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Small cell conversion complicated with hypertrophic pulmonary osteoarthropathy after targeted therapy for advanced EGFR-mutated lung adenocarcinoma: A case report

 Cancer Center, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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Date of Submission27-Mar-2022
Date of Decision15-Nov-2022
Date of Acceptance15-Nov-2022
Date of Web Publication23-Mar-2023


In recent years, with the opening of the era of precision therapy, the treatment of patients with positive driver genes is a hot issue in global research. EGFR is the most common driver gene in NSCLC, with a positivity rate of 17%. Although targeted drugs for EGFR mutations can benefit this population with efficacy, target therapy resistance inevitably occurs. The presented case suggests that a patient with advanced lung adenocarcinoma with EGFR mutation who developed pathological-type conversion of small cell lung cancer complicated with the development of hypertropic pulmonary osteoarthropathy (HPOA) after 6 months of targeted therapy. This case demonstrates that early diagnosis of HPOA can predict the occurrence of target resistance and pathologic conversion in patients with positive driver genes, providing new clues for the clinical management of lung cancer.

Keywords: Case report, EGFR mutation, hypertrophic pulmonary osteoarthropathy (HPOA), small cell conversion, targeted therapy resistance

How to cite this URL:
Zhang S, Chen L, Zhu K, Meng R. Small cell conversion complicated with hypertrophic pulmonary osteoarthropathy after targeted therapy for advanced EGFR-mutated lung adenocarcinoma: A case report. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Jun 1]. Available from:

   Introduction Top

In recent years, with the opening of the era of precision therapy, the landscape of lung cancer treatment has undergone a radical change. EGFR is the most common driver mutation in lung cancer, and targeted therapy can achieve an efficiency of 58–83% in EGFR mutation population.[1] The median survival can be improved to 18–30 months.[2] However, drug resistance problems inevitably arise eventually. After first-generation EGFR-TKI, about 60% of patients have T790M resistance mutation. Other resistance mechanisms include small cell conversion, c-Met amplification, and HER2 amplification.[2] Small cell conversion occurs in only 3–15% of patients with lung adenocarcinoma, but it should not be ignored in clinical practice.[3] Hypertrophic pulmonary osteoarthropathy (HPOA) is an important complication of lung cancer, which seriously affects patients' quality of life.[4] Here, we describe a case of small cell conversion combined with HPOA after targeted therapy in a patient with advanced lung adenocarcinoma with EGFR mutation.

