A 67-year-old African American woman was evaluated for abnormal computed tomography (CT) scan of the chest in February 2013 after finding incidental pulmonary nodules in an abdominal CT. The patient denied any respiratory or constitutional symptoms or use of illicit drugs. She was a chronic active smoker with a 40 pack-year history. There was no family or personal history of cancer or occupational exposure to toxins. Physical examination was entirely normal.
Chest CT on February 2013 showed focal right perihilar consolidation suspicious for malignancy (Fig. 1A). Flexible fiberoptic bronchoscopy revealed an endobronchial lesion at the orifice of the right middle lobe (Fig. 2A). Histopathology of endobronchial biopsies revealed a carcinoid tumor. Immunostains were positive for synapthophysin and chromogranin (Fig. 3).
In May 2013, the patient finally agreed for lobectomy of the right middle lobe; a preoperative bronchoscopy showed decrease in the size of the endobronchial lesion. Spontaneous regression (SR) of the tumor was suspected and the procedure was cancelled.
The patient underwent serial follow-up bronchoscopies (Table 1); she was able to quit smoking, and she remains asymptomatic. There have been no changes in medications, no new vaccinations, no over-the-counter medication use, and no dietary changes elicited during follow-up. Repeated chest CT scans performed on May and November 2013 and November 2014 remain stable with no new findings (Figs. 1B–D).
Spontaneous regression of cancers (SRC) was described by Drs Everson and Cole in their classic editorial in Journal of the American Medical Association 1959.1 They defined SRC as the partial or complete disappearance of a malignant tumor in the absence of treatment or in the presence of therapy, which is considered inadequate to exert a significant influence on the growth of neoplastic disease. History of SRC is detailed in Table 2.
SRC is rare in thoracic malignancies; a review of SRC in thoracic cancers found 5 of 76 (6.5%) cases of true primary thoracic malignancy.5 Neuroendocrine tumors with SRC have been described in the gastric and pelvic carcinoid, with only 1 case of carcinoid of the lung reported in the English literature, and this was associated with pregnancy.6 The cases of SRC have generally been confirmed by serial imaging and/or bronchoscopy and rarely at autopsy. Our patient had carcinoid tumor of the lung followed up over a 2-year period, which showed both bronchoscopic and pathologic resolution of the tumor.
The main hypothesis for SRC is some form of immunomodulation. Causes for B-cell or T-cell modulation include infection and hormonal and paraneoplastic syndromes. In the prechemotherapy era, some cases were associated with infections, which led to the development of vaccines to promote immunity. The best known of these “Coleys toxins” were used in patients with sarcomas, melanomas, lymphomas, and carcinomas.7 The immunotherapy of cancer has made significant strides due to improved understanding of the underlying principles of tumor biology and immunology. Immunotherapy research has focused on the discovery of tumor antigens (TAs) that could confer specificity to immune cells that detect and destroy cancer cells. The first successful identification of TAs recognized by T cells occurred in 1991, with identification of multiple TAs in a variety of solid tumors.3 Of a variety of TAs, immunologic checkpoint blockade with antibodies that target cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) has demonstrated promise in a variety of malignancies. PD-1 receptor is an inhibitory T-cell receptor that is engaged by its 2 known ligands, PD-L1 and PD-L2, which play a pivotal role in the ability of tumor cells to evade the host’s immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function. In a report on neuroendorine carcinoma cancer, 18.5% showed PD-L1 expression in tumor-infiltrating macrophages and 48% showed PD-1-positive lymphocytes.8 It is possible that host response to infection may exhibit cross-reactivity to TAs resulting in SRC. We wonder whether antibodies blocking PD-1 and/or PD-L1 are seen in patients with SRC.
Immunological stimulation by trauma with the use of Nd-YAG laser irradiation, ethanol injection, transbronchial lung biopsy, and surgery has been associated with SRC.9–11 Smith12 reported SRC of the lung with incomplete surgical resection, and surgical trauma was described as the potential cause in 71 of 176 cases of SRC described by Cole.9 Bronchoscopy contributing to SR of lung cancers has been described as well.13
Hirano et al14 reported an association of paraneoplastic syndrome with SR of small cell cancer; 3 of 8 cases had paraneoplastic sensory neuropathy. Anti-Hu, anti-Yo, and anti-Ri antibodies can be found in patient with paraneoplastic sensory neuropathy, and they exhibit cross-reactivity to both tumor and nervous tissue.14
This is the first report of SRC of a carcinoid tumor followed up during a 2-year period with serial bronchoscopy and biopsies until complete resolution was demonstrated. Although SRC remains an enigmatic event for patients and treating physicians, caution is advised when discussing this phenomenon. To quote the immortal words of Everson and Cole: “the remote possibility of SRC may be of some psychotherapeutic value in offering hope to patients and relatives of patients with “incurable cancer.” The simple thought that regression of a cancer might be possible will change the patient’s attitude from that of complete despair to that of hopeful toleration. The professionals should use knowledge of this phenomenon in an endeavor to comfort the patient and relatives in the trying days of terminal cancer. With proper precaution the physician can do this without being guilty of offering “false hopes.” Close monitoring of the tumor with serial imaging and ideally pathologic confirmation is mandated if this pathway is chosen.
1. Everson TC, Cole WH. Spontaneous regression
of malignant disease. J Am Med Assoc. 1959;169:1758–1759.
2. Grange JM, Stanford JL, Stanford CA. Campbell De Morgan’s ‘Observations on cancer’, and their relevance today. J R Soc Med. 2002;95:296–299.
3. Boon T, Cerottini JC, Van den Eynde B, et al. Tumor
antigens recognized by T lymphocytes. Annu Rev Immunol. 1994;12:337–365.
4. Challis GB, Stam HJ. “The spontaneous regression
of cancer. A review of cases from 1900 to 1987”. Acta Oncol (Madr). 1990;29:545–550.
5. Kumar T, Patel N, Talwar A. Spontaneous regression
of thoracic malignancies. Respir Med. 2010;104:1543–1550.
6. Luosto R, Koikkalainen K, Sipponen P. Spontaneous regression
of a bronchial carcinoid
tumour following pregnancy. Ann Chir Gynaecol Fenn. 1974;63:342–345.
7. Nauts HC, Fowler GA, Bogatko FH. A review of the influence of bacterial infection and of bacterial products (Coley’s toxins) on malignant tumors in man. Acta Med Scand Suppl. 1953;276:1–103.
8. Schultheis AM, Scheel AH, Ozretić L, et al. PD-L1 expression in small cell neuroendocrine
carcinomas. Eur J Cancer. 2015;51:421–426.
9. Cole WH. Efforts to explain spontaneous regression
of cancer. J Surg Oncol. 1981;17:201–209.
10. Cole WH. Relationship of causative factors in spontaneous regression
of cancer to immunologic factors possible effective in cancer. J Surg Oncol. 1976;8:391–411.
11. Saito Y, Shiba M, Yamakawa H, et al. A case of spontaneous regression
of lung cancer with skin metastasis. Nihon Kyobu Shikkan Gakkai Zasshi. 1991;29:95–100.
12. Smith RA. Cure of lung cancer from incomplete surgical resection. Br Med J. 1971;2:563–565.
13. Nomura M, Fujimura M, Matsuda T. Spontaneous regression
of small cell lung cancer. Nihon Kyobu Shikkan Gakkai Zasshi. 1994;32:324–327.
14. Hirano S, Nakajima Y, Morino E, et al. A case of spontaneous regression
of small cell lung cancer with progression of paraneoplastic sensory neuropathy. Lung Cancer. 2007;58:291–295.