Metastatic Small Cell Carcinoma Research Articles

Ectopic Cushing Syndrome Secondary to Metastatic Small Cell Carcinoma of Unknown Primary: A Multidisciplinary Approach

Ectopic Cushing Syndrome Secondary to Metastatic Small Cell Carcinoma of Unknown Primary: A Multidisciplinary Approach

Effect of chemotherapy alone or combined with immunotherapy for locally advanced or metastatic genitourinary small cell carcinoma: a real-world retrospective study

BackgroundGenitourinary small cell carcinoma is rare, and has a poor prognosis. However, effective treatment options for this disease are limited. We present a study to assess the efficacy of chemotherapy alone or combined with immunotherapy for locally advanced or metastatic genitourinary small cell carcinoma (GSCC).MethodsWe performed a retrospective analysis of patients with locally advanced or metastatic GSCC from Jan 2013 to September 2022 at Sun Yat-sen University Cancer Center. The survival and safety profiles were analyzed.ResultsForty-two GSCC patients were enrolled, which included 20 with chemotherapy plus immunotherapy and 22 with chemotherapy alone. The median follow-up time was 15.13 months (95% CI, 8.84–21.42). The addition of immunotherapy to chemotherapy demonstrated no significant difference in median progression-free survival (p = 0.37). However, the median overall survival (OS) was 22.97 and 14.03 months with immunotherapy plus chemotherapy and chemotherapy alone, respectively (HR = 0.69, 95%CI 0.08–0.55, p = 0.017). Two patients with immunotherapy plus chemotherapy achieved clinical complete remission. The overall response rate for patients receiving chemotherapy combined with immunotherapy was 65%, which was higher in comparison to those treated with chemotherapy alone (50%). Univariate and multivariate analyses demonstrated that chemotherapy combined with immunotherapy independently achieved favorable OS. Four patients experienced immunotherapy-related adverse events, with one developing grade 3 hypothyroidism.ConclusionsAmong patients with locally advanced or metastatic GSCC, immunotherapy combined with chemotherapy might be thought of as a potentially effective treatment option for patients with GSCC.

S4100 A Case of Metastatic Small Cell Carcinoma With Small Bowel Primary

S4100 A Case of Metastatic Small Cell Carcinoma With Small Bowel Primary

S2335 Metastatic Small Cell Carcinoma of the Lung Presenting as Rectal Bleeding

S2335 Metastatic Small Cell Carcinoma of the Lung Presenting as Rectal Bleeding

Cytological spectrum of testicular malignancies with histopathological correlation: A retrospective analysis.

Testicular malignancy is the most common solid organ cancer occurring in young men. The most common testicular malignancy is germ cell tumor. Extragonadal malignancies such as lymphomas are rare. Testicular fine-needle aspiration cytology (FNAC) in cancer is a bit controversial amidst fear of tumor seeding along the needle tract. Nevertheless, its largely safe, cost-effective technique providing a quick and fairly reliable diagnosis. A retrospective analysis of testicular malignancies on FNAC over a period of 9 years with cyto-histological correlation wherever possible was carried out. FNAC slides and cell blocks with immunocytochemistry wherever done were retrieved. A total of 74 cases were obtained. The age ranged from 1 year to 65 years. Infiltration by leukemia was the most common malignancy detected in pediatric population, while germ cell tumors were common amongst young adults and middle-aged men. In elderly, metastatic carcinoma, infiltration by lymphoma were identified. On FNAC, 38 cases were of leukemic infiltration, 27 of germ cell tumors (subtyped as mixed germ cell tumors-15 cases, seminoma-11 cases, and yolk sac tumor-1 case) with two cases each of non-Hodgkin lymphoma, Leydig cell tumor, metastatic adenocarcinoma, and one case each of metastatic small cell carcinoma, rhabdomyosarcoma, and malignant neoplasm. Histological correlation was available in 15/74 cases. Only 3 cases were discordant. Seeding of tumor along the needle tract was not seen. The current study deciphers the cytological spectrum of testicular malignancies on FNAC and highlights its importance as a reliable modality for a prompt diagnosis of testicular tumors guiding patient management.