   Case Presentation Top

A 61-year-old female with no smoking history was referred to our hospital because of sputum and cough. Chest computed tomography (CT) in February 2019 showed an upper lobe of the right lung with a size of about 3.5 × 2.5 × 2.1 cm and a lower lobe of the left lung with a size of about 9.6 × 6.7 × 7.0 cm [Figure 1]a, [Figures 3]a. Admission physical examination showed no positive signs and good performance status (ECOG 1). Positron emission tomography–CT (PET-CT) scan showed a soft tissue mass in the lower lobe of the left lung with distal obstruction and a ground glass density nodule in the upper lobe of the right lung; the above was considered malignant tumor [Figure 1]b. Metastases of the lung tumor were identified in the left adrenal gland, left scapula, and lumbar spine [Figure 1]c. A CT-guided biopsy of left lung was performed in April 2019. Pathology was suggestive of left lung invasive adenocarcinoma [Figure 1]d, [Table 1]. Based on above results, this patient was diagnosed with stage IVb, cT4N2M1c (contralateral lung, adrenal gland, bone) AJCC8th TNM classification. Two cycles of standard pemetrexed chemotherapy (500 mg/m2, 21 days/cycle) were performed after assessment of no contraindications to chemotherapy. The efficacy was evaluated as stable disease (SD) [Figure 3]b. An EGFR gene mutation test identified a Leu858Arg point mutation in exon 21, and a KRAS gene exon 2 G12V mutation was identified. Detailed results of genetic testing are shown in [Table 2]. On May 2019, daily treatment with 250 mg/day oral gefitinib was initiated. The response assessment was partial remission (PR) for the lungs in July 2019 [Figure 3]c. In October 2019, the lung lesions were larger than before [Figure 3]d. Second biopsy was performed in December 2019. Pathology was suggestive of left lung hypo-fractionated carcinoma consistent with small cell carcinoma [Figure 1]e. After the patient's pathological type underwent small cell transformation, the serum NSE continued to increase, whereas CEA did not change significantly [Figure 2]h. In January 2020, radiotherapy (60 Gy in 8 fractions in 2 weeks) was administered to the left lesion. In June 2020, CT showed radiation pneumonitis, which improved after anti-infection treatment [Figure 3]e. In August 2020, the patient showed bone pain symptoms and bone ECT showed symmetrical active metabolism of the upper and lower limbs, similar to the “orbital sign”-like changes [Figure 2]a. The patient demonstrated clubbing of the fingers and feet [Figure 2]b, [Figure 2]c, [Figure 2]d, [Figure 2]e, [Figure 2]f, [Figure 2]g. Therefore, experts of in-hospital MDTs were required to re-evaluate his situation, which considered the possibility of HPOA. The third biopsy was performed on May 20, 2020. The pathology showed a hypo-fractionated carcinoma of the left lung, which was consistent with adenocarcinoma of the lung [Figure 1]f. Further refinement of pelvic magnetic resonance imaging (MRI) enhancement showed abnormal enhancing foci on the left sacroiliac joint surface, and metastasis was considered [Figure 3]f. Radiotherapy (30Gy in 3 fractions in 3 days) to the left iliac bone was performed in September 2020. Three cycles of camrelizumab were performed from September to November, 2020 [Figure 3]g. During this period, the patient was found to have a left dorsal shoulder mass and a broken left foot, and an X-ray of the left foot showed osteoporosis of the left foot and bone destruction at the end of the little phalanx [Figure 2]i, [Figure 2]j, [Figure 2]k. Ultrasound-guided fine-needle aspiration cytology of the left dorsal shoulder mass showed metastatic cancer [Figure 2]l, [Figure 2]m, [Figure 2]n. The patient had a sudden loss of consciousness on December 28, 2020, and the cranial CT showed a 2.5 × 3.7 cm slightly hypo-intense shadow in the right cerebellar hemisphere and a slightly dense nodular shadow in the right occipital subcortex, considering brain metastases above [Figure 3]h. The patient was treated with symptomatic support for dehydration, and her symptoms resolved.
Figure 1: Imaging and histological finding data of patients. (a) Chest CT scan revealed the soft tissue density mass shadow in the lower lobe of the left lung, with a size of about 9.6 × 6.7 × 7.0 cm with a high possibility of malignancy considered (red arrow). Partial solid nodular shadow in the posterior segment of the upper lobe of the right lung, surrounded by multiple long and short burrs, with a size of about 3.5 × 2.5 × 2.1 cm (red arrow). (b) PET-CT scan showed the soft tissue mass in the lower lobe of the left lung with abnormally increased metabolism and distal obstruction, considering a malignant neoplastic lesion in the lower lobe of the left lung with distal atelectasis (red arrow). (c) Slightly hypodense nodule in the medial limb of the left adrenal gland with increased metabolism, considering metastasis (red arrow). (d) Histopathological result showed left lung invasive adenocarcinoma at diagnosis (hematoxylin and eosin staining; ×100). (e) Histopathological result showed small cell carcinoma after 6-month gefitinib therapy (hematoxylin and eosin staining; ×100). (f) Histopathological result showed left lung invasive adenocarcinoma after bone PD (hematoxylin and eosin staining; ×100)

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Figure 2: Imaging of HPOA and changes of serum NSE and CEA. (a) Bone scintigraphy showed a bilateral symmetrical and diffuse accumulation of the radioisotope in the end of bone of the extremities. (b) Localized raised mass on the back of the left shoulder with localized redness and swelling with crusting. (c and d) Clubbing of the fingers. (e-g) Clubbing of the end of the little phalanx (red arrow). (h) Patient's serum NSE dropped to normal after chemotherapy and TKI therapy and then slowly elevated from 14.17 ng/ml to 20.44 ng/ml in the TKI resistance period and surpassed CEA to occupy the dominant position (purple arrow). However, the serum CEA was normal (2.44 ng/ml and 3.27 ng/ml) during the period of small cell transformation (serum CEA normal level, 0–5.0 ng/ml; serum NSE normal level, 0–16.5 ng/ml). (i-k) X-ray of the left foot showed osteoporosis of the left foot and bone destruction at the end of the little phalanx (i: Cross-section, j: Left Foot AP, k: Left Foot LAT; red arrow). (l-n) B-scan ultrasonography showed a non-homogeneous echogenic mass of approximately 33.5 × 29.3 × 27.3 mm in size with clear borders, and an abundant blood flow signal was seen in the left dorsal shoulder

