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Multiple Pulmonary Nodules in a 70-Year-Old Female With a History of Breast Cancer
CHEST
Postgraduate Education Corner PULMONARY AND CRITICAL CARE PEARLS
Multiple Pulmonary Nodules in a 70-Year-Old Female With a History of Breast Cancer Sharon Lynn Gambino, DO; Christopher S. King, MD; and Christopher J. Lettieri, MD, FCCP
(CHEST 2009; 136:938 –941)
70-year-old woman was referred to the pulmoA nary clinic for the evaluation of multiple pulmo-
nary nodules that had been noted on a routine surveillance CT scan performed after a diagnosis of breast cancer. On presentation to the pulmonary clinic, she denied symptoms, including dyspnea, hemoptysis, weight loss, fevers, chills, or night sweats. She did report a dry, nonproductive cough of several months duration. The patient’s medical history was significant for stage 1 (T1bN0M0) infiltrating breast carcinoma that had been diagnosed approximately 1 year prior to the current presentation. Treatment had consisted of a lumpectomy, and negative surgical margins were achieved. The patient declined radiation therapy and was given therapy with anastrazole. The patient also reported a history of hypertension, hyperlipidemia, peripheral vascular disease, and collagenous colitis. Prior surgeries included the recent lumpectomy, an appendectomy, carotid endarterectomy, and a total abdominal hysterectomy. Her medications included mesalamine, simvastatin, lisinopril, atenolol, clopidogrel, and anastrazole. The patient had no notable travel history. She had a 15-pack-year smoking history, but had quit 13 years prior.
distress. Cardiac, abdominal, and lung examinations revealed no abnormalities. She had no clubbing or edema. No skin rash was noted. There was no evidence of synovitis. Laboratory, Radiographic, and Bronchoscopy Findings A CT scan was performed for routine cancer screening 1 year after the initial diagnosis. It revealed numerous, noncalcified, lower lobe-predominant nodules bilaterally, which were increased in size and number when compared with a CT scan from 2 years earlier (Fig 1). No lymphadenopathy was noted. The patient had known pulmonary nodules at the time of diagnosis of her breast cancer, which were stable radiographically for 2 years. During her initial pulmonary evaluation, the CT scan results were discussed and the patient declined further evaluation or intervention. However, the patient did agree to repeat imaging for surveillance. The results of the initial laboratory tests at
Physical Examination The patient’s vitals signs were within normal limits. The patient was a thin, elderly woman in no acute Manuscript received December 19, 2008; revision accepted March 21, 2009. Affiliations: From the Departments of Internal Medicine (Dr. Gambino), and Pulmonary and Critical Care Medicine (Drs. King and Lettieri), Walter Reed Army Medical Center, Washington, DC. © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). Correspondence to: Sharon Lynn Gambino, DO, Walter Reed Army Medical Center, Internal Medicine, 6900 Georgia Ave NW, Washington, DC 20307; e-mail: [email protected] DOI: 10.1378/chest.08-2994 938
Figure 1. Chest CT scan showing multiple, small parenchymal nodules predominantly located in the lower lobes. Postgraduate Education Corner
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on October 11, 2009 © 2009 American College of Chest Physicians
Figure 2. Chest CT scan obtained 6 months after that in Figure 1, showing a further increase in the size and number of the pulmonary nodules.
this time, which included CBC count, chemistry panel, and liver function, were normal.
Figure 3. Open lung biopsy specimen (hematoxylin-eosin, original ⫻40).
What is the likely diagnosis?
Clinical Course A repeat CT scan was performed 6 months later (Fig 2). This CT scan revealed a further increase in the size and number of multiple, bilateral, lower lobe-predominant nodules without lymphadenopathy. A routine laboratory evaluation was repeated, and the results remained normal. A bronchoscopy was performed for further evaluation, including BAL and transbronchial biopsies. No endobronchial lesions were noted. The findings of BAL fluid acid-fast bacilli testing and fungal smears and cultures were negative. Transbronchial biopsy specimens revealed only chronic inflammation. The patient was then referred for surgical lung biopsy. The lung biopsy specimen is shown in Figure 3.
