- Neuroendocrine neoplasms of Lung. Curr Diag Pathol 1997 ;4:239-250.

- Histological Typing of Lung and Pleural Tumors. Berlin: Springer, 1999:

- On the origin of the so-called tumorlets of the lung. Hum Pathol 1976; 7:461-9.

- The histogenesis and development of pulmonary tumorlets. Cancer 1977; 39:1135-45.

- Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC, 2004:

Background The clinical significance of multiple carcinoid tumorlets in surgical lung specimens has not been systematically analyzed. We reviewed our experience to determine the range of clinical circumstances associated with this finding. Methods We reviewed clinical records, available imaging, and pathology materials from patients evaluated at Mayo Clinic Rochester (1987-2000) with 2 or more carcinoid tumors or tumorlets in lung specimens. Results Twenty-eight of 294 patients with diagnoses of carcinoid tumor or tumorlet had >/= 2 lesions. Twenty-six (93%) were women; mean age was 65 years. Patients fell into three groups: multiple nodules (17), solitary lung nodules on pre-operative imaging (7), and airflow limitation (4). Approximately half of patients with multiple nodules had respiratory complaints; two had Cushing syndrome. Ten (58.8%) were suspected of having pulmonary metastases, including seven with previously diagnosed malignancies. Intrathoracic lymph node metastases were present in three patients, none of whom experienced recurrent disease. One patient had a carcinoid tumor resected 8 years later. Another developed extrathoracic metastases three years after presentation and was alive with disease two years later. Only one patient with airflow limitation had a syndrome resembling diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Conclusions Our series represents the largest compilation of multiple carcinoid tumors or tumorlets. Our analysis reveals that multiple carcinoid tumors or tumorlets occur most commonly in patients with multiple nodules resembling metastatic disease. Significant airflow limitation is rare. Long term survival is excellent although patients experience persistent disease.

Carcinoid tumorlets simulate pulmonary metastases in women with breast cancer. Hum Pathol. 2006 Jul;37(7):839-44. Epub 2006 May 19.

A pulmonary carcinoid tumorlet (PCT) is a nodular proliferation of neuroendocrine cells smaller than 0.5 cm. On computed tomographic (CT) imaging, these nodules are nonspecific in appearance and can mimic metastatic disease. Cases of multiple PCTs diagnosed between 1992 and 2003 in patients with history of breast cancer were identified through a search of the pathology files. The clinical information was abstracted from the medical records. We identified 12 women with a history of breast cancer and biopsy-proven PCTs, who were treated at our institution in a period of 12 years. Only 3 women were smokers. The mean age at diagnosis of the breast cancer was 62.8 years. The breast cancer was invasive carcinoma in 10 cases (9 ductal and 1 lobular) and ductal carcinoma in situ and malignant phyllodes tumor in 1 case each. Six women received radiotherapy; 5, chemotherapy; and 4, hormonal treatment, alone or in combination. Pulmonary carcinoid tumorlets were identified within 5 months from diagnosis of the breast malignancy in 7 patients and at follow-up (range, 57-162 months) in the remaining 5. In all cases, the PCTs consisted of multiple pulmonary nodules that were radiologically interpreted as suspicious for pulmonary metastases. Misdiagnosis of metastatic carcinoma was rendered intraoperatively by frozen section analysis in 3 cases. None of the patients had known metastatic disease at the time of diagnosis of PCTs. Three patients subsequently developed recurrent disease, including 2 with extramammary spread. Pulmonary carcinoid tumorlets are radiologic and histologic mimickers of pulmonary metastases in patients with a history of breast cancer. Consideration should be given to the possibility of PCTs in patients with breast cancer with pulmonary nodules, even if multiple.

Pulmonary tumorlets: CT findings.AJR Am J Roentgenol. 2004 Aug;183(2): 293-6.

OBJECTIVE: Pulmonary tumorlets are defined in pathologic terms as benign localized neuroendocrine cell proliferations a few millimeters in size that are usually associated with damaged and ectatic small airways. The purpose of this study was to determine the frequency with which pulmonary tumorlets can be seen on CT and to describe their CT appearance. CONCLUSION: In 33 patients with proven tumorlets, a nodule was visible on CT in the same region as that of the resected specimen. Despite its ominous-sounding name, a pulmonary tumorlet represents benign tissue that may manifest as a subcentimeter pulmonary nodule and should be considered in the differential diagnosis of small pulmonary nodules visible on CT.