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Figure 3: Treatment process and therapeutic effect. (a-h) CT/MRI scanning. PD, progressive disease; SD, stable disease; PR, partial remission

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Table 1: Results of immunohistochemical staining (On April 2, 2019)

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Table 2: Results of genetic testing (On April 30, 2021)

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   Discussion Top

Small cell conversion is a relatively rare mechanism of acquired drug resistance, and the underlying mechanism of small cell phenotypic conversion after EGFR-TKI therapy is not yet clear. The mechanism may be as follows: The tumor initially has two mixed cellular components, and the adenocarcinoma happens to dominate the dominant part at the time of initial diagnosis, and as the number of NSCLC cells decreases because of treatment, the SCLC component of the initial tumor becomes dominant.[5],[6] In this case, small cell conversion was confirmed by lung puncture in December 2019, and the pathology of the third biopsy in August 2020 again suggested adenocarcinoma of the lung, perhaps because the patient had two tumor components at the initial diagnosis. In addition, it is possible that targeted therapy resistance prompted the conversion of adenocarcinoma cells to the small cell cancer cell component.[5] Therefore, this case suggests the criticality of multiple biopsies in the management of lung cancer. It was shown that genomic sequencing of lung adenocarcinoma tumor samples that progressed with EGFR-TKI therapy showed that SCLC maintained the same EGFR mutation type as adenocarcinoma, suggesting that the persistence of the same EGFR mutation indicated that the SCLC phenotype originated from primary adenocarcinoma.[7],[8] It was found that lung adenocarcinoma patients with EGFR exon 19 deletion were more likely to undergo small cell lung cancer conversion than patients with EGFR 21 L858R mutation, which may also correlate with the fact that patients with EGFR exon 19 mutation are more likely to benefit from EGFR-TKI-based drugs in the long term in clinical practice.[9]

Regarding the possible association of adenocarcinoma cell conversion to small cell carcinoma with genetic mutations, Offin et al. compared patients with EGFR/RB1/TP53 mutated lung cancer diagnosed by second-generation sequencing from 2014 to 2018 with patients with untreated, metastatic EGFR-mutated but RB1 and TP53-unmutated lung cancer[10] and confirmed that patients carrying EGFR, TP53, and RB1 mutations are more likely to develop small cell conversion during targeted therapy compared to other EGFR mutated lung cancer patients. Therefore, SCLC conversion needs to be highly suspected when drug resistance occurs during treatment, and the importance of secondary biopsies or even multiple biopsies needs to be emphasized. Studies have shown that genotype analysis of re-biopsies of lung cancer patients with small cell conversion suggests that RB1 gene deletion is present in 100% of the patients' lung cancer tissues,[11] perhaps because targeted drugs inhibit the expression of genes in lung adenocarcinoma-related pathways, which results in a predominant expression of small cell lung cancer genes and thus small cell conversion. In addition, patients with advanced lung adenocarcinoma who received immunotherapy also had small cell conversion, and there was no significant difference in gene expression histology before and after immunotherapy.[12] Although the incidence of this conversion phenomenon in the mechanism of immunotherapy resistance is not enough, it indicates the importance of gene mutations in the mechanism of tumor conversion and warrants further in-depth exploration.

HPOA is a syndrome characterized by a triad of osteochondritis, pestle and mortar finger, and joint pain and swelling.[13] Bone involvement includes periosteal new bone formation, mainly bilateral and symmetrical, along the epiphyseal portion of the tubular bones of the upper and lower extremities.[14] In this case, a patient with advanced lung adenocarcinoma underwent small cell pathological-type conversion after two cycles of chemotherapy and 6 months of first-line EGFR-TKI therapy. The patient's NSE and other small cell-type tumor markers were always higher than normal since the initial diagnosis, whereas the patient developed bone pain and decreased blood calcium levels after targeted therapy; then a combination of bone ECT and left foot X-rays confirmed the patient with HPOA.

