas: An asymptomatic case of highly elevated CA 19-9 related to lung adenocarcinomaJOP. J Pancreas (Online)2016176653655


R Matthew C Steven Utility of 18F-FDG PET in Evaluating Cancers of LungJ Nucl Med Technol2005336974


X Y Wang F Yang C Jin D L Fu Utility of PET/CT in diagnosis staging, assessment of resectability and metabolic response of pan-creatic cancerWorld J Gastroenterol201420421558015589


© 2020 Published by Innovative Publication. This is an open access article under the CC BY-NC license (