Pulmonary "tumorlet" as a neoplastic condition? Cesk Patol. 2001 Nov;37(4):182-4.

A 66-year-old woman, non-smoker, with a diffuse bilateral pulmonary interstitial involvement caused by multiple carcinoid tumorlets associated with a diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). The process has developed during the last two years of the patient's life. There were no pathologic changes in the remnant pulmonary parenchyma. Moreover, the minute typical carcinoid (5.2 mm) was encountered after extensive pulmonary tissue examination. The spectrum of DIPNECH, multiple tumorlets, and typical carcinoid tumor demonstrates a possible neoplastic character of the pulmonary tumorlet.

A case of lung tumorlets with pulmonary carcinoid.Kyobu Geka. 2000 Oct;53(11):969-71.

It has been postulated that differential pathological diagnosis of lung tumorlet from pulmonary carcinoid is very important to decide the therapeutic strategy, because both of them are pathologically consisted of similar type of cells originated from same cells. At the present, although lung tumorlet is considered to be a hyperplastic lesion of Kultschitzky cells which is located in the epithelial cell of the bronchial mucosa by stimuli such as hypoxia and inflammation, but it occasionally recognized in the normal lung and the concept that it is a subtype of carcnoid is also undeniable. In this paper, a case of lung tumorlet with minute pulmonary carcinoid suggesting a subtype of carcinoid operated upon in our department is presented. Although simple pulmonary resection is a method of choice for pulmonary carcinoid, but it is still controversial as to therapeutic strategy for the lung tumorlet, because it is a benign entity and not tumorous lesion. However pulmonary resection with a close subsequent followed-up study must be a best method of choice for the case with lung tumorlet includes a minute lesion of carcinoid seen in this particular case.

High cellular atypia in a pulmonary tumorlet. Report of a case with cytologic findings. Acta Cytol. 2000 Mar-Apr;44(2):242-6.

BACKGROUND: Pulmonary tumorlets are localized lesions of neuroendocrine cell proliferation, usually found in association with chronic pulmonary inflammation. Since they are mostly incidental histologic or radiologic discoveries, they have received little attention, and there have been no reports on their detailed cytology. We describe for the first time the cytologic features of a pulmonary tumorlet and discuss its differential diagnosis. CASE: An abnormal nodule in the right lung field was discovered on a regular checkup by chest roentgenogram in a 70-year-old, nonsmoking female. Intraoperative aspiration cytology demonstrated cohesive, spindle-shaped cells arranged in fascicles or singly. Since these cells showed nuclear atypia, such as hyperchromasia, a coarsely granular chromatin pattern and nuclear grooving, a nonepithelial malignant lesion was suspected and upper lobectomy performed. The final diagnosis was a pulmonary tumorlet on the basis of histologic examination of the resected material. CONCLUSION: This is the first cytologic report of a pulmonary tumorlet. In this case, differential diagnosis was made of a tumor consisting predominantly of spindle-shaped cells. Although cytologic findings included nuclear atypia, the lesion was not malignant.

11q13 allelic imbalance discriminates pulmonary carcinoids from tumorlets. A microdissection-based genotyping approach useful in clinical practice.Am J Pathol. 1999 Aug;155(2):633-40.

Pulmonary tumorlets are minute neuroendocrine cell proliferations believed to be precursor lesions to pulmonary carcinoids. Little is known of their molecular pathogenesis because of their small size. Using tissue microdissection, we evaluated 11q13 region allelic imbalance in the pathogenesis of pulmonary tumorlet/carcinoid lesions. The int-2 gene was selected because of its chromosomal location at 11q13 in close proximity to MEN1, a tumor suppressor gene frequently mutated in familial forms of neuroendocrine cancer. Three cohorts of patients were studied: subjects with typical carcinoid tumors and coexisting tumorlets (n = 5), typical carcinoids without tumorlets (n = 6), and tumorlets alone without carcinoid lesions (n = 5). A total of 11 carcinoids and 11 tumorlets were microdissected from 4-micrometer-thick histological sections. Genotyping was designed to detect allelic imbalance of the int-2 gene and involved DNA sequencing of two closely spaced deoxynucleotide polymorphisms. Subjects shown to be informative were evaluated for allelic imbalance in tumorlet/carcinoid tissue. Eight of 11 (73%) carcinoids manifested allelic, in contrast to only one of 11 (9%) of tumorlets. Int-2 allelic imbalance was significantly associated with carcinoid tumor formation (P < 0.01). In patients having both carcinoid tumors and tumorlets, the latter showed allelic balance and were thus discordant in genotype with coexisting carcinoid excluding pathogenesis of tumorlets from intramucosal spread from carcinoid tumors. Int-2 allelic imbalance was shown to be an early event in carcinoid tumor formation by virtue of the absence of allelic imbalance for other common cancer-related gene disturbances involving 11p13 (Wilms' tumor), 3p25 (von-Hippel-Lindau), and 17p13 (p53). Demonstration of 11q13 allelic imbalance by microdissection/genotyping may be a useful discriminatory marker for pulmonary neuroendocrine neoplasia.

A pulmonary tumorlet with caseous granuloma associated with atypical mycobacterium. Nihon Kokyuki Gakkai Zasshi. 1998 May;36(5):464-8.

We encountered a case of pulmonary tumorlet with caseous granuloma associated with atypical mycobacterium. A 73-year-old woman was admitted to the hospital because a chest x-ray film showed enlargement of an abnormal shadow in the middle lobe of the right lung. Primary lung cancer was suspected and right middle lobectomy was performed. Acid-fast bacilli (Gaffky 1) were found in a caseous lesion and examination of intraoperatively obtained frozen specimens showed caseous granulomas. The bacilli were later identified as Mycobacterium avium complex. The permanent specimen showed a minute lesion consisting of small clusters of epithelial cells resembling carcinoid tumor in contact with granulomatous tissue. Histopathological examination revealed argyrophilia on Grimelius stain and immunoreactivity to chromogranin-A in the clusters of epithelial cells. Although these results are consistent with small cell carcinoma or peripheral carcinoid tumor, pulmonary tumorlet was diagnosed because of the lesion's small and minimal cytologic atypia, and because of chronic pulmonary damage around the lesion. Pulmonary tumorlets are minute, usually microscopic, tumor-like lesions mostly found in damaged lung tissue obtained at autopsy or during surgery. Morphological diagnosis is sometimes very difficult, but recently these lesions have been regarded as hyperplastic lesions arising in pulmonary neuroendocrine cells (Kultschitzky cells) and caused by chronic pulmonary damage, such as hypoxia and inflammation. Pulmonary tumorlets must be considered in the differential diagnosis of minute lesions suspected to be small cell carcinoma or peripheral carcinoid tumor.

Pulmonary tumorlet. Report of 5 cases.Arch Bronconeumol. 1996 Nov;32(9): 489-91.

Lung tumorlets are small collections of neuroendocrine cells derived from Kulchitsky cells of the bronchial epithelium. Such cells are usually found by chance, are considered benign and rarely metastasize. We describe 5 cases of tumorlets diagnosed by chance in patients with prior lung disease requiring histology. Even though the behavior of tumorlets is benign, patients in whom they have been found should receive follow-up X-rays, as lymphatic metastasis in the region has occasionally been described.

Satellite cells in pulmonary carcinoid tumorlets and carcinoids. Cesk Patol. 1996 Aug;32(3):97-100.

Pulmonary tissue of twenty-four patients with carcinoid tumorlets and twenty-three typical carcinoid tumors was studied immuno- histochemically for stellate-shaped S-100 protein positive (sustentacular) cells. Sustentacular cells (SCs) have been calculated per 10,000 tumorlet or carcinoid elements. The presence of SCs was proved in 18 subjects (75%) of all examined tumorlet cases with quantitative frequency between 13 and 196 SCs per 10,000 tumorlet cells. These elements were also found in 18 carcinoid tumors (79%) of all 23 investigated cases with quantitative frequency between 5 and 927 SCs per 10,000 carcinoid cells. The cluster analysis showed two separate clusters in both groups of lesions with strikingly high frequency of SCs, i.e., from 66 up to 196 SCs/10,000 tumorlet elements and from 138 up to 923 CSs/10.000 carcinoid cells, respectively. SCs may not be used as an indicator of biological behaviour of pulmonary neuroendocrine tumors for their a broad frequency spectrum in examined benign lesions, i.e. tumorlets and typical carcinoid tumors.

S-100 protein positive (sustentacular) cells in pulmonary carcinoid tumorlets: a quantitative study of 24 cases.Pathol Res Pract. 1996 May;192(5):414-7.

Stellate-shaped S-100 protein positive sustentacular cells (SCs) appear to correlate inversely with the degree of tumor malignancy in some neuroendocrine tumors. Therefore, the SCs have been investigated in carcinoid pulmonary tumorlets and subsequently examined quantitatively in order to provide a basis for estimation of this phenomenon in tumorlet related lesions, especially carcinoids and neuroendocrine carcinomas. Pulmonary tissue from twenty-four patients with carcinoid tumorlets was studied immunohistochemically for S-100 protein positive SCs together with glial fibrillary acidic protein, actin, desmin, vimentin and cytokeratins. Tumorlet SCs were calculated per 10,000 tumorlet elements. The presence of SCs was proven in 18 subjects (75%) of all examined cases with quantitative frequency between 13 and 196 SCs per 10,000 tumorlet elements. The histogram showed three separate clusters of cases. Cluster 2 and cluster 3 with strikingly high frequency of SCs, i.e. from 66 up to 196 SCs per 10,000 tumorlet cells, may represent the biphasic differentiation potential of tumorlet elements. The mentioned lesions could be regarded as the possible precursors of pulmonary paragangliomas or paraganglioid carcinoids.

Pulmonary carcinoid tumor--tumorlet type: a case report.Zhonghua Yi Xue Za Zhi (Taipei). 1995 Apr;55(4):339-42.

A rare case of bronchiectasis with carcinoid tumor, tumorlet type, is reported. The patient was a 53-year-old female who underwent lobectomy of the right middle and lower lobes for severe hemorrhage secondary to bronchiectasis. No tumor was seen on chest X-ray or by gross examination of the lung. Microscopically, there were multiple tumorlets in the pulmonary parenchyma surrounding the bronchiole and small bronchus. The tumor cells stained positive for neuron-specific enolase, keratin and chromogranin stain. The morphology, and staining properties suggested that the pulmonary tumorlets were carcinoid tumor. No tumor cells were identified in the four peribronchial lymph nodes. The patient is disease-free after four years of follow-up.

A case of pulmonary tumorlet with tuberculoma misdiagnosed as small cell lung carcinoma by transbronchial lung biopsy.Kyobu Geka. 1995 Feb;48(2):165-8.

A 59-year-old woman was picked up by chest X-ray findings. Her CT scan film showed a tumor shadow in the upper lobe of the left lung, and by transbronchial lung biopsy, she was diagnosed as a small cell lung carcinoma. Lobectomy was performed, but the lesion was diagnosed as tuberculoma by frozen section. Furthermore, on postoperative histological examination, a minute lesion of tumorlet, which was histologically identical to that preoperatively detected by transbronchial lung biopsy was found in the adjacent tissues of the tuberculoma. Pulmonary tumorlet is clinically a rare lesion, but the diagnosis and treatment for small-sized tumor or tumor-like lesion may be carefully done, taking into account the existence or co-existence of tumorlet lesion.

Carcinoid tumor of the lung: clinicopathological and immuno-histochemical studies. Eur J Surg Oncol. 1992 Apr;18(2):180-7.

Carcinoid tumors of the lung in 10 patients were treated surgically and both the clinicopathological manifestations and immunohistochemistry were examined in detail. Five were central carcinoid tumors, located in the main, lobar or segmental bronchus and five were peripheral carcinoid tumors, located in the subsegmental bronchus or beyond. Histologically, eight of the tumors were typical carcinoid tumors, one was an atypical carcinoid tumor, and one a carcinoid tumorlet. Three growth types were also established: polypoid type, iceberg type and intrapulmonary type. The central carcinoid tumors belonged either to the polypoid type or iceberg type, while the peripheral carcinoid tumors were of the intrapulmonary type. Both the iceberg and intrapulmonary types may invade the peribronchial or parenchymal tissues more frequently than does the polypoid type. Immunohistochemically, argyrophilia and neuron-specific enolase (NSE) were detected in all the tumors examined and six stained for polypeptide hormones such as adrenocorticotropic hormone (ACTH) and/or pancreatic polypeptide (PP). Of these, five had epithelial markers such as keratin, epithelial membrane antigen (EMA) and/or carcino-embryonic antigen (CEA). These findings suggest that a carcinoid tumor of the lung originates from primitive multipotential stem cells such as those of a neuroendocrine or epithelial nature.