In conclusion, we describe a patient with advanced EGFR-mutated lung adenocarcinoma who received targeted therapy and developed HPOA in combination with pathologic conversion. This case is the first to suggest that early detection of HPOA in combination with patients' bone pain symptoms, signs, tumor markers, changes in blood calcium and hormone levels, and bone ECT can predict the occurrence of targeted drug resistance and pathologic type conversion in driver gene-positive patients in advance, providing new clues for early diagnosis and treatment of lung cancer.

Ethical statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Medical Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (ethical approval number: S412) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.


Rui Meng conceived the case report, Sijia Zhang collected the literature, Kuikui Zhu drafted and revised the manuscript, Leichong Chen prepared the figures and participated in writing. Both authors approved the final manuscript.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Roca E, Amoroso V, Berruti A. Osimertinib in EGFR Mutation–Positive Advanced NSCLC. N Engl J Med 2018;378:1261-2.  Back to cited text no. 1
da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol 2011;6:49-69.  Back to cited text no. 2
Marcoux N, Gettinger SN, O'Kane G, Arbour KC, Neal JW, Husain H, et al. EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: Clinical outcomes. J Clin Oncol 2019;37:278-85.  Back to cited text no. 3
Fang YH, Hsu CC, Hsieh MJ, Hung MS, Tsai YH, Lin YC. Impact of hypertrophic pulmonary osteoarthropathy on patients with lung cancer. Onco Targets Ther 2017;10:5173-7.  Back to cited text no. 4
Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin. Lancet Oncol 2015;16:e165-72.  Back to cited text no. 5
Engelman JA, Oser MG, Niederst MJ, Sequist LV. Transformation from NSCLC to SCLC: When did it happen?-Authors' reply. Lancet Oncol 2015;16:e309-10.  Back to cited text no. 6
Ferrer L, Giaj Levra M, Brevet M, Antoine M, Mazieres J, Rossi G, et al. A brief report of transformation from NSCLC to SCLC: Molecular and therapeutic characteristics. J Thorac Oncol 2019;14:130-4.  Back to cited text no. 7
Lai L, Meng W, Wei J, Zhang X, Tan Z, Lu Y, et al. Transformation of NSCLC to SCLC after 1st- and 3rd-generation EGFR-TKI resistance and response to EP regimen and erlotinib: 2 CARE-compliant case reports. Medicine (Baltimore) 2021;100:e25046.  Back to cited text no. 8
Jiang SY, Zhao J, Wang MZ, Huo Z, Zhang J, Zhong W, et al. Small-cell lung cancer transformation in patients with pulmonary adenocarcinoma: A case report and review of literature. Medicine (Baltimore) 2016;95:e2752.  Back to cited text no. 9
Offin M, Chan JM, Tenet M, Rizvi HA, Shen R, Riely GJ, et al. Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes. J Thorac Oncol 2019;14:1784-93.  Back to cited text no. 10
Lim SM, Syn NL, Cho BC, Soo RA. Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: Mechanisms and therapeutic strategies. Cancer Treat Rev 2018;65:1-10.  Back to cited text no. 11
Sehgal K, Varkaris A, Viray H, VanderLaan PA, Rangachari D, Costa DB. Small cell transformation of non-small cell lung cancer on immune checkpoint inhibitors: Uncommon or under-recognized? J Immunother Cancer 2020;8:e000697.  Back to cited text no. 12
Holling HE, Brodey RS, Boland HC. Pulmonary hypertrophic osteoarthropathy. Lancet 1961;2:1269-74.  Back to cited text no. 13
Ito T, Goto K, Yoh K, Niho S, Ohmatsu H, Kubota K, et al. Hypertrophic pulmonary osteoarthropathy as a paraneoplastic manifestation of lung cancer. J Thorac Oncol 2010;5:976-80.  Back to cited text no. 14

Correspondence Address:
Rui Meng,
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan - 430022
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_280_22


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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