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Carcinoid Tumor of the Larynx
Auris' Nasus' Larynx (Tokyo) 18, 39-53 (1991)
CARCINOID TUMOR OF THE LARYNX Kiminori SATO, M.D., Yuichiro HIGAKI, M.D., Shinji SAKAGUCHI, M.D., Minoru HIRANO, M.D., Akira TANIMURA, M.D.,* and Yasuyuki SASAGURI, M.D.* Department of Otolaryngology-Head and Neck Surgery and *Second Department of Pathology, KlIrlime University School of Medicine, KUr1ll11e, Japan
Carcinoid tumor of the larynx is a rare neoplasm. Two cases of laryngeal carcinoid tumor are reported and the relevant literature is reviewed. One patient was an 82-year-old male who complained of odynophagia. The tumor was located on the left arytenoid and neck metastasis were present when he died 3 years after surgery. The other patient was an 82year-old male who complained of hoarseness. His tumor was located in the left ventricle. Bone metastasis was detected one month after surgery and he died of distant metastasis two months following surgery. A review of the literature showed that carcinoid tumors of the larynx are aggressive and malignant, with distant metastasis being the most common cause of death. This tumor is unresponsive to radiotherapy and chemotherapy, so adequate surgical excision remains the only effective treatment. Carcinoid tumors are most commonly seen in the vermiform appendix, small intestine, and tracheobronchial tree. Carcinoid tumor of the larynx, however, is rare. Since GOLDMAN, HOOD, and SINGLETON (1969) first reported a case of carcinoid tumor of the epiglottis, 33 cases (Table 1) have been reported in the English and Japanese literature. The present paper reports 2 new cases of carcinoid tumor of the larynx and also includes a review of the literature. CASE REPORTS
Case I An 82-year-old male developed pain on swallowing in November 1978. The symptom gradually worsened and was later accompanied by hoarseness and cough. A painless lump on the right side of his neck developed early in June 1983. He Received for publication
March 28, 1990 39
K. SATO et al.
40
visited a private otolaryngological clinic and was referred to the Kurume University Hospital on June 20 of the same year. Typical symptoms like episodic flushing of the skin, diarrhea, or asthma Wfre not observed. He had a history of smoking six or seven cigarettes per day for 50 years. On physical examination, a lobulated tumor covered with normal epithelium was found in the larynx. The tumor was mainly located in the left arytenoid region and involved the left aryepiglottic fold and the interarytenoid region. Both vocal folds were intact and mobile. No retention of saliva was observed in the piriform sinuses. Deep cervical node (20 X 15 mm) was detected on the right side by palpation. The lymphnode was elastically firm and mobile. Laryngograms revealed a lobulated and smooth-surfaced tumor in the left arytenoid region (Fig. 1). Both vocal folds were intact. A CT scan of the larynx revealed a dense mass. Chest roentgenograms were normal. The maximum phonation time was 7.6 s and the mean air flow rate was 234 mIls, indicating a slight degree of glottic incompetence. Hematological parameters were all within the normal range. An unusual type of neoplasm was strongly suspected from the results of investigation. On July 4, we performed surgery. We first attempted to remove the mass endoscopically, but the mass proved too large to be removed via a conventional endolaryngeal procedure so we switched to an external approach. The mass was exposed with a transepiglottic pharyngolaryngotomy (HIRANO and KURITA, 1984). The base of the mass was located mainly in the left arytenoid region, involving the left aryepiglottic fold and inter arytenoid region. The tumor appeared to be highly vascularized and was covered with normal epithelium (Fig. 2a). Palpation
Fig. 1.
Laryngogram showing a tumor on the left arytenoid region (arrow).
CARCINOID TUMOR OF THE LARYNX
41
Fig, 2, Views during surgery, a: After transepiglottic pharyngolaryngotomy , (A) tumor, (B) the right vocal fold, b: After the removal of the tumor. (A) the location of the base of the tumor. (B) the right vocal fold ,
Fig, 3,
Excised tumor is lobulated and covered with epithelium , The scale is graded in mm ,
42
K . SA TO el at.
revealed slight invasion into the adjacent tissue. We extirpated the tumor using a CO 2 laser (Fig. 2b) and only mild bleeding occurred during the operation. The cervical node was also extirpated. The laryngeal tumor was lobulated, dark red in color, and 25 X 23 X 20 mm in size (Fig. 3). Histological examination revealed that both the laryngeal tumor and the cervical lymphnode lesion were carcinoid tumors. The covering mucosa, which was stratified squamous epithelium, was not involved histologically. The cells were small and uniform with round nuclei. Slight nuclear pleomorphism and mitotic figures were apparent, and the cells showed either a solid or trabecular arrangement. The lesion was surrounded by vascular connective tissue (Fig. 4), and intravascular invasion was observed. Numerous normal laryngeal glands
Fig. 4. A histological micrograph of the excised tumor. Tumor cells consist of eosinophilic cytoplasm and small, round nuclei. Tumor nests, surrounded by a vascular connective tissue stroma, are observed (hematoxylin and eosin stain) .
Fig. 5. A histological micrograph showing cytoplasmic argyrophil granules. The granules are abundant as small, dark, round structures in the cytoplasm of each cell (arrow) (Grimelius stain).
CARCINOID TUMOR OF THE LARYNX
43
were recognized at the base of the tumor. Grimelius stain revealed argyrophilic granules in the cytoplasm of the tumor cells (Fig. 5). Fontana-Masson (argentaffin) staining was negative. After establishment of the diagnosis, a thorough examination of the entire body was performed, and no other lesions were detected. Bilateral radical neck dissection was strongly recommended to the patient, but was not accepted. The patient was discharged on August 17 without any clinical evidence of disease. The patient noticed a left neck mass in January 1985, but did not return to our hospital until August 20, 1985. During physical examination a left upper deep cervical node, 50 X 60 mm in size, was found on palpation. This node was hard and firmly fixed to the surrounding tissue. The larynx was free from disease, but the left vocal fold was fixed in the paramedian position and atrophic. No distant metastasis were detected so radical neck dissection was attempted, but the mass was unresectable because it was fixed to the carotid artery. He was discharged from our hospital on September 30 and died of heart failure on July 19, 1986. Cervical Iymphnode metastasis was found, but no recurrence of the primary or any distant metastasis were observed. Case 2 An 82-year-old male developed hoarseness in October 1987. He consulted an otolaryngologist and was referred to the Kurume University Hospital on November 19. Typical symptoms of the carcinoid syndrome were again not
Fig. 6. Fiberscopic investigation reveals a swollen left ventricular fold (arrow). A: arytenoids.