An uncanny case of paraneoplastic calcitriol mediated hypercalcaemia.

A 77-year-old female patient with a history of treated breast cancer and a recently diagnosed laryngeal cancer presented with severe hypercalcaemia associated with suppressed parathyroid hormone (PTH) levels. Her initial investigations included 25-hydroxy vitamin D levels, short synacthen test, bone scan, myeloma screen and thyroid function tests which were within normality. A computerised tomography (CT) scan showed some right lung apical fibrotic changes. Her PTH-related peptide (PTHrP) was normal and sarcoidosis was also excluded. Her previous and current malignancies were thought to be unlikely behind her hypercalcaemia. Her 1,25-dihydroxy vitamin D (calcitriol) levels were found to be elevated. Her hypercalcaemia was initially managed with intravenous fluids and intermittent bisphosphonates infusions which would transiently reduce her calcium levels. Steroid treatment was initiated which improved her hypercalcaemia; however, the calcium levels rebounded on tapering the steroids down, a pre-requisite prior to a positron emission computerised tomography (PET-CT) scan to determine the source of the excess calcitriol production. This was cancelled following an emergency admission with marked hypercalcaemia and acute renal and liver injury. A contemporary CT scan showed a right apical lung mass with hepatic lesions suggestive of a disseminated lung primary. The histology obtained from a liver biopsy was compatible with metastatic small-cell lung carcinoma. Unfortunately, her clinical condition deteriorated further and she did not survive. To the best of our knowledge, this is the first report in the literature describing calcitriol-mediated hypercalcaemia due to a small-cell lung cancer. Paraneoplastic hypercalcaemia may manifest even without overt detection of the primary cancer. The workup for paraneoplastic hypercalcaemia should be meticulous. Both bisphosphonates and steroids are useful in the initial management of calcitriol-mediated hypercalcaemia, but the definitive management is the treatment of the cause.

Primary Cutaneous Diffuse Large B Cell Lymphoma, Leg Type: A Rare Neoplasm Masquerading as Squamous Cell Carcinoma

Primary Cutaneous Diffuse Large B Cell Lymphoma, Leg Type (PCDLBCL, LT) comprises 4% of all cutaneous lymphomas, and it presents as an aggressive form of lymphoma. Rarely do pathologist/cytologists find specimens of PCDLBCL, LT on Fine Needle Aspiration Cytology (FNAC). The mimickers on FNAC are metastatic small cell carcinoma, Merkel Cell Carcinoma (MCC), Malignant Melanoma (MM), Cutaneous Alveolar Rhabdomyosarcoma and Primary Cutaneous Ewing's Sarcoma (PCES). A 75-year-old female patient presented in the Department of Surgery with multiple nodules on the leg for three months. On cytology small round cell tumour with possibility of non hodgkin lymphoma was given and biopsy was advised. The confirmation of PCDLBCL, LT on cytology is not recommended however, it is emphasised that it can be picked up on FNAC and distinguished from its mimickers. Because of the aggressive nature and poor prognosis with the frequent relapses and tendency for extracutaneous spread, it is considered to be a distinct type of cutaneous lymphoma which needs to be diagnosed and treated as early as possible.

Unusual liver Involvement by Small Cell Carcinoma Arising in an Ovarian Malignant Mixed Mullerian Tumor

