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A 38-Year-Old Man With An Ataxic Gait, Night Sweats, and Weight Loss
[
Pulmonary, Critical Care, and Sleep Pearls
]
A 38-Year-Old Man With An Ataxic Gait, Night Sweats, and Weight Loss Elyana Matayeva, DO; Theresa Henson, MD; and Artur Alaverdian, MD
A 38-year-old Jamaican man with no medical history presented with worsening right-sided weakness. He developed an ascending hemiparesis that began in the right lower extremity 3 months ago and progressed to the right upper extremity this past month. Over the past 3 months, the patient has had unintentional weight loss and an ataxic gait, and for the past month he has had night sweats. He denied headache, vision changes, numbness, tingling, cough, or chest pain. Social history was significant for 20 smoking packyears and daily use of marijuana. CHEST 2019; 156(6):e133-e136
CASE PRESENTATION:
Physical Examination Findings The patient’s vital signs on admission were: temperature, 36.8oC; heart rate, 64 beats/min; BP, 109/74 mm Hg; respiratory rate, 14 breaths/min; and oxygen saturation, 99% on room air. On general appearance, he was in no acute respiratory distress, and he was fully alert and oriented. Neurologic findings were significant for right proximal lower extremity strength of 4/5 and right distal lower extremity strength of 1/5 with a leg-swinging gait on his right lower extremity. Reflexes were normal throughout with sensation fully intact. Lungs were clear to auscultation bilaterally.
Diagnostic Studies The patient’s CBC and basic metabolic profile were within normal limits except for a normocytic anemia with a hemoglobin level of 12.9 g/dL. A CT brain scan showed large areas of white matter edema in the frontal lobes bilaterally, with underlying bilateral hypodense cystic masses with the largest measuring 4.2 2.5 cm with a midline shift of 2.5 mm (Figs 1 and 2). A CT thorax scan revealed a spiculated nodule in the right
AFFILIATIONS: From the Nassau University Medical Center (Drs Matayeva and Henson), East Meadow, NY; and the White Plains Hospital (Dr Alaverdian), White Plains, NY. The abstract of this case was presented as a poster presentation at the CHEST Annual Meeting, October 6-10, 2018, San Antonio, TX.
chestjournal.org
Figure 1 – Left frontal lobe cystic mass lesion with surrounding white matter edema.
upper lobe measuring 1.7 1.9 2.1 cm with mild superior pleural retraction and right paratracheal lymphadenopathy (Fig 3). Left-sided craniotomy was
CORRESPONDENCE TO: Elyana Matayeva, DO, Nassau University Medical Center, 2201 Hempstead Turnpike, East Meadow, NY 11554; e-mail: [email protected] Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.07.007
e133
Figure 4 – Brain specimen with immunostains of CK5/6 suggesting squamous cell origin, implying this is metastatic squamous cell carcinoma.
Figure 2 – Large bilateral frontal lobe mass lesions with surrounding white matter edema and a midline shift.
performed to resect the cystic frontal lobe tumor. Histologic analysis was notable for metastatic squamous cell carcinoma with the following supportive immunohistochemistry: positive CK5, CK6, CK7, P63, and Ki-67 (Fig 4). Results of a CT scan-guided needle biopsy of the right upper lobe nodule were nonrevealing.
What is the next best step? What is the diagnosis?
Figure 3 – Spiculated nodule in the right upper lobe measuring 1.7 1.9 2.1 cm.