Fig. 7. Laryngogram showing the swollen left ventricular fold (arrow).
44
K. SA TO et al.
present. He had a history of smoking 10 cigarettes per day for 50 years. On physical examination, the left ventricular fold was found to be swollen and covered with normal epithelium (Fig. 6). Both vocal folds were mobile. Palpation revealed upper and middle cervical lymphnodes, 20 X 20 and 25 X 25 mm in size, on the left side. The lymphnodes were elastically firm and mobile. The left ventricular fold was swollen and the ventricle was not depicted on laryngograms (Fig. 7). A CT scan revealed a relatively low density mass in the region of the ventricle (Fig. 8). Chest roentogenograms were normal. The maximum phonation time was 17.2 s and the mean air flow rate was 119 mIls. Hematological values were all within the normal range. Supraglottic carcinoma (ventricular carcinoma) was the working diagnosis. On December 7, 1987, we performed hemilaryngectomy and radical neck dissection on the left side. The postoperative course was good but the patient complained of abdominal pain and tenderness on December 21. Abdominal X-rays revealed free air, suggesting perforation of a duodenal ulcer. Distal partial gastrectomy was performed on December 22.
Fig. 8. CT scan detects a low density mass at the left ventricular fold (arrow).
Fig. 9. Coronal section of the excised hemilarynx. Tumor is located at the ventricle involving the ventricular fold and vocal fold (arrow). VF: ventricular fold, VP: vocal process (hematoxylin and eosin stain).
CARCINOID TUMOR OF THE LARYNX
45
On January 4, 1988, he developed a neck mass that was 15 X 15 mm in size on the right side. A right radical neck dissection was subsequently performed. Histological examination revealed that both the laryngeal tumor and cervical Iymphnode lesions were carcinoid tumors. A tumor was located in the posterior portion of the ventricle and invaded into the paraglottic space (Fig. 9). Tumor cells with eosinophilic cytoplasm and round or ovoid nuclei showed solid, sheetlike, and acinar arrangements. Moderate nuclear pleomorphism and mitotic figures were present. Glands lined with microvilli were observed (Fig. 10). Evidence of cytoplasmic granules could be demonstrated with Grimelius (argyrophil) stain (Fig. 11), but not with Fontana-Masson (argentaffin) stain. Immunohistochemical studies showed negative immunoreactivity for calcitonin and somatostatin.
Fig. 10. A histological micrograph of the excised tumor. Tumor cells consist of eosinophilic cytoplasm and round or ovoid nuclei. Tumor cells show solid and acinar arrangements (hematoxylin and eosin stain).
Fig. 11. A histological micrograph showing cytoplasmic argyrophil granules (arrow). Gland formations with microvillus lining are apparent (m) (Grimelius stain).
46
K, SATO et aI,
On hematological examination, the red cell count was 3,080,000/mm3, the hemoglobin was 9,0 g/dl, and the platelet count was 41,000/mm3, serum, GOT was 119 IU/liter and LDH was 2,359 IU/liter, A bone marrow biopsy showed myelocarcinomatosis, Blood transfusion and chemotherapy were performed, but the patient died on February 11, 1988,
DISCUSSION
Carcinoid tumors most commonly appear as infiltrating neoplasms in the vermiform appendix and small intestine, and have also been known to occur in the tracheobronchial tree, Carcinoid tumors arise from the enterochromaffin cells (Kulchitsky cells) derived from the primitive gut. WILLIAMS and SANDLER (1963) subdivided carcinoid tumors into three groups according to the embryology of the site of origin of the neoplasm: I) those arising from the foregut (bronchi, stomach, biliary tract, and pancreatic ducts); 2) those arising from the midgut (lower duodenum, jejunum, ileum, cecum, and appendix); and 3) those arising from the hindgut (descending colon and rectum), The larynx and the tracheobronchial tree are both derived from the fore-gut. However, carcinoid tumors of the larynx are not so frequent as those of the tracheobronchial tree, There have been 33 cases rtported in the English or Japanese literature, A review of these 35 cases (including the present 2) is given here (Tables 1 and 2), Age and sex, Twenty-six cases were male and 9 cases were female, The age ranged from 47 to 82 years with an average of 61 years, Thus, carcinoid tumor of the larynx occurs later in life with a higher frequency in the male, Location, The supraglottic region was involved in virtually all cases: the arytenoid in lO, the epiglottis in 9, the ventricular fold in 6, the aryepiglottic fold in 5, and the ventricle in I, The exceptions to this trend were supraglottic and glottic involvement in one case and subglottic origin in another case, Carcinoid tumors may frequently occur in the supraglottic region because Kulchitsky cells are mainly distributed there, but these cells have not been identified in the normal human larynx, Symptoms, The carcinoid syndrome occasionally occurs with foregut carcinoids, whereas carcinoid tumors of the larynx do not exibit the secondary systemic symptoms seen in the classic carcinoid syndrome, Thus, the symptoms of the carcinoid tumor are almost identical to those of carcinoma of the larynx, Six cases complained of odynophagia, Treatment, recurrence, and prognosis, Irradiation of the primary lesion was performed in 7 cases, this treatment was not effective in 5 of the 7 cases and they were subsequently controlled by surgery, In one responding case, a recurrence at the primary site later occurred and was controlled by surgery, In the other responding case, the patient died of distant metastasis immediately after radio-
Epiglot.t.is
Aryepiglot.t.ic Lump in fold(R) t.hroat.(4yrs) Aryt.enoid(R) Hoarseness (15mos)
12)Duvall et. 70 M (1983) al 67 M
Epiglot.t.is
Hoarseness (4mos)
Vocal fold (L) Supraglot.t.is Epiglot.t.is Hoarseness (3mos) Sore t.hroat. Neck mass (6wks) Hoarseness (3yrs)
Hoarseness (3.5yrs)
Vent.ricular fold(R)
Final
None
Rad(NR) Ch
Rad(55Gy) TL LE
Rad(NR)
PL,RND(L)
TL
Rad(40Gy) TL,RND(R)
LE,RND(R) Rad(80Gy)
None
None
None
None
NR
Primaey lesion (6mos) None
DOC (15mos) NR
DOD (45mos)
NED (22mos)
NR
NED (2yrs)
NR
DOC (5yrs) DOD (6wks)
None
TL
Rad(20Gy) Ch None
DOD (2yrs) DOD (2mos)
Bone (NR)
PL
DOD (2yrs) NED (6mos)
(Io:t.erJlall Qutcome
Recurrence Skin (10mos) None
Rad(50Gy) TL,RND PL
Init.ial
treatment
Summary of 35 cases.