Tumorlets of the lung--an ultrastructural study.Ultrastruct Pathol. 1991 Mar-Apr;15(2):189-95.

A tumorlet of the lung is a minute tumorlike lesion found in damaged lungs in close association with the bronchioles. Histochemical and ultrastructural studies identify proliferating cells in the tumorlets as Kultschitzky-type cells. However, the pathological significance of the tumorlets, whether they are hyperplastic or neoplastic, is still controversial. Previous ultrastructural studies on the tumorlets have been carried out on formalin-fixed lung tissues. The case examined in this study was of typical tumorlets found in a so-called middle lobe syndrome of the lung of a 52-year-old woman. Tumorlets were located within the bronchiolar mucosa surrounded directly by a basal lamina and by the bronchiolar nonendocrine epithelial cells. There were no signs of invasion into the surrounding connective tissues or into lymphaticlike spaces. Between the covering bronchiolar epithelial cells and the subjacent proliferating Kultschitzky cells, specific sites of cell-to-cell attachment were noted. This finding, in addition to previously reported clinicopathological characteristics, indicates that the proliferating Kultschitzky-type cells in the tumorlets might be non-neoplastic and that tumorlets are due to hyperplasia of pure Kultschitzky-type cells, thus resembling neuroepithelial bodies of the lung.

The tumorlet carcinoid in bronchiectasis-changed lungs. An example of a multifocal, endocrine tumor.Pneumologie. 1990 Feb;44 Suppl 1:607-9.

Tumorlets of the lungs are multifocal hyperplasias of endocrine cells which may develop via nodular hyperplasia into peripheral, occasionally also metastatic, carcinoids. They are observed with a particular frequency in bronchiectasis. Resected material obtained from patients with bronchiectasis (4 women, 3 men, mean age 43.5 years, range 19-66 years) were submitted to conventional histological studies employing HE, PAS and van Gieson staining, and also to an immunohistological analysis. Conventional staining sufficed to identify endocrine cell proliferations in the scarred lung tissue in 3 preparations. An assignment to bronchioles and alveoli with conventional histology was, in view of the extensive scarring of the lung parenchyma, very difficult, but was accomplished with the aid of immunohistological investigation. As a multifocal tumour, the tumourlet suggests itself as a model, employing immunohistochemistry, for studying the formal genesis of neuroendocrine tumours of the lung, since it shows the earliest intra-epithelial neoplastic transformations through in situ tumour to carcinoid.

Diffuse panbronchiolitis with multiple tumorlets. A quantitative study of the Kultschitzky cells and the clusters.Acta Pathol Jpn. 1985 Sep;35(5):1221-31.

An autopsy case of diffuse panbronchiolitis with incidentally observed multiple tumorlets was reported. Quantitative study revealed the distribution and number of single Kultschitzky cell and its cluster. These cells were more frequently observed in the present case than in 20 control cases, and moreover, they tended to occur more frequently in the pulmonary segment in which tumorlets were found and there was an apparent transition of them into tumorlets. Immunohistochemically, gastrin-releasing peptide, calcitonin, and serotonin were demonstrable in the cells which consisted of both tumorlets and Kultschitzky cell clusters. It is suggested that the Kultschitzky cell is a precursor cell of the tumorlet and that tumorlet is benign, being hyperplastic in nature.

Pulmonary tumorlet. A form of peripheral carcinoid. Cancer. 1976 Mar;37(3):1469-77.

Twenty cases of pulmonary tumorlet are presented. Approximately one-third of the tumors occurred in lungs severely scarred by bronchiectasis or other inflammatory processes; the other two-thirds were found in lungs with little to no scarring. In the former instances, tumorlets were found in large scars in which identifying architectural features had been destroyed. In the latter, the tumorlets were seen in minute fibrous nodules, surrounding or obliterating small bronchi or bronchioles. Argyrophilic granules were demonstrated in 14 of 15 cases; in the electron microscope these were consistent with neurosecretory granules. Their location, silver staining properties, and ultrastructure suggest that pulmonary tumorlets are minute peripheral carcinoid tumors.

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