e134 Pulmonary, Critical Care, and Sleep Pearls
[
156#6 CHEST DECEMBER 2019
]
Next step: Surgical resection is the next best step. A right-sided open thoracotomy was performed for a right upper lobe wedge resection. Histologic analysis revealed adenosquamous carcinoma with lymphovascular invasion and positive mucin stains (Figs 5 and 6). Endothelial growth factor receptor (EGFR), KRAS, and ALK immunohistochemistry came back negative. Diagnosis: Adenosquamous lung cancer with squamous cell brain metastasis. Discussion Adenosquamous lung cancer (ASLC) is a subtype of non-small cell lung carcinoma that contains both adenocarcinoma and squamous cell carcinoma cells. It comprises only 0.4% to 4.0% of all primary lung cancers. ASLC has a tendency to metastasize earlier and has a higher mortality rate compared with adenocarcinoma or squamous cell histologic types individually. ASLC is commonly seen in patients aged > 50 years, although there has been increased incidence in the population of younger patients. There is a male predominance, and most of the patients are cigarette smokers. The histogenesis of ASLC neoplasm has been investigated for many years; however, it is still unclear. The ASCL tumor contains two phenotypes with two different lineages: columnar cells and squamous cells. The two theories that exist are monoclonality and polyclonality, otherwise known as the “collision” tumor. Monoclonality suggests that the squamous cell carcinomatous and adenocarcinomatous components
Figure 5 – Lung specimen with mixed squamous cell and adenocarcinoma histological features.
chestjournal.org
Figure 6 – Lung specimen with a positive mucin stain, which is a feature of adenocarcinoma.
derive from common tumor stem cells and then differentiate into separate histologic types. This scenario implies that ASLC serves as a transitional stage between adenocarcinoma and squamous cell carcinoma. With this theory, it is possible to have metastasis with only one histologic type. In contrast, polyclonality suggests that there is a collision of two tumors that were derived from two separate stem cells. To make a diagnosis of ASLC, each histologic component must comprise at least 10% of the tumor. Transbronchial needle aspiration has only 25% diagnostic accuracy for ASLC, and surgical resection is therefore often required to obtain a specimen size sufficient to make a histologic diagnosis. Furthermore, using immunohistochemistry markers in combination with histologic analysis can increase the likelihood of an accurate diagnosis. Common immunohistochemistry markers include CK5/6, CK7, p63, TTF-q, and p40. EGFR mutations are rarely seen in squamous cell carcinoma, whereas they are often seen in adenocarcinomas. Interestingly, 44% of ASLC are found to have EGFR mutations. Therefore, if a transbronchial biopsy is used to obtain a small specimen biopsy specimen and is found to have an EGFR mutation with squamous cell carcinoma histology, one should consider ASLC as the actual diagnosis. Because there is a lack of understanding regarding the true molecular composition of this malignancy, there is no standard therapy regimen. Treatment for ASLC depends on the genotype of the cancer. If there is a driver-type mutation such as EGFR, then an EGFR tyrosine kinase inhibitor can be used as targeted therapy. EGFR mutations in ASLC have a tyrosine kinase inhibitor response rate similar to that of
e135
adenocarcinoma. If brain metastasis is identified, surgical resection is recommended. If tumors are unable to be resected, standard chemotherapy plus whole-brain radiotherapy is recommended. ASLC is known to have a strong ability to invade with early-stage metastasis and a poor prognosis. The prognosis of patients who underwent surgery and received no targeted therapy had a 3-year survival rate of 52% and a 5-year survival rate of 15%. The median survival for ASLC with distant metastasis or local recurrence is 39 months. Brain metastasis is found in 50% of all patients with lung cancer. In ASLC, time to brain metastasis was < 6 months; brain metastasis is therefore often present at the time of diagnosis. Similarly, lymph node metastasis is considered to be highly invasive with a poor prognosis. There is a higher incidence of lymph node metastasis in ASLC than in single adenosquamous and squamous cell carcinoma.
Clinical Course Upon discharge, the patient was followed up by oncology. No targeted therapy was used because immunohistochemistry, including EGFR mutation, returned negative. The patient and oncology team agreed to pursue radiation treatment. Despite these efforts, the patient died 1 month later. As mentioned earlier, the histogenesis of this malignancy has long been debated; however, the current case supports the theory of monoclonality. This case illustrates the rapid and aggressive nature of ASLC.
2. ASLC should be considered if results of a transbronchial biopsy reveal a squamous cell tumor with an EGFR mutation. 3. ASLC is the most aggressive non-small cell lung carcinoma compared with individual histology with an average of 6 months’ time to brain metastasis. 4. Patients with ASLC who undergo tumor resection without targeted chemotherapy have only a 15% fiveyear survival rate.
Acknowledgments Financial/nonfinancial disclosure: None declared. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Suggested Readings Kang SM, Kang HJ, Shin JH, et al. Identical epidermal growth factor receptor mutations in adenocarcinomatous and squamous cell carcinomatous components of adenosquamous carcinoma of the lung. Cancer. 2007;109(3):581-587. Burkart B, Shilo K. Metastatic squamous cell carcinoma component from an adenosquamous carcinoma of the lung with identical epidermal growth factor receptor mutations. Case Rep Pulmonology. 2015;2015:283875. Liwen F, Haitang Y, Feng Y, et al. Clinical outcomes of epidermal growth factor receptor tyrosine kinase inhibitors in recurrent adenosquamous carcinoma of the lung after resection. Onco Targets Ther. 2017;10:239245. Kong M, Jin J, Cai X. Characteristics of lymph node metastasis in resected adenosquamous lung cancer. Medicine (Baltimore). 2017;96(48):e8870. Yang P, Li WL, Zhou JX. Peritoneum as the sole distant metastatic site on lung adenosquamous carcinoma: a case report. J Med Case Rep. 2017;11: 274.
Clinical Pearls
Borczuk A. Uncommon type of lung carcinoma with mixed histology: sarcomatoid carcinoma, adenosquamous carcinoma, and mucoepidermoid carcinoma. Arch Pathol Lab Med. 2018;142(8):914-921.
1. Surgical resection is required to accurately diagnose ASLC histologically.
Pan F, Cui S, Wang W, Gu A, Jiang L. Survival analysis for lung adenosquamous carcinoma patients with brain metastasis. J Cancer. 2018;9(2):3707-3712.
e136 Pulmonary, Critical Care, and Sleep Pearls
[
156#6 CHEST DECEMBER 2019
]
Pulmonary, Critical Care, and Sleep Pearls
]
A 38-Year-Old Man With An Ataxic Gait, Night Sweats, and Weight Loss Elyana Matayeva, DO; Theresa Henson, MD; and Artur Alaverdian, MD
A 38-year-old Jamaican man with no medical history presented with worsening right-sided weakness. He developed an ascending hemiparesis that began in the right lower extremity 3 months ago and progressed to the right upper extremity this past month. Over the past 3 months, the patient has had unintentional weight loss and an ataxic gait, and for the past month he has had night sweats. He denied headache, vision changes, numbness, tingling, cough, or chest pain. Social history was significant for 20 smoking packyears and daily use of marijuana. CHEST 2019; 156(6):e133-e136
CASE PRESENTATION:
Physical Examination Findings The patient’s vital signs on admission were: temperature, 36.8oC; heart rate, 64 beats/min; BP, 109/74 mm Hg; respiratory rate, 14 breaths/min; and oxygen saturation, 99% on room air. On general appearance, he was in no acute respiratory distress, and he was fully alert and oriented. Neurologic findings were significant for right proximal lower extremity strength of 4/5 and right distal lower extremity strength of 1/5 with a leg-swinging gait on his right lower extremity. Reflexes were normal throughout with sensation fully intact. Lungs were clear to auscultation bilaterally.
Diagnostic Studies The patient’s CBC and basic metabolic profile were within normal limits except for a normocytic anemia with a hemoglobin level of 12.9 g/dL. A CT brain scan showed large areas of white matter edema in the frontal lobes bilaterally, with underlying bilateral hypodense cystic masses with the largest measuring 4.2 2.5 cm with a midline shift of 2.5 mm (Figs 1 and 2). A CT thorax scan revealed a spiculated nodule in the right
AFFILIATIONS: From the Nassau University Medical Center (Drs Matayeva and Henson), East Meadow, NY; and the White Plains Hospital (Dr Alaverdian), White Plains, NY. The abstract of this case was presented as a poster presentation at the CHEST Annual Meeting, October 6-10, 2018, San Antonio, TX.
chestjournal.org
Figure 1 – Left frontal lobe cystic mass lesion with surrounding white matter edema.
upper lobe measuring 1.7 1.9 2.1 cm with mild superior pleural retraction and right paratracheal lymphadenopathy (Fig 3). Left-sided craniotomy was
CORRESPONDENCE TO: Elyana Matayeva, DO, Nassau University Medical Center, 2201 Hempstead Turnpike, East Meadow, NY 11554; e-mail: [email protected] Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.07.007
e133
Figure 4 – Brain specimen with immunostains of CK5/6 suggesting squamous cell origin, implying this is metastatic squamous cell carcinoma.
Figure 2 – Large bilateral frontal lobe mass lesions with surrounding white matter edema and a midline shift.
performed to resect the cystic frontal lobe tumor. Histologic analysis was notable for metastatic squamous cell carcinoma with the following supportive immunohistochemistry: positive CK5, CK6, CK7, P63, and Ki-67 (Fig 4). Results of a CT scan-guided needle biopsy of the right upper lobe nodule were nonrevealing.
What is the next best step? What is the diagnosis?
Figure 3 – Spiculated nodule in the right upper lobe measuring 1.7 1.9 2.1 cm.
e134 Pulmonary, Critical Care, and Sleep Pearls
[
156#6 CHEST DECEMBER 2019
]
Next step: Surgical resection is the next best step. A right-sided open thoracotomy was performed for a right upper lobe wedge resection. Histologic analysis revealed adenosquamous carcinoma with lymphovascular invasion and positive mucin stains (Figs 5 and 6). Endothelial growth factor receptor (EGFR), KRAS, and ALK immunohistochemistry came back negative. Diagnosis: Adenosquamous lung cancer with squamous cell brain metastasis. Discussion Adenosquamous lung cancer (ASLC) is a subtype of non-small cell lung carcinoma that contains both adenocarcinoma and squamous cell carcinoma cells. It comprises only 0.4% to 4.0% of all primary lung cancers. ASLC has a tendency to metastasize earlier and has a higher mortality rate compared with adenocarcinoma or squamous cell histologic types individually. ASLC is commonly seen in patients aged > 50 years, although there has been increased incidence in the population of younger patients. There is a male predominance, and most of the patients are cigarette smokers. The histogenesis of ASLC neoplasm has been investigated for many years; however, it is still unclear. The ASCL tumor contains two phenotypes with two different lineages: columnar cells and squamous cells. The two theories that exist are monoclonality and polyclonality, otherwise known as the “collision” tumor. Monoclonality suggests that the squamous cell carcinomatous and adenocarcinomatous components
Figure 5 – Lung specimen with mixed squamous cell and adenocarcinoma histological features.
chestjournal.org
Figure 6 – Lung specimen with a positive mucin stain, which is a feature of adenocarcinoma.
derive from common tumor stem cells and then differentiate into separate histologic types. This scenario implies that ASLC serves as a transitional stage between adenocarcinoma and squamous cell carcinoma. With this theory, it is possible to have metastasis with only one histologic type. In contrast, polyclonality suggests that there is a collision of two tumors that were derived from two separate stem cells. To make a diagnosis of ASLC, each histologic component must comprise at least 10% of the tumor. Transbronchial needle aspiration has only 25% diagnostic accuracy for ASLC, and surgical resection is therefore often required to obtain a specimen size sufficient to make a histologic diagnosis. Furthermore, using immunohistochemistry markers in combination with histologic analysis can increase the likelihood of an accurate diagnosis. Common immunohistochemistry markers include CK5/6, CK7, p63, TTF-q, and p40. EGFR mutations are rarely seen in squamous cell carcinoma, whereas they are often seen in adenocarcinomas. Interestingly, 44% of ASLC are found to have EGFR mutations. Therefore, if a transbronchial biopsy is used to obtain a small specimen biopsy specimen and is found to have an EGFR mutation with squamous cell carcinoma histology, one should consider ASLC as the actual diagnosis. Because there is a lack of understanding regarding the true molecular composition of this malignancy, there is no standard therapy regimen. Treatment for ASLC depends on the genotype of the cancer. If there is a driver-type mutation such as EGFR, then an EGFR tyrosine kinase inhibitor can be used as targeted therapy. EGFR mutations in ASLC have a tyrosine kinase inhibitor response rate similar to that of
e135
adenocarcinoma. If brain metastasis is identified, surgical resection is recommended. If tumors are unable to be resected, standard chemotherapy plus whole-brain radiotherapy is recommended. ASLC is known to have a strong ability to invade with early-stage metastasis and a poor prognosis. The prognosis of patients who underwent surgery and received no targeted therapy had a 3-year survival rate of 52% and a 5-year survival rate of 15%. The median survival for ASLC with distant metastasis or local recurrence is 39 months. Brain metastasis is found in 50% of all patients with lung cancer. In ASLC, time to brain metastasis was < 6 months; brain metastasis is therefore often present at the time of diagnosis. Similarly, lymph node metastasis is considered to be highly invasive with a poor prognosis. There is a higher incidence of lymph node metastasis in ASLC than in single adenosquamous and squamous cell carcinoma.
Clinical Course Upon discharge, the patient was followed up by oncology. No targeted therapy was used because immunohistochemistry, including EGFR mutation, returned negative. The patient and oncology team agreed to pursue radiation treatment. Despite these efforts, the patient died 1 month later. As mentioned earlier, the histogenesis of this malignancy has long been debated; however, the current case supports the theory of monoclonality. This case illustrates the rapid and aggressive nature of ASLC.
2. ASLC should be considered if results of a transbronchial biopsy reveal a squamous cell tumor with an EGFR mutation. 3. ASLC is the most aggressive non-small cell lung carcinoma compared with individual histology with an average of 6 months’ time to brain metastasis. 4. Patients with ASLC who undergo tumor resection without targeted chemotherapy have only a 15% fiveyear survival rate.
Acknowledgments Financial/nonfinancial disclosure: None declared. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Suggested Readings Kang SM, Kang HJ, Shin JH, et al. Identical epidermal growth factor receptor mutations in adenocarcinomatous and squamous cell carcinomatous components of adenosquamous carcinoma of the lung. Cancer. 2007;109(3):581-587. Burkart B, Shilo K. Metastatic squamous cell carcinoma component from an adenosquamous carcinoma of the lung with identical epidermal growth factor receptor mutations. Case Rep Pulmonology. 2015;2015:283875. Liwen F, Haitang Y, Feng Y, et al. Clinical outcomes of epidermal growth factor receptor tyrosine kinase inhibitors in recurrent adenosquamous carcinoma of the lung after resection. Onco Targets Ther. 2017;10:239245. Kong M, Jin J, Cai X. Characteristics of lymph node metastasis in resected adenosquamous lung cancer. Medicine (Baltimore). 2017;96(48):e8870. Yang P, Li WL, Zhou JX. Peritoneum as the sole distant metastatic site on lung adenosquamous carcinoma: a case report. J Med Case Rep. 2017;11: 274.
Clinical Pearls
Borczuk A. Uncommon type of lung carcinoma with mixed histology: sarcomatoid carcinoma, adenosquamous carcinoma, and mucoepidermoid carcinoma. Arch Pathol Lab Med. 2018;142(8):914-921.
1. Surgical resection is required to accurately diagnose ASLC histologically.
Pan F, Cui S, Wang W, Gu A, Jiang L. Survival analysis for lung adenosquamous carcinoma patients with brain metastasis. J Cancer. 2018;9(2):3707-3712.
e136 Pulmonary, Critical Care, and Sleep Pearls
[
156#6 CHEST DECEMBER 2019
]