Dysphagia (2yrs) Abnormal sensat.ion during swallowing ( lyr) NR
COl1ra:t.iQol
59 M 11) Nonomura et. al(1983)
9)Capper et. 49 M (1981) al 61 F 10)Paladugu et. al(1982)
55 M 7) GapanyGapanavicius et. al (1981) 76 M 8)Tamai et. (1981) al
5)Markel et. 74 M (1980) al 6)Tachi et. 59 M (1981) al
Table 1. Sympt.om
Neck mass Skin nodule (6mos) Aryepiglot.t.ic Hoarseness fold(R) (1yr) Skin nodule Epiglot.t.is (6mos)
Subglot.t.is
NR F 3)Ferlit.o (1976) 4) Kamimura 50 M et. al (1980)
Epiglot.t.is
Epiglot.t.is
54 M
1) Goldman et. al(1969) 2) Horikawa et. al (1972)
Epiglot.t.is
Sex
Locat.ion
73 M
Aut.hors
Age
None
Skin, Axillary, cervical and inguinal lymphnodes, Mult.iple organ (heart., pancreas, et.c. ) None
Cervical lymphnodes
None
Cervical lymphnodes
Skin, Mult.iple organs (heart., pancreas, lung, liver, et.c. ) Cervical lymphnodes
Skin, Mult.iple organs (heart. , pancreas, lung, liver, et.c. ) None
Bone
Cervical lymphnodes, Skin None
Met.ast.asis
- -- - - - -
J>. ....,
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Z
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r
tn
::t
...,
'"I:I
0
;:0
0
~
C
...,
0
2
Z
()
()
» ;:0
Aryepiglot.t.ic Hoarseness fold(L) Sore t.hroat. (NR) Aryepiglot.t.ic Sore t.hroat. fold(L) (2yrs) Aryt.enoid Hoarseness Sore t.hroat. (Hmos) Aryt.enoid Hemopt.ysis Hoarseness (3mos)
17) Weighill 73 M et. al (1986)
Aryt.enoid
Arytenoid
Aryt.enoid
63 F
55 M
61 F
72 M
None
LE
(4mos)
(6mos) NED (24mos) NED (8yrs)
DOD
NR
NR
DOC (During t.reat.ment.) NED (NR) DOD (4yrs)
Final ou.t.J:;.Qme NED (10mos)
TL,RND
None
NED
(2mos)
Ch,Rad(NR) St.oma,Lung DOD TL,RND Mediastinum (6.5yrs) Thorax (68mos) LE Primary DOC lesion (26yrs) (9yrs) TL,RND None NED (3mos)
None
Skin
NR
Cervical lymphnode (L) (2yrs) None
None
PL
PL RND(L) Rad(NR) Rad(40Gy)
PL RND(L)
PL RND(R)
LE
RND(R)
Recurrence (In:t.erllall Primary lesion (18mos) None
(continued)
Init.ial t z:eatmeoL Rad (64Gy)
Table I
Hoarseness Dysphagia (lyr) Sore t.hroat. Hoarseness (9mos) Throat. lump Odynophagia (1.5mos)
Vent.ricular fold(L)
16)Guerrier 54 M et. al(1985)
18) Snyderman 80 M et. al (1986) 68 M 19)5t.anley et. al(1986)
Supraglot.t.is
Hoarseness (4dys) Lump in t.hroat.(NR) Sore t.hroat. Dysphagia (5yrs) Hoarseness Dysphagia (3mos) Dysphonia (6mos)
Sympt.om (Durat.ionl NR
15) Goldman 57 F et. al(1985)
59 M
Vent.ricular foldeR) Epiglot.t.is
Supraglot.t.is
14)Blok et. 50 F ( 1985) al 53 M
Locat.ion
Aryt.enoid(R)
Sex
Age
13)Mills et. 68 M al (1984)
Aut.hors
Cervical lymphnode
Cervical lymphnode
Cervical lymphnode
Lung, Thorax, Mediast.inum
None
None
Cervical lymphnodes(Bil) Skin
Cervical lymphnodes(L)
Cervical lymphnodes(L)
Cervical and axillary lymphnodes, Lung
Cervical lymphnodes(Bil) Breast. None
None
Met.ast.asis
~
~
0
:> ...,
t.I.l
:r::
.l>00
66 M
55 M
12M
61 M
Ventricle(L)
Primary lesion Skin (6mos) Pelitonium Liver(NR)
(lmo~
PL,RND(L)
LE
Rad(36Gy) TL,RND(L) Ch,TL RND(R) TL
Neck
Neck(L) (l9mos) Liver (2mos) Neck (Bil) (l3mos) Lung,Liver (3.6yrs) Neck(L) (18mos)
TL,RND(R) None Rad(59.8Gy) LE None
RL,RND(L) Rad(63Gy)
LE
DOD
(3yrs)
(9mos) NED (3 . 5yrs) NED (25mos) DOD (2mos) DOD (4yrs)
NED
DOD (41mos)
DOC (16mos)
Cervical lymphnodes
Cervical lymphnodes Liver Cervical lymphnodes Lung, Liver
Cervical lymphnodes
None
None
Cervical lymph node , Liver, Retropelitonium
Skin
DOD Cervical lymphnodes (lmo) (2mos)~one NR: not reported, Rad: Radiation, Ch: Chemotherapy, TL: Tot.al laryngect.omy, PL: Partial laryngectomy, LE: Local excision, RND: Radical neck dissect.ion, DOD: Died of disease, DOC: Died of ot.her cause, NED : No evidence of disease
82 M
Odynophagia (4.5yrs) Neck mass (3wks) Hoarseness
Odynophagia Int.ermittent. loss of voice (6mos) Aryepiglottic Dysphagia fold(L) Odynophagia Hoarseness (2mos) Epig1ot.t.is Neck mass (3wks) Arytenoid(R) Hemopt.ysis (lmo) Ventricular Odynophagia fold(L) (4mos) Ventricular Hoarseness fold(R) (4mos) Ventricular Odynophagia fold (R) (lOmos)
Arytenoid(L)
25)Sato et al 82 M Arytenoid(L) (l990)
21)Patterson et al(1987) 22)Tanaka et al (1987) 23)Koshii et al (1989) 24)Miyahara et al(1988)
47 F
50 F
20)Baugh et 53 M al (l987)
(J )-
\0
~
><
Z
-<
;:tI
)-
t'""'
::r: rn
-l
o 'T]
;:tI
o
c::: 3::