www.chestjournal.org
CHEST / 136 / 3 / SEPTEMBER, 2009
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on October 11, 2009 © 2009 American College of Chest Physicians
939
Answer: Multiple pulmonary carcinoid tumors and tumorlets
Discussion Pulmonary carcinoid tumors and tumorlets are nodular proliferations of neuroendocrine cells. Tumorlets are defined as nodules ⬍ 5 mm, while carcinoid tumors are ⬎ 5 mm. This distinction is somewhat arbitrary, as carcinoid tumors and tumorlets share similar histologic and immunohistochemical features. Carcinoid tumors and tumorlets often coexist, although it is unknown whether carcinoid tumorlets evolve into tumors. Our understanding of the clinical significance of carcinoid tumors and tumorlets has evolved over time. Early reports described tumorlets as a purely reactive phenomenon of no consequence that was associated with chronic lung diseases, including bronchiectasis, pulmonary fibrosis, granulomatous inflammation, and giant cell pneumonia, although tumorlets have been documented in otherwise normal pulmonary parenchyma. While generally described as benign, tumorlets also have the potential for lymph node metastases. Additionally, potential associations with airflow obstruction and ectopic hormone production have been recognized. Similar to our patient, the scenario in which a diagnosis of pulmonary carcinoid tumorlets is most commonly made is following surgical lung biopsy performed for the concern of pulmonary metastases, often in older women with a history of breast cancer. The prevalence of pulmonary carcinoid tumorlets is not well defined, but appears to be a rare occurrence, affecting ⬍ 0.5% of the population.
Figure 4. Open lung biopsy specimen (synaptophysin, original ⫻10). 940
Figure 5. Open lung biopsy specimen (chromogranin, original ⫻20).
Pulmonary carcinoid tumorlets are often asymptomatic, although about one-half of patients will report a cough. A syndrome consisting of symptomatic airflow obstruction and diffuse hyperplasia of pulmonary neuroendocrine cells has been described, termed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Histopathologically, the term DIPNECH specifically describes the proliferation of neuroendocrine cells superficial to the basement membrane and confined to the bronchial and bronchiolar epithelium. When there is extension beyond the basement membrane, the neuroendocrine proliferations are called tumorlets. The term DIPNECH has been used loosely in the literature for the syndrome described above, which has been reported in association with both neuroendocrine proliferation and carcinoid tumorlets. Spirometry is normal in the majority of patients with pulmonary carcinoid tumorlets; however, patients can have moderate-to-severe airflow obstruction. Cushing syndrome, acromegaly, and carcinoid syndrome may occur, usually in the setting of a dominant carcinoid nodule, although these syndromes may also be associated with carcinoid tumorlets. Radiographically, pulmonary carcinoid tumorlets are nonspecific, small nodules that are generally multiple and often bilateral. The nodules are more commonly smooth and spherical, although they may have irregular, poorly circumscribed edges. The small size of these lesions precludes effective bronchoscopic or transthoracic needle biopsy, so when concern for metastatic disease arises surgical lung biopsy is required. On immunohistochemical staining, carcinoid tumors and tumorlets stain strongly positive for chromogranin and synaptophysin, facilitating diagnosis; however, the features may be somewhat indistinct without special staining to recognize them. Postgraduate Education Corner
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on October 11, 2009 © 2009 American College of Chest Physicians
Pulmonary carcinoid tumorlets are generally regarded as a benign condition with an excellent prognosis. In the absence of symptoms, diffuse carcinoid tumorlets require no specific treatment. Close observation with serial imaging and attention focused on change in a particular nodule is a reasonable strategy. In cases of a dominant, peripherally located, parenchymal carcinoid tumor associated with carcinoid tumorlets, local resection is indicated. Treatment with chemotherapy, somatostatin analogues, or interferon can be considered in patients with syndromes of ectopic hormone production or multiple carcinoid tumors. Data from randomized controlled trials documenting the efficacy of these therapies is lacking. The patient’s lung biopsy specimen stained strongly positive for the neuropeptides synaptophysin and chromogranin, as shown in Figures 4 and 5, respectively, suggesting a neuroendocrine tumor. The results of the immunohistochemical staining and the histologic appearance were consistent with a diagnosis of carcinoid tumors and tumorlets. An octreotide scan revealed no uptake outside of the lung or within the lung lesions, although this may have been due to their small size. The measurement of a 24-h urine 5-hydroxyindoleacetate level was normal. The patient was referred to the oncology service, which elected to treat her with octreotide given the diffuse nature of her disease. She continues to do well with minimal symptoms and stable imaging findings. Clinical Pearls 1. Pulmonary carcinoid tumorlets should be considered in the differential diagnosis of multiple bilateral nodules. In patients with a prior malignancy, tumorlets may mimic pulmonary metastases. 2. Syndromes of ectopic hormone production, including Cushing syndrome, carcinoid syndrome, and acromegaly, have been associated with pulmonary carcinoid tumorlets.
www.chestjournal.org
3. Pulmonary carcinoid tumorlets can rarely be associated with moderate-to-severe airflow obstruction in a syndrome termed DIPNECH. 4. The clinical course of pulmonary carcinoid tumorlets is generally benign, although lymph nodes metastases have on rare occasions been reported.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the US Government.