Abstract Introduction/Objective Malignant mixed Mullerian tumor (MMMT) is a rare and aggressive tumor with patient survival of fewer than three years. MMMT harbors multilineage differentiation associated with malignant epithelial and stromal components. Awareness and familiarity with these characteristics are essential for patient stratification and clinical management. Methods/Case Report A 64-year-old female presented with refractory lower abdominal pain and bloating. Imaging studies revealed a 14-cm pelvic mass. The patient underwent urgent hysterectomy with salpingo-oophorectomy. She was diagnosed with ovarian MMMT(A) and received chemotherapy. The patient returned 2 months later with new- onset abdominal pain. CT detected numerous liver lesions; a biopsy was performed. Results (if a Case Study enter NA) The liver biopsy revealed metastatic small cell carcinoma (SCC[B], positive for synaptophysin and CD56; Ki67 >90%.). However, no concurrent lesions were identified on imaging. Further testing was attempted to locate the source of the SCC. Re-review of the MMMT with additional tissue sectioning identified sheets of high-grade pleomorphic malignant cells with a high N:C ratio, arranged in rosettes and without mucin. Additional immunohistochemistry labeled this MMMT diffusely with synaptophysin(C), chromogranin, and CD56. Furthermore, microscopic foci of MMMT showed higher grade histomorphology similar to the liver SCC which stained for PAX5(D). These findings illustrate a rare MMMT with a neuroendocrine carcinoma/SCC component which gave rise to liver metastasis. Conclusion This unusual liver SCC in a patient with prior MMMT exemplifies the multipotent malignant potential of MMMT and demonstrates the importance of having a spectrum of differentials and carrying out meticulous histomorphologic and ancillary analyses, especially when there is unusual histomorphology and discordance in clinical course.

ODP020 A Challenging Case of Poorly Differentiated Carcinoma with Neuroendocrine Differentiation and Adrenal Mass

Abstract Background Neuroendocrine tumors (NETs) account for about 0.5% of all newly diagnosed malignancies. The most frequent primary sites are the gastrointestinal tract or pancreatic (62%-67%) and the lung (22%-27%). All poorly differentiated NETs have a Ki-67 index of greater than 20% and WHO grade of 3. The determination of the site of origin can be challenging in widely metastatic poorly differentiated NETs. Clinical Case A 51-year man with a history of hypertension and type 2 diabetes mellitus presented with angioedema while on lisinopril for years. Apart from a month's history of bilateral flank pain, he denied diarrhea, flushing, stridor, or shortness of breath. CT abdomen showed an 8.2×8. 0×7.9 cm right adrenal mass with a few punctate calcifications, hepatomegaly with multiple liver metastases, multiple retroperitoneal, hepatoduodenal, retrocrural adenopathy, and T4 metastatic lesion. CT chest showed bulky mediastinal and supraclavicular lymph nodes with trachea narrowing. All those lesions were FDG avid on PET/CT scan. Core biopsy of right supraclavicular lymph node revealed a poorly differentiated carcinoma with neuroendocrine differentiation and high proliferative index (25-50%). On cell block, it was negative for (AE1/AE3 (-), CAM5.2 (-), CK7, CK20, vimentin, desmin, CEA, EMA, CD45, CD20, and TTF-1 but positive for CK903 (focal +), synaptophysin (+), chromogranin (+), calretinin (focally +), inhibin (focally +). Based on the immunohistochemical stain, it was concluded as a metastatic small cell carcinoma of unknown origin. He was treated with carboplatin, etoposide, and atezolizumab and received 5 cycles. Endocrine was consulted two months after his initial presentation. Urine normetanephrine was > 4-fold elevated. Blood pressure was controlled on Doxazosin at 4 mg bid. The 10 gene-panel for hereditary pheochromocytoma and Paraganglioma (PGL) was negative. There was a progression of mediastinal adenopathy while on treatment with narrowing of proximal intrathoracic trachea requiring elective tracheostomy. Based on imaging findings and elevated normetanephrine, we believe he has metastatic pheochromocytoma and PGL. His chemo regimen was switched to Cyclophosphamide, Vincristine, and Dacarbazine (CVD). He finished 8 cycles of CVD with an overall reduction in the size of lymph nodes (both above and below the diaphragm) and right adrenal mass. His plasma normetanephrine level was also significantly improved. Presentation: No date and time listed

Surgical resection of mediastinal metastasis from small cell carcinoma of bladder: case report

BackgroundIsolated mediastinal metastasis from a malignant tumor and small cell carcinoma of the bladder are both very rare.Case presentationA 76-year-old woman who had undergone surgery for bladder cancer twice was referred to our hospital for a right paracardiac mass noted in chest computed tomography findings, and resection of the tumor was performed. Histological analysis of the mediastinal tumor revealed it to be a metastatic small cell carcinoma of the bladder. At 4 months after surgery, multiple metastatic lesions were found in the chest and liver, and chemotherapy for small cell carcinoma was started.ConclusionsWe present this case of mediastinal metastasis of small cell carcinoma of the bladder, which is very rare, to show the importance of surgical resection of an isolated mediastinal tumor. Such a procedure should be considered, as histological diagnosis of the tumor could be useful for determining therapeutic options.

S2223 A Rare Case of Sporadic Metastatic Rectal Small Cell Carcinoma With Primary Biliary Cholangitis

S2223 A Rare Case of Sporadic Metastatic Rectal Small Cell Carcinoma With Primary Biliary Cholangitis

Long-term Outcomes of Local and Metastatic Small Cell Carcinoma of the Urinary Bladder and Genomic Analysis of Patients Treated With Neoadjuvant Chemotherapy.

Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (<pT2pN0) and pathologic complete response (pT0pN0) rates of 48% and 38%, respectively, with median follow-up of 7.2 years, and median DFS and OS of 5.6 and 14.5 years, respectively. NAC responders (<ypT2N0) had superior median DFS (14.5 vs. 0.6 years, hazard ratio [HR] 0.24, P< .001) and OS (14.5 vs. 2.5 years, HR 0.31, P = .002). DFS rates for responders and nonresponders were 76% and 27% at 5 years, and 71% and 23% at 10 years, respectively. Local and central nervous system recurrences were infrequent. Median progression-free survival (PFS) and OS for M1 disease were 6.9 and 10.3 months, respectively. Genomic profiling was performed on 47 NAC patients. Loss of ERCC2 function was significantly enriched among those with pathologic complete response to NAC (mutations present in 50% of pathologic complete responders vs. 15% nonresponders, P = .045). M0 SCCB is chemo-sensitive and patients have excellent long-term survival following response to NAC. Patients with M1 disease have poor survival despite systemic therapy. Loss-of-function mutations of ERCC2 were associated with pathologic complete response to NAC.

Cutaneous metastases of non-cutaneous neuroendocrine neoplasms: A histopathologic review of 15 cases.

Cutaneous metastases from non-cutaneous neuroendocrine neoplasms are rare; however, distinction from primary neuroendocrine carcinomas of the skin (Merkel cell carcinoma) guides clinical management. We performed a retrospective review from September 1, 2010 to September 30, 2020 of the histopathologic, immunohistochemical, and clinical characteristics of metastatic neuroendocrine neoplasms to the skin from non-cutaneous primaries. Fourteen patients were identified for the study (nine males and five females; mean age of 59.5 years). Fifteen skin specimens from 14 patients were available for review. At the time of skin biopsy, a known non-cutaneous neuroendocrine neoplasm was present in 50% of patients. Primary sites of neuroendocrine carcinoma included lung (n=5), terminal ileum (n=2), and one each from prostate, breast, rectum, uterus, esophagus, and sinus, with one unknown (suspected bladder malignancy). Eleven of fourteen patients are dead of disease; one was lost to follow-up. All 15 specimens showed subcutaneous/deep dermal involvement with six involving the papillary dermis and one involving the epidermis. The tumors ranged from well to poorly differentiated. Two of fifteen specimens showed focal CK20 positivity (one metastatic uterine small cell carcinoma and one metastatic ileal carcinoid). TTF-1 was performed in 13 specimens and was positive in six, of which two were of non-pulmonary origin. While immunohistochemical stains, in particular CK20, CK7, and TTF-1, are integral in the workup of confirming the origin of neuroendocrine tumors found in the skin, results vary and are often non-specific for a single primary site. Therefore, complete radiologic imaging as well as clinical correlation should be recommended to further aid in the identification of a non-cutaneous primary neoplasm.

Real-world experience managing unresectable or metastatic small cell carcinoma of the prostate.

Unresectable and metastatic small cell carcinoma of the prostate (SCPC) is a rare and aggressive disease that is under-represented in clinical trials. We carried out a retrospective chart review of metastatic or unresectable SCPC patients at British Columbia (BC) Cancer centers, studying diagnosis and treatment patterns. Drug-dispensing records from the six BC Cancer centers were obtained from 2002-2017. For each patient, information was collected on baseline information prior to therapy and for each line of treatment. Treatments at each line were compared regarding time to progression and overall survival by Kaplan-Meier curves. Forty-one patients received treatment; 65.6% had metastatic disease and 61% had pure small cell carcinoma. Median time from treatment to death was 10 months (95% confidence interval [CI] 6-16). Patients with initially prostate-confined disease had a better median overall survival (mOS) of 21 months (95% CI 13-34) compared to those with initially locally advanced (mOS 19 months, 95% CI 5-37) and metastatic disease (mOS 8 months, 95% CI 6-10) (log-rank p=0.0364). All patients received either cisplatin- or carboplatin-based combination chemotherapy as the first-line treatment and 36.7% received second-line therapy. Time to second-line therapy was eight months for those who presented with metastatic SCPC, compared to 13 months for those with initial non-metastatic SCPC. This single-province, multi-institution cohort reports data on unresectable and metastatic SCPC and highlights the poor prognosis of this rare disease entity.

Complete heart block ensuing from a metastatic small cell carcinoma: a case report

IntroductionNotwithstanding the diagnostic and therapeutic advancements, the incidence of cardiac metastases has increased in recent decades. Lung cancers are the most common primary malignant neoplasms with cardiac metastasis potential. The clinical presentation of cardiac metastases is either silent or vague, and largely depends on the infiltrated location and tumor burden. Although arrhythmias are not uncommon in metastatic cardiac tumors, complete heart block is relatively a rare manifestation. We present a case of complete heart block due to a metastatic small cell carcinoma in a 67-year-old male of African origin.Case presentationA 67-year-old male of African origin from rural Tanzania was referred to us for expert management. He is a retired agromechanic with over 30 years exposure to asbestos-containing brake linings. His past medical history was unremarkable, but the family-social history was evident for a heavy alcohol intake and chronic cigarette smoking. He presented with a 24-week history of progressive shortness of breath and an 8-week history of recurrent syncopal attacks coupled with a significant weight loss. He had normal echocardiographic findings, however, the electrocardiogram showed features of complete heart block. Chest X-ray showed a homogeneous opacification on the right side and computed tomography scan revealed a solid right lung mass with metastases to the liver, heart, bowels, and bone. He underwent bronchoscopy, which revealed an endobronchial mass obstructing the bronchus intermedius. Histological examination of a section of lung biopsy taken during bronchoscopy confirmed the diagnosis of a small cell carcinoma. The patient underwent dual chamber pacemaker implantation with successful sinus rhythm restoration. He made an informed refusal of chemotherapy and inevitably died 18 months post pacing.ConclusionsDespite the advancements in medical diagnostics and management, lung cancers are often diagnosed in advanced stages, with an inevitable grave prognosis. Small cell carcinoma has the potential to metastasize to the heart, resulting in complete heart block.

NeuN, a DNA-binding neuron-specific protein expressed by Merkel cell carcinoma: analysis of 15 cases.

SummaryAimMerkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma, with an increasing worldwide incidence. It presents as a painless red to purple nodule on sun-exposed skin. MCC is presumed to arise from resident cutaneous Merkel cells. The pathogenesis of MCC is likely multifactorial with immunosuppression, UV-induced skin damage, and Merkel cell polyomavirus contributing to the development. The diagnosis of MCC relies upon characteristic morphologic features and use of immunohistochemical stains. Histologically, the differential diagnosis of Merkel cell carcinoma includes the ‘small round cell’ tumor group, particularly metastatic small cell carcinoma and hematological malignancies. This study investigates the expression of NeuN antibody, which recognizes the protein NeuN, normally present in most neuronal cell types and neuronal tumors, in Merkel cell carcinomas.Methods and resultsFifteen cases of Merkel cell carcinoma (7 men and 7 women; mean age 74 years) were retrieved from the institute database between the years 2011-2020. The immunohistochemical profile was investigated: CK20 (14/14), Neurofilament, (12/12), Synaptophysin (14/14); Chromogranin A (11/13), PAX5 (10/12), TDT (5/12), CK7 (1/14), TTF1 (0/14). Infection by Polyoma virus was detected in 11 of 14 patients. Most tumors showed middle/strong expression of NeuN. No cutaneous structures, or epidermal Merkel cells, showed expression of NeuN. The expression of NeuN was investigated in 17 primary small cell lung carcinomas: 2 cases were positive for Neu-N.ConclusionsAwareness of the staining pattern of Neu-N could aid in diagnosis of Merkel cell carcinoma, avoiding misinterpretation and erroneous diagnosis with other tumors.

Primary Small-Cell Carcinoma of the Hard Palate: An Extremely Rare Occasion

: Most primary small cells carcinoma develop from the lung, and extra-pulmonary small cell carcinoma accounts for less than 5% of all small cell carcinoma cases. In the head and neck region, the most common sites are the larynx and salivary glands; however primary involvement of the palate is extremely rare. The extra-pulmonary small cell carcinoma is similar to its pulmonary counterpart regarding morphology, immunohistochemistry, and electron microscopy features and derives from pluripotential stem cells that develop neuroendocrine features. There is growing evidence regarding the ability of extra-pulmonary small cell carcinoma to arise from pluripotent basilar cells capable of divergent differentiation with the consequence of arising neuroendocrine phenotype as a trans-differentiation phenomenon in the progression of an organ-specific carcinoma. The differentiation between primary and metastatic extra-pulmonary small cell carcinoma is challenging. There is also no standard guideline for treatment as it is a rare occasion, and there is no consensus between radiation oncologists and cancer surgeons about the best treatment strategy. In this study, a very rare case of hard palate small cell carcinoma with neuroendocrine pathology features is presented. To our best of knowledge, this is the third case report of extra-pulmonary small cell carcinoma involving the palate in the literature review. Knowing the clinical presentation and pathology characteristics of such rare tumor in addition to follow-up outcome can be highly useful to establish a reliable guideline for hard palate small cell carcinoma management.

MRI Features and Pathological Findings of Metastatic Renal Small Cell Carcinoma: A Rare Case Report

MRI Features and Pathological Findings of Metastatic Renal Small Cell Carcinoma: A Rare Case Report

Clinicopathologic features of metastatic small cell carcinoma of the prostate to the liver: a series of four cases

BackgroundSmall cell neuroendocrine carcinoma of the prostate (SCNECP) is a rare, aggressive subtype of prostate carcinoma. Most SCNECP arise from conventional prostate adenocarcinoma (CPAC) treated with androgen deprivation therapy (ADT).Case presentationsWe identified four cases of CPAC treated with ADT, which evolved to SCNECP with liver metastasis. The average interval between the diagnosis of CPAC and SCNECP was 102 months (range: 12 to 168). Histologically, the tumors showed nests of cells with high nuclear:cytoplasmic ratios, granular chromatin, and frequent mitoses. All cases were synaptophysin, chromogranin, and AE1/AE3 positive, with a Ki-67 labeling index ≥70%. NKX3.1 was negative in all but one case and TTF-1 was positive in half. Weak ERG positivity by IHC was seen in one case which also demonstrated the TMPRSS2-ERG gene rearrangement; all other cases were negative for ERG by IHC. Serum prostate specific antigen (PSA) levels were normal to near-normal in all. The median interval between the diagnosis of SCNECP and death was 3.25 months (range: 0.75 to 26).ConclusionsOur case series highlights the importance of considering a prostate primary, even in the setting of normal PSA levels and loss of prostate markers, when diagnosing neuroendocrine carcinoma in the liver. Further, we emphasize the significance of diagnosing SCNECP that metastasizes to the liver, as it portends a particularly dismal prognosis.

A Rare Type of Testicular Metastasis of Small Cell Carcinoma from the Lung: Case Report and Review of the Literature

Testicular neoplasms are approximately one percent of all malignancies in men and seen mostly second-to-fourth decade of life. Testicular metastasis is seen very rare in all literature. Most common metastasis site to testis is prostate except hematologic malignancies. However, from lung cancer is seen rarely either. To our knowledge, herein we report one of the rarest case describing a sixty-two year old male patient with the history of small cell carcinoma (SCC) of the lung and underwent chemotherapy-radiotherapy who admitted to the clinic with testicular mass undergone radical orchiectomy. The histopathologic examination revealed metastatic SCC of the lung.