-l
Z o S
;:tI (J
50
K. SA TO Table 2.
et. al(1969) 2)Horikawa et. al(1972) 3) Ferlit.o (1976) 4) Kamimura et. al(1980) 5)Markel et. al(1980) 6)Tach1 et. al(198l) 7)GapanyGapanavicius et. al(1981) 8)Tamai et. al(1981) 9)Capper et. al(1981) 10)Paladugu et. al (1982)
II} Nonomura
et. al(1983) 12) Duvall et. al(1983)
13)M1lls et. al(1984) 14)Blok et. al(1985)
15) Goldman et. al(1985) 16)Guerrier et. al(1985) l7)We1gh1l1 et. al(1986) 18) Snyderman et. al(l986) 19)5t.anley et. al(1986)
20)Baugh et. al(1987)
Serot.onin Init.ial 5 HIAA d1~~ NR Carcinoma
Argyrophil Argentaffin NeurosecreLory reactl on_~a ctiQn granUles in TEM
NR
Neg
NR
NR
NR
NR
NR
Nil
NR
NR
NR
NR
NR
Normal range NR
Undifferentialed carcinoma Carcinoid tumor
Pos
Neg
NR
Pos
NR
Pos
Normal range Normal range
Undifferent.1at.ed carcinoma AnaplasLlc carcinoma
Pos
Neg
Pas
NR
Undifferent.1at.ed carcinoma Undifferent.iat.ed carcinoma Well different.iat.ed adenocarcinoma Undifferent.iat.ed carcinoma .Undifferent iated carcinoma Carcinoid t.umor Poorly different.iat.ed carcinoma Carcinoid lumor
NR NR
Normal range Normal range
NR
Normal range
Normal range
NR NR
Carcinoid tumor
Undifferentiated
(Primary les10n) Neg Neg (Met.ast.at.1c les10n) Pos Pos Pos Neg
Pas
NR
Neg
Pos
Neg
Neg
Pos
Pos
Neg
Pas
Pos
Neg
Pos
Pos Pos
Neg NR
Pas Pos
Pos
NR
Pos
Pos Pos
NR NR
Pos Pos
Pas
Neg
Pas
NR
NR
Pos
NR
Carcinoid t.umor
Pas
NR
Pos
Normal
Carcinoid Lumor
Pos
Neg
Pos
Normal range
Adenocarcinoma
Pas
Nil
Pos
Poorly different.iat.ed carcinoma Adenocarcinoma
Pos
Neg
Pos
Pas
Neg
Pos
Oxyphilic carcinoma
Pos
Neg
Pos
Oxyph i lic neuroendocrine carcinoma Carcinoid lumor Undifferenliat.ed carcinoma Squamous cell carcinoma Carcinoid tumor
Pos
Neg
Pos
NR NR
NR NR
NR NR
NR
NR
NR
Pas
NR
Pos
CarcinOid t.umor
Pas
NR
POs
Poorly Differentiat.ed squamous cell carcinoma Poorly different.iated squamous cell carcinoma CarcinOid t.umor
Pas
NR
NR
Pos
NR
Pos
Normal
range
Normal range
range
Normal range Normal range Normal range Normal range NR Normal range NR
Normal range Normal range
24) Miyahara
NR
NR
Normal Pas range Normal Carcinoid t.umor Pas range NR: NOt. reported, Pes: Positive, Neg: Negative
25)sat.o et. al(1990)
Pos
squamous cell carcinoma Poorly DlfferenLiaLed s quamous cell carcinoma Carcinoid t.umor
21) Pat.t.erson et. al(1987) 22)Tanaka et. al(1987) 23)Koshii et. al(1987) et. al(1988)
al.
Summary of laboratory tests and histopathological findings of 35 cases.
Authors 1) Goldman
el
Neg
Nil
Neg
NR
CARCINOID TUMOR OF THE LARYNX
51
therapy. Irradiation of metastatic skin lesions was performed in 3 cases, but no effect was evident. Postoperative radiotherapy was conducted in 4 cases. Thus, radiotherapy has not been shown to control laryngeal carcinoids. Chemotherapy was administered in 6 cases at some point in their course but this treatment was not effective. Local excision was carried out in 8 cases and 3 of these developed a primary recurrence. Partial laryngectomy was performed in 9 cases, none of which had recurrence. Total laryngectomy was performed in 12 cases and again no recurrence was found. Therefore, neck metastasis was well controlled by neck dissection. Thirteen cases died of the disease, and 5 cases died from other causes. Distant metastasis was the most common cause of death. Carcinoid tumor of the larynx is agressive, malignant, and unresponsive to radiotherapy or chemotherapy. Therefore, adequate surgical excision is currently the only effective treatment. Metastasis. Among the 35 patients with laryngeal carcinoid tumors, metastasis was observed in 24 at some point in their course. The cervicallymphnodes were the most common site of metastasis and were involved in 19 cases. Thirteen cases presented with distant metastases: subcutaneous metastasis in 6, lung metastasis in 5, liver metastasis in 5, and bone metastasis in 2. Multiple organ metastasis (heart, pancreas, etc.) were found in 3 cases. Interestingly, 4 of 6 cases suffering from skin metastasis complained of pain. Metastasis to skin and bone are common with foregut and hindgut carcinoids (WILLIAMS and SANDLER, 1963), and laryngeal carcinoid shows a similar tendency. Distant metastasis occurred frequently and was the most common cause of death. Laboratory tests. Serum levels of serotonin and urinary levels of its metabolite, 5-hydroxy indoleacetic acid, were examined in 20 cases. All cases were within the normal range. After LEMBECK (1953) reported that carcinoid tumors contained high levels of serotonin, excessive secretion serotonin by the tumor was taken to indicate the carcinoid syndrome. Laryngeal carcinoid tumors did not contain large amounts of serotonin. Initial histological diagnosis. Eight cases were diagnosed as undifferentiated carcinoma, and 5 cases were termed poorly differentiated carcinoma on the basis of biopsy specimens. Laryngeal carcinoid tumors frequently have atypical histological features and may be misdiagnosed as undifferentiated or poorly differentiated carcinoma. Argyrophil or argentaffin reaction. Among the 27 cases for which an argyrophil reaction was reported, 26 were Grimelius stain positive. One case was Grimelius negative in the primary lesion but positive in the metastatic lesion. Almost all of the cases reporting an argentaffin reaction were Fontana-Masson stain negative. WILLIAMS and SANDLER (1963) have pointed out that carcinoid tumors arising from the foregut are usually argyrophil positive and argentaffin
52
K . SATO el al.