Suggested Readings Hausman DH, Weimann RB. Pulmonary tumorlet with hilar lymph node metastasis: report of a case. Cancer 1967; 20: 1515–1519 D’Agati VD, Perzin KH. Carcinoid tumorlets of the lung with metastasis to a peribronchial lymph node: report of a case and review of the literature. Cancer 1985; 55:2472–2476 Aguayo SM, Miller YE, Waldron JA Jr, et al. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med 1992; 327:1285–1288 Brown MJ, English J, Muller NL. Bronchiolitis obliterans due to neuroendocrine hyperplasia: high-resolution CT: pathologic correlation. AJR Am J Roentgenol 1997; 168:1561–1562 Pirie FJ, Motala AA, Amod A, et al. Cushing’s syndrome caused by ectopic ACTH secretion from pulmonary tumourlets. S Afr Med J 2001; 91:952–954 Fessler MB, Cool CD, Miller YE, et al. Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells in a patient with acromegaly. Respirology 2004; 9:274 –277 Kosmidis PA. Treatment of carcinoid of the lung. Curr Opin Oncol 2004; 16:146 –149 Darvishian F, Ginsberg MS, Klimstra DS, et al. Carcinoid tumorlets simulate pulmonary metastases in women with breast cancer. Hum Pathol 2006; 37:839 – 844 Aubry M, Thomas CF, Jett JR, et al. Significance of multiple carcinoid tumors and tumorlets in surgical lung specimens analysis of 28 patients. Chest 2007; 131:1635–1643
CHEST / 136 / 3 / SEPTEMBER, 2009
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on October 11, 2009 © 2009 American College of Chest Physicians
941
Postgraduate Education Corner PULMONARY AND CRITICAL CARE PEARLS
Multiple Pulmonary Nodules in a 70-Year-Old Female With a History of Breast Cancer Sharon Lynn Gambino, DO; Christopher S. King, MD; and Christopher J. Lettieri, MD, FCCP
(CHEST 2009; 136:938 –941)
70-year-old woman was referred to the pulmoA nary clinic for the evaluation of multiple pulmo-
nary nodules that had been noted on a routine surveillance CT scan performed after a diagnosis of breast cancer. On presentation to the pulmonary clinic, she denied symptoms, including dyspnea, hemoptysis, weight loss, fevers, chills, or night sweats. She did report a dry, nonproductive cough of several months duration. The patient’s medical history was significant for stage 1 (T1bN0M0) infiltrating breast carcinoma that had been diagnosed approximately 1 year prior to the current presentation. Treatment had consisted of a lumpectomy, and negative surgical margins were achieved. The patient declined radiation therapy and was given therapy with anastrazole. The patient also reported a history of hypertension, hyperlipidemia, peripheral vascular disease, and collagenous colitis. Prior surgeries included the recent lumpectomy, an appendectomy, carotid endarterectomy, and a total abdominal hysterectomy. Her medications included mesalamine, simvastatin, lisinopril, atenolol, clopidogrel, and anastrazole. The patient had no notable travel history. She had a 15-pack-year smoking history, but had quit 13 years prior.
distress. Cardiac, abdominal, and lung examinations revealed no abnormalities. She had no clubbing or edema. No skin rash was noted. There was no evidence of synovitis. Laboratory, Radiographic, and Bronchoscopy Findings A CT scan was performed for routine cancer screening 1 year after the initial diagnosis. It revealed numerous, noncalcified, lower lobe-predominant nodules bilaterally, which were increased in size and number when compared with a CT scan from 2 years earlier (Fig 1). No lymphadenopathy was noted. The patient had known pulmonary nodules at the time of diagnosis of her breast cancer, which were stable radiographically for 2 years. During her initial pulmonary evaluation, the CT scan results were discussed and the patient declined further evaluation or intervention. However, the patient did agree to repeat imaging for surveillance. The results of the initial laboratory tests at
Physical Examination The patient’s vitals signs were within normal limits. The patient was a thin, elderly woman in no acute Manuscript received December 19, 2008; revision accepted March 21, 2009. Affiliations: From the Departments of Internal Medicine (Dr. Gambino), and Pulmonary and Critical Care Medicine (Drs. King and Lettieri), Walter Reed Army Medical Center, Washington, DC. © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). Correspondence to: Sharon Lynn Gambino, DO, Walter Reed Army Medical Center, Internal Medicine, 6900 Georgia Ave NW, Washington, DC 20307; e-mail: [email protected] DOI: 10.1378/chest.08-2994 938
Figure 1. Chest CT scan showing multiple, small parenchymal nodules predominantly located in the lower lobes. Postgraduate Education Corner
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on October 11, 2009 © 2009 American College of Chest Physicians
Figure 2. Chest CT scan obtained 6 months after that in Figure 1, showing a further increase in the size and number of the pulmonary nodules.
this time, which included CBC count, chemistry panel, and liver function, were normal.
Figure 3. Open lung biopsy specimen (hematoxylin-eosin, original ⫻40).
What is the likely diagnosis?
Clinical Course A repeat CT scan was performed 6 months later (Fig 2). This CT scan revealed a further increase in the size and number of multiple, bilateral, lower lobe-predominant nodules without lymphadenopathy. A routine laboratory evaluation was repeated, and the results remained normal. A bronchoscopy was performed for further evaluation, including BAL and transbronchial biopsies. No endobronchial lesions were noted. The findings of BAL fluid acid-fast bacilli testing and fungal smears and cultures were negative. Transbronchial biopsy specimens revealed only chronic inflammation. The patient was then referred for surgical lung biopsy. The lung biopsy specimen is shown in Figure 3.
www.chestjournal.org
CHEST / 136 / 3 / SEPTEMBER, 2009
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on October 11, 2009 © 2009 American College of Chest Physicians
939
Answer: Multiple pulmonary carcinoid tumors and tumorlets
Discussion Pulmonary carcinoid tumors and tumorlets are nodular proliferations of neuroendocrine cells. Tumorlets are defined as nodules ⬍ 5 mm, while carcinoid tumors are ⬎ 5 mm. This distinction is somewhat arbitrary, as carcinoid tumors and tumorlets share similar histologic and immunohistochemical features. Carcinoid tumors and tumorlets often coexist, although it is unknown whether carcinoid tumorlets evolve into tumors. Our understanding of the clinical significance of carcinoid tumors and tumorlets has evolved over time. Early reports described tumorlets as a purely reactive phenomenon of no consequence that was associated with chronic lung diseases, including bronchiectasis, pulmonary fibrosis, granulomatous inflammation, and giant cell pneumonia, although tumorlets have been documented in otherwise normal pulmonary parenchyma. While generally described as benign, tumorlets also have the potential for lymph node metastases. Additionally, potential associations with airflow obstruction and ectopic hormone production have been recognized. Similar to our patient, the scenario in which a diagnosis of pulmonary carcinoid tumorlets is most commonly made is following surgical lung biopsy performed for the concern of pulmonary metastases, often in older women with a history of breast cancer. The prevalence of pulmonary carcinoid tumorlets is not well defined, but appears to be a rare occurrence, affecting ⬍ 0.5% of the population.
Figure 4. Open lung biopsy specimen (synaptophysin, original ⫻10). 940
Figure 5. Open lung biopsy specimen (chromogranin, original ⫻20).
Pulmonary carcinoid tumorlets are often asymptomatic, although about one-half of patients will report a cough. A syndrome consisting of symptomatic airflow obstruction and diffuse hyperplasia of pulmonary neuroendocrine cells has been described, termed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Histopathologically, the term DIPNECH specifically describes the proliferation of neuroendocrine cells superficial to the basement membrane and confined to the bronchial and bronchiolar epithelium. When there is extension beyond the basement membrane, the neuroendocrine proliferations are called tumorlets. The term DIPNECH has been used loosely in the literature for the syndrome described above, which has been reported in association with both neuroendocrine proliferation and carcinoid tumorlets. Spirometry is normal in the majority of patients with pulmonary carcinoid tumorlets; however, patients can have moderate-to-severe airflow obstruction. Cushing syndrome, acromegaly, and carcinoid syndrome may occur, usually in the setting of a dominant carcinoid nodule, although these syndromes may also be associated with carcinoid tumorlets. Radiographically, pulmonary carcinoid tumorlets are nonspecific, small nodules that are generally multiple and often bilateral. The nodules are more commonly smooth and spherical, although they may have irregular, poorly circumscribed edges. The small size of these lesions precludes effective bronchoscopic or transthoracic needle biopsy, so when concern for metastatic disease arises surgical lung biopsy is required. On immunohistochemical staining, carcinoid tumors and tumorlets stain strongly positive for chromogranin and synaptophysin, facilitating diagnosis; however, the features may be somewhat indistinct without special staining to recognize them. Postgraduate Education Corner
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on October 11, 2009 © 2009 American College of Chest Physicians
Pulmonary carcinoid tumorlets are generally regarded as a benign condition with an excellent prognosis. In the absence of symptoms, diffuse carcinoid tumorlets require no specific treatment. Close observation with serial imaging and attention focused on change in a particular nodule is a reasonable strategy. In cases of a dominant, peripherally located, parenchymal carcinoid tumor associated with carcinoid tumorlets, local resection is indicated. Treatment with chemotherapy, somatostatin analogues, or interferon can be considered in patients with syndromes of ectopic hormone production or multiple carcinoid tumors. Data from randomized controlled trials documenting the efficacy of these therapies is lacking. The patient’s lung biopsy specimen stained strongly positive for the neuropeptides synaptophysin and chromogranin, as shown in Figures 4 and 5, respectively, suggesting a neuroendocrine tumor. The results of the immunohistochemical staining and the histologic appearance were consistent with a diagnosis of carcinoid tumors and tumorlets. An octreotide scan revealed no uptake outside of the lung or within the lung lesions, although this may have been due to their small size. The measurement of a 24-h urine 5-hydroxyindoleacetate level was normal. The patient was referred to the oncology service, which elected to treat her with octreotide given the diffuse nature of her disease. She continues to do well with minimal symptoms and stable imaging findings. Clinical Pearls 1. Pulmonary carcinoid tumorlets should be considered in the differential diagnosis of multiple bilateral nodules. In patients with a prior malignancy, tumorlets may mimic pulmonary metastases. 2. Syndromes of ectopic hormone production, including Cushing syndrome, carcinoid syndrome, and acromegaly, have been associated with pulmonary carcinoid tumorlets.
www.chestjournal.org
3. Pulmonary carcinoid tumorlets can rarely be associated with moderate-to-severe airflow obstruction in a syndrome termed DIPNECH. 4. The clinical course of pulmonary carcinoid tumorlets is generally benign, although lymph nodes metastases have on rare occasions been reported.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the US Government.
Suggested Readings Hausman DH, Weimann RB. Pulmonary tumorlet with hilar lymph node metastasis: report of a case. Cancer 1967; 20: 1515–1519 D’Agati VD, Perzin KH. Carcinoid tumorlets of the lung with metastasis to a peribronchial lymph node: report of a case and review of the literature. Cancer 1985; 55:2472–2476 Aguayo SM, Miller YE, Waldron JA Jr, et al. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med 1992; 327:1285–1288 Brown MJ, English J, Muller NL. Bronchiolitis obliterans due to neuroendocrine hyperplasia: high-resolution CT: pathologic correlation. AJR Am J Roentgenol 1997; 168:1561–1562 Pirie FJ, Motala AA, Amod A, et al. Cushing’s syndrome caused by ectopic ACTH secretion from pulmonary tumourlets. S Afr Med J 2001; 91:952–954 Fessler MB, Cool CD, Miller YE, et al. Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells in a patient with acromegaly. Respirology 2004; 9:274 –277 Kosmidis PA. Treatment of carcinoid of the lung. Curr Opin Oncol 2004; 16:146 –149 Darvishian F, Ginsberg MS, Klimstra DS, et al. Carcinoid tumorlets simulate pulmonary metastases in women with breast cancer. Hum Pathol 2006; 37:839 – 844 Aubry M, Thomas CF, Jett JR, et al. Significance of multiple carcinoid tumors and tumorlets in surgical lung specimens analysis of 28 patients. Chest 2007; 131:1635–1643
CHEST / 136 / 3 / SEPTEMBER, 2009
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on October 11, 2009 © 2009 American College of Chest Physicians
941