negative. Our review of the literature indicates that laryngeal carcinoid tumors appear to show a similar tendency. Transmission electron microscopy (TEM). All of the tumors subjected to TEM showed neurosecretory granules. If the histological findings revealed no typical carcinoid tumor cell arrangement, or if the argyrophil reaction was negative, neurosecretory granules identified by TEM provided the final diagnosis. The term carcinoid tumor was introduced by OBERNDORFER (1907), to describe tumors of the small intestine which were less agressive than most carcinomas. However, carcinoid tumors of non-appendiceal sites are most often malignant and metastasize more frequently than those of appendiceal origin (PEARSON and FITZGERALD, 1949). Our literature review showed that all laryngeal carcinoid tumors had a high degree of malignancy and a grave prognosis.
REFERENCES BAUGH, R. F., WOLF, G. T ., LLOYD, R. V., MCCLATCHEY, K. D ., and EVANS, D. A.: Carcinoid (neuroendocrine carcinoma) of the larynx. Ann. 0101. Rhinol. Laryngol. 96: 315-321, 1987. BLOK, P. H. H. M., MANNI, J. J ., VAN DEN BROEK, P., VAN HAELST, U. J. G . M ., and SLOOH, J. L.: Carcinoid of the larynx. A report of three cases and a review of the literature. Laryngoscope 95: 715-719,1985. CAPPER, J. W. R., MICHAELS, L., and GREGOR, T.: A malignant carcinoid tumor of the supraglottic larynx. l. Laryngol. 0101.95: 963-971, 1981. DUVALL, E., JOHNSTON, A., McLAY, K., and PIRIS, J.: Carcinoid tumor of the larynx. J. Laryngol. 0101.97: 1073-1080, 1983. FERLITO, A.: Histological classification of larynx and hypopharynx cancers. Acla Ololaryngol. 342: 9-88, 1976. GAPANY-GAPANAVICIUS, B., and KENAN, S.: Carcinoid tumor of the larynx. Ann. 0101. Rhinol. Laryngol. 90: 42--47, 1981. GOLDMAN, N . c., HOOD, C. 1., and SINGLETON, G. T . : Carcinoid of the larynx. Arch. 010laryngol. 90: 90-93, 1969. GOLDMAN, N. c., KATIBAH, G. M ., and MEDINA, J.: Carcinoid tumor of the larynx. Ear Nose Throal l. 64: 130-134, 1985. GUERRIER, Y., LALLEMANT, J. G., CHARLIN, B., and PAGES, A . : A carcinoid tumor of the larynx. ORL 47: 113-118, 1985. HIRANO, M., and KURITA, S.: Transepiglottic pharyngolaryngotomy. l. Ololaryngol. 87: 603606, 1984. HORIKAWA, T., and MATSUBARA, H.: A carcinoid tumor of the epiglottis. Ololaryngology (Tokyo) 44: 437-440, 1972. KAMIMURA, R., MIYATA, S., MATSUI, 0., TAKASHIMA, T ., and NONOMURA, A.: Carcinoid of the larynx. lpn. l . Cancel' Clin. 26 : 1255-1258, 1980. KOSHII, K., HIRABAYASHI, H ., UNO, K., OHGAKI, H., AKIYAMA, K ., SOEDA, H., and HINOHARA, T. : A case of carcinoid tumor of the larynx. J. lpn. Bronchoesophagol. Soc. 38: 452-456, 1987. LEMBECK, F . : 5-Hydroxytryptamine in a carcinoid tumor. Nalure 172 : 910-911,1953 . MARKEL, S. F., MAGIELSKI, J. E ., and BEALS, T. F.: Carcinoid tumor of the larynx. Arch. Ololaryngol. 106: 777-778, 1980. MILLS, S. E., and JOHNS, M. E.: Atypical carcinoid tumor of the larynx. Arch. Ololaryngol. 110: 58-62, 1984.
CARCINOID TUMOR OF THE LARYNX
53
MIYAHARA, H., SATO, T., YOSHINO, K., UMATANI, K., and TSURUTA, Y.: Carcinoid tumor of the larynx. Pract. Otol. (Kyoto) 81: 1761-1767, 1988. NONOMURA, A., SHINTANI, T., KONO, N., KAMIMURA, R., and OHTA, G.: Primary carcinoid tumor of the larynx and review of the literature. Acta PatllOl. lpn. 33: 1041-1049, 1983. OBERNDORFER, S.: Karzinoide Tumoren des Dlinndarms. Frank! Zschr. PatllOl. 1: 426-432,
1907. PALADUGU, R. R., NATHWANI , B. N., GOODSTEIN, J., DARDI, L. E ., MEMOLI, V. E., and GOULD, V. E.: Carcinoma of the larynx with mucosubstance production and neuroendocrine differentiation . An ultra structural and immunohistochemical study. Cancer 49: 343-349,
1982. PATTERSON. S. D., and YARINGTON, CT.: Carcinoid tumor of the larynx. The role of conservative therapy. AI/I/. Otol. Rhinal. Laryngol. 96: 12-14, 1987. PEARSON, C. M., and FITZGERALD, P. J.: Carcinoid tumors. A reemphasis of their malignant nature. Cancer 2: 1005-1026, 1949. SNYDERMAN, C, JOHNSON, J . T., and BARNES, L.: Carcinoid tumor of the larynx: Case report and review of the world literature. Otolaryngol. Head Neck Surg. 95: 158-164, 1986. STANLEY, R. J., DESANTO, L. W., and WEILAND, L. H .: Oncocytic and oncocytoid carcinoid tumors (well-differentiated neuroendocrine carcinomas) of the larynx. Arch. Otolaryngo .1
Head Neck Surg. 112: 529-535, 1986. TACHI, T., TAMORI, M., KAMIMURA, R ., SHINTANI, T., and FUKUSHlRO, R.: Laryngeal carcinoid tumor with skin metastasis. lpn. l. Clil1. Dermatol. 35 : 581-586, 1981. TAMAI, S. , 1RI, H ., MARUYAMA, T., KASAHARA, M ., AKATSUKA , S., SAKURAI, S., and MURAKAMI, Y.: Laryngeal carcinoid tumor. Light and electron microscopic studies. Callcer 48: 2256-
2259, 1981. TANAKA, M., HASEGAWA, T., KIN, S., TAMAOKI, H., KOTOU, K., and YOSHIDA, J.: A case of atypical carcinoid of the larynx. Otolaryngology (Tokyo) 59: 663-669, 1987. WEIGHILL, J. S., TANKEL, J. W ., and MENE, A.: Carcinoid tumour of the larynx (A case report and review of the literature). l. LarYlIgol. Otol. 100: 1421-1426,1986. WILLIAMS, E. D., and SANDLER, M.: The classification of carcinoid tumors. Lancet 1: 238-239,
1963.
Request reprints to:
Dr. K. Sato, Department of Otolaryngology-Head and Neck Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830, Japan
CARCINOID TUMOR OF THE LARYNX Kiminori SATO, M.D., Yuichiro HIGAKI, M.D., Shinji SAKAGUCHI, M.D., Minoru HIRANO, M.D., Akira TANIMURA, M.D.,* and Yasuyuki SASAGURI, M.D.* Department of Otolaryngology-Head and Neck Surgery and *Second Department of Pathology, KlIrlime University School of Medicine, KUr1ll11e, Japan
Carcinoid tumor of the larynx is a rare neoplasm. Two cases of laryngeal carcinoid tumor are reported and the relevant literature is reviewed. One patient was an 82-year-old male who complained of odynophagia. The tumor was located on the left arytenoid and neck metastasis were present when he died 3 years after surgery. The other patient was an 82year-old male who complained of hoarseness. His tumor was located in the left ventricle. Bone metastasis was detected one month after surgery and he died of distant metastasis two months following surgery. A review of the literature showed that carcinoid tumors of the larynx are aggressive and malignant, with distant metastasis being the most common cause of death. This tumor is unresponsive to radiotherapy and chemotherapy, so adequate surgical excision remains the only effective treatment. Carcinoid tumors are most commonly seen in the vermiform appendix, small intestine, and tracheobronchial tree. Carcinoid tumor of the larynx, however, is rare. Since GOLDMAN, HOOD, and SINGLETON (1969) first reported a case of carcinoid tumor of the epiglottis, 33 cases (Table 1) have been reported in the English and Japanese literature. The present paper reports 2 new cases of carcinoid tumor of the larynx and also includes a review of the literature. CASE REPORTS
Case I An 82-year-old male developed pain on swallowing in November 1978. The symptom gradually worsened and was later accompanied by hoarseness and cough. A painless lump on the right side of his neck developed early in June 1983. He Received for publication
March 28, 1990 39
K. SATO et al.
40
visited a private otolaryngological clinic and was referred to the Kurume University Hospital on June 20 of the same year. Typical symptoms like episodic flushing of the skin, diarrhea, or asthma Wfre not observed. He had a history of smoking six or seven cigarettes per day for 50 years. On physical examination, a lobulated tumor covered with normal epithelium was found in the larynx. The tumor was mainly located in the left arytenoid region and involved the left aryepiglottic fold and the interarytenoid region. Both vocal folds were intact and mobile. No retention of saliva was observed in the piriform sinuses. Deep cervical node (20 X 15 mm) was detected on the right side by palpation. The lymphnode was elastically firm and mobile. Laryngograms revealed a lobulated and smooth-surfaced tumor in the left arytenoid region (Fig. 1). Both vocal folds were intact. A CT scan of the larynx revealed a dense mass. Chest roentgenograms were normal. The maximum phonation time was 7.6 s and the mean air flow rate was 234 mIls, indicating a slight degree of glottic incompetence. Hematological parameters were all within the normal range. An unusual type of neoplasm was strongly suspected from the results of investigation. On July 4, we performed surgery. We first attempted to remove the mass endoscopically, but the mass proved too large to be removed via a conventional endolaryngeal procedure so we switched to an external approach. The mass was exposed with a transepiglottic pharyngolaryngotomy (HIRANO and KURITA, 1984). The base of the mass was located mainly in the left arytenoid region, involving the left aryepiglottic fold and inter arytenoid region. The tumor appeared to be highly vascularized and was covered with normal epithelium (Fig. 2a). Palpation
Fig. 1.
Laryngogram showing a tumor on the left arytenoid region (arrow).
CARCINOID TUMOR OF THE LARYNX
41
Fig, 2, Views during surgery, a: After transepiglottic pharyngolaryngotomy , (A) tumor, (B) the right vocal fold, b: After the removal of the tumor. (A) the location of the base of the tumor. (B) the right vocal fold ,
Fig, 3,
Excised tumor is lobulated and covered with epithelium , The scale is graded in mm ,
42
K . SA TO el at.
revealed slight invasion into the adjacent tissue. We extirpated the tumor using a CO 2 laser (Fig. 2b) and only mild bleeding occurred during the operation. The cervical node was also extirpated. The laryngeal tumor was lobulated, dark red in color, and 25 X 23 X 20 mm in size (Fig. 3). Histological examination revealed that both the laryngeal tumor and the cervical lymphnode lesion were carcinoid tumors. The covering mucosa, which was stratified squamous epithelium, was not involved histologically. The cells were small and uniform with round nuclei. Slight nuclear pleomorphism and mitotic figures were apparent, and the cells showed either a solid or trabecular arrangement. The lesion was surrounded by vascular connective tissue (Fig. 4), and intravascular invasion was observed. Numerous normal laryngeal glands
Fig. 4. A histological micrograph of the excised tumor. Tumor cells consist of eosinophilic cytoplasm and small, round nuclei. Tumor nests, surrounded by a vascular connective tissue stroma, are observed (hematoxylin and eosin stain) .
Fig. 5. A histological micrograph showing cytoplasmic argyrophil granules. The granules are abundant as small, dark, round structures in the cytoplasm of each cell (arrow) (Grimelius stain).
CARCINOID TUMOR OF THE LARYNX
43
were recognized at the base of the tumor. Grimelius stain revealed argyrophilic granules in the cytoplasm of the tumor cells (Fig. 5). Fontana-Masson (argentaffin) staining was negative. After establishment of the diagnosis, a thorough examination of the entire body was performed, and no other lesions were detected. Bilateral radical neck dissection was strongly recommended to the patient, but was not accepted. The patient was discharged on August 17 without any clinical evidence of disease. The patient noticed a left neck mass in January 1985, but did not return to our hospital until August 20, 1985. During physical examination a left upper deep cervical node, 50 X 60 mm in size, was found on palpation. This node was hard and firmly fixed to the surrounding tissue. The larynx was free from disease, but the left vocal fold was fixed in the paramedian position and atrophic. No distant metastasis were detected so radical neck dissection was attempted, but the mass was unresectable because it was fixed to the carotid artery. He was discharged from our hospital on September 30 and died of heart failure on July 19, 1986. Cervical Iymphnode metastasis was found, but no recurrence of the primary or any distant metastasis were observed. Case 2 An 82-year-old male developed hoarseness in October 1987. He consulted an otolaryngologist and was referred to the Kurume University Hospital on November 19. Typical symptoms of the carcinoid syndrome were again not
Fig. 6. Fiberscopic investigation reveals a swollen left ventricular fold (arrow). A: arytenoids.
Fig. 7. Laryngogram showing the swollen left ventricular fold (arrow).
44
K. SA TO et al.
present. He had a history of smoking 10 cigarettes per day for 50 years. On physical examination, the left ventricular fold was found to be swollen and covered with normal epithelium (Fig. 6). Both vocal folds were mobile. Palpation revealed upper and middle cervical lymphnodes, 20 X 20 and 25 X 25 mm in size, on the left side. The lymphnodes were elastically firm and mobile. The left ventricular fold was swollen and the ventricle was not depicted on laryngograms (Fig. 7). A CT scan revealed a relatively low density mass in the region of the ventricle (Fig. 8). Chest roentogenograms were normal. The maximum phonation time was 17.2 s and the mean air flow rate was 119 mIls. Hematological values were all within the normal range. Supraglottic carcinoma (ventricular carcinoma) was the working diagnosis. On December 7, 1987, we performed hemilaryngectomy and radical neck dissection on the left side. The postoperative course was good but the patient complained of abdominal pain and tenderness on December 21. Abdominal X-rays revealed free air, suggesting perforation of a duodenal ulcer. Distal partial gastrectomy was performed on December 22.
Fig. 8. CT scan detects a low density mass at the left ventricular fold (arrow).
Fig. 9. Coronal section of the excised hemilarynx. Tumor is located at the ventricle involving the ventricular fold and vocal fold (arrow). VF: ventricular fold, VP: vocal process (hematoxylin and eosin stain).
CARCINOID TUMOR OF THE LARYNX
45
On January 4, 1988, he developed a neck mass that was 15 X 15 mm in size on the right side. A right radical neck dissection was subsequently performed. Histological examination revealed that both the laryngeal tumor and cervical Iymphnode lesions were carcinoid tumors. A tumor was located in the posterior portion of the ventricle and invaded into the paraglottic space (Fig. 9). Tumor cells with eosinophilic cytoplasm and round or ovoid nuclei showed solid, sheetlike, and acinar arrangements. Moderate nuclear pleomorphism and mitotic figures were present. Glands lined with microvilli were observed (Fig. 10). Evidence of cytoplasmic granules could be demonstrated with Grimelius (argyrophil) stain (Fig. 11), but not with Fontana-Masson (argentaffin) stain. Immunohistochemical studies showed negative immunoreactivity for calcitonin and somatostatin.
Fig. 10. A histological micrograph of the excised tumor. Tumor cells consist of eosinophilic cytoplasm and round or ovoid nuclei. Tumor cells show solid and acinar arrangements (hematoxylin and eosin stain).
Fig. 11. A histological micrograph showing cytoplasmic argyrophil granules (arrow). Gland formations with microvillus lining are apparent (m) (Grimelius stain).
46
K, SATO et aI,
On hematological examination, the red cell count was 3,080,000/mm3, the hemoglobin was 9,0 g/dl, and the platelet count was 41,000/mm3, serum, GOT was 119 IU/liter and LDH was 2,359 IU/liter, A bone marrow biopsy showed myelocarcinomatosis, Blood transfusion and chemotherapy were performed, but the patient died on February 11, 1988,
DISCUSSION
Carcinoid tumors most commonly appear as infiltrating neoplasms in the vermiform appendix and small intestine, and have also been known to occur in the tracheobronchial tree, Carcinoid tumors arise from the enterochromaffin cells (Kulchitsky cells) derived from the primitive gut. WILLIAMS and SANDLER (1963) subdivided carcinoid tumors into three groups according to the embryology of the site of origin of the neoplasm: I) those arising from the foregut (bronchi, stomach, biliary tract, and pancreatic ducts); 2) those arising from the midgut (lower duodenum, jejunum, ileum, cecum, and appendix); and 3) those arising from the hindgut (descending colon and rectum), The larynx and the tracheobronchial tree are both derived from the fore-gut. However, carcinoid tumors of the larynx are not so frequent as those of the tracheobronchial tree, There have been 33 cases rtported in the English or Japanese literature, A review of these 35 cases (including the present 2) is given here (Tables 1 and 2), Age and sex, Twenty-six cases were male and 9 cases were female, The age ranged from 47 to 82 years with an average of 61 years, Thus, carcinoid tumor of the larynx occurs later in life with a higher frequency in the male, Location, The supraglottic region was involved in virtually all cases: the arytenoid in lO, the epiglottis in 9, the ventricular fold in 6, the aryepiglottic fold in 5, and the ventricle in I, The exceptions to this trend were supraglottic and glottic involvement in one case and subglottic origin in another case, Carcinoid tumors may frequently occur in the supraglottic region because Kulchitsky cells are mainly distributed there, but these cells have not been identified in the normal human larynx, Symptoms, The carcinoid syndrome occasionally occurs with foregut carcinoids, whereas carcinoid tumors of the larynx do not exibit the secondary systemic symptoms seen in the classic carcinoid syndrome, Thus, the symptoms of the carcinoid tumor are almost identical to those of carcinoma of the larynx, Six cases complained of odynophagia, Treatment, recurrence, and prognosis, Irradiation of the primary lesion was performed in 7 cases, this treatment was not effective in 5 of the 7 cases and they were subsequently controlled by surgery, In one responding case, a recurrence at the primary site later occurred and was controlled by surgery, In the other responding case, the patient died of distant metastasis immediately after radio-
Epiglot.t.is
Aryepiglot.t.ic Lump in fold(R) t.hroat.(4yrs) Aryt.enoid(R) Hoarseness (15mos)
12)Duvall et. 70 M (1983) al 67 M
Epiglot.t.is
Hoarseness (4mos)
Vocal fold (L) Supraglot.t.is Epiglot.t.is Hoarseness (3mos) Sore t.hroat. Neck mass (6wks) Hoarseness (3yrs)
Hoarseness (3.5yrs)
Vent.ricular fold(R)
Final
None
Rad(NR) Ch
Rad(55Gy) TL LE
Rad(NR)
PL,RND(L)
TL
Rad(40Gy) TL,RND(R)
LE,RND(R) Rad(80Gy)
None
None
None
None
NR
Primaey lesion (6mos) None
DOC (15mos) NR
DOD (45mos)
NED (22mos)
NR
NED (2yrs)
NR
DOC (5yrs) DOD (6wks)
None
TL
Rad(20Gy) Ch None
DOD (2yrs) DOD (2mos)
Bone (NR)
PL
DOD (2yrs) NED (6mos)
(Io:t.erJlall Qutcome
Recurrence Skin (10mos) None
Rad(50Gy) TL,RND PL
Init.ial
treatment
Summary of 35 cases.
Dysphagia (2yrs) Abnormal sensat.ion during swallowing ( lyr) NR
COl1ra:t.iQol
59 M 11) Nonomura et. al(1983)
9)Capper et. 49 M (1981) al 61 F 10)Paladugu et. al(1982)
55 M 7) GapanyGapanavicius et. al (1981) 76 M 8)Tamai et. (1981) al
5)Markel et. 74 M (1980) al 6)Tachi et. 59 M (1981) al
Table 1. Sympt.om
Neck mass Skin nodule (6mos) Aryepiglot.t.ic Hoarseness fold(R) (1yr) Skin nodule Epiglot.t.is (6mos)
Subglot.t.is
NR F 3)Ferlit.o (1976) 4) Kamimura 50 M et. al (1980)
Epiglot.t.is
Epiglot.t.is
54 M
1) Goldman et. al(1969) 2) Horikawa et. al (1972)
Epiglot.t.is
Sex
Locat.ion
73 M
Aut.hors
Age
None
Skin, Axillary, cervical and inguinal lymphnodes, Mult.iple organ (heart., pancreas, et.c. ) None
Cervical lymphnodes
None
Cervical lymphnodes
Skin, Mult.iple organs (heart., pancreas, lung, liver, et.c. ) Cervical lymphnodes
Skin, Mult.iple organs (heart. , pancreas, lung, liver, et.c. ) None
Bone
Cervical lymphnodes, Skin None
Met.ast.asis
- -- - - - -
J>. ....,
><
Z
-<
» ;:0
r
tn
::t
...,
'"I:I
0
;:0
0
~
C
...,
0
2
Z
()
()
» ;:0
Aryepiglot.t.ic Hoarseness fold(L) Sore t.hroat. (NR) Aryepiglot.t.ic Sore t.hroat. fold(L) (2yrs) Aryt.enoid Hoarseness Sore t.hroat. (Hmos) Aryt.enoid Hemopt.ysis Hoarseness (3mos)
17) Weighill 73 M et. al (1986)
Aryt.enoid
Arytenoid
Aryt.enoid
63 F
55 M
61 F
72 M
None
LE
(4mos)
(6mos) NED (24mos) NED (8yrs)
DOD
NR
NR
DOC (During t.reat.ment.) NED (NR) DOD (4yrs)
Final ou.t.J:;.Qme NED (10mos)
TL,RND
None
NED
(2mos)
Ch,Rad(NR) St.oma,Lung DOD TL,RND Mediastinum (6.5yrs) Thorax (68mos) LE Primary DOC lesion (26yrs) (9yrs) TL,RND None NED (3mos)
None
Skin
NR
Cervical lymphnode (L) (2yrs) None
None
PL
PL RND(L) Rad(NR) Rad(40Gy)
PL RND(L)
PL RND(R)
LE
RND(R)
Recurrence (In:t.erllall Primary lesion (18mos) None
(continued)
Init.ial t z:eatmeoL Rad (64Gy)
Table I
Hoarseness Dysphagia (lyr) Sore t.hroat. Hoarseness (9mos) Throat. lump Odynophagia (1.5mos)
Vent.ricular fold(L)
16)Guerrier 54 M et. al(1985)
18) Snyderman 80 M et. al (1986) 68 M 19)5t.anley et. al(1986)
Supraglot.t.is
Hoarseness (4dys) Lump in t.hroat.(NR) Sore t.hroat. Dysphagia (5yrs) Hoarseness Dysphagia (3mos) Dysphonia (6mos)
Sympt.om (Durat.ionl NR
15) Goldman 57 F et. al(1985)
59 M
Vent.ricular foldeR) Epiglot.t.is
Supraglot.t.is
14)Blok et. 50 F ( 1985) al 53 M
Locat.ion
Aryt.enoid(R)
Sex
Age
13)Mills et. 68 M al (1984)
Aut.hors
Cervical lymphnode
Cervical lymphnode
Cervical lymphnode
Lung, Thorax, Mediast.inum
None
None
Cervical lymphnodes(Bil) Skin
Cervical lymphnodes(L)
Cervical lymphnodes(L)
Cervical and axillary lymphnodes, Lung
Cervical lymphnodes(Bil) Breast. None
None
Met.ast.asis
~
~
0
:> ...,
t.I.l
:r::
.l>00
66 M
55 M
12M
61 M
Ventricle(L)
Primary lesion Skin (6mos) Pelitonium Liver(NR)
(lmo~
PL,RND(L)
LE
Rad(36Gy) TL,RND(L) Ch,TL RND(R) TL
Neck
Neck(L) (l9mos) Liver (2mos) Neck (Bil) (l3mos) Lung,Liver (3.6yrs) Neck(L) (18mos)
TL,RND(R) None Rad(59.8Gy) LE None
RL,RND(L) Rad(63Gy)
LE
DOD
(3yrs)
(9mos) NED (3 . 5yrs) NED (25mos) DOD (2mos) DOD (4yrs)
NED
DOD (41mos)
DOC (16mos)
Cervical lymphnodes
Cervical lymphnodes Liver Cervical lymphnodes Lung, Liver
Cervical lymphnodes
None
None
Cervical lymph node , Liver, Retropelitonium
Skin
DOD Cervical lymphnodes (lmo) (2mos)~one NR: not reported, Rad: Radiation, Ch: Chemotherapy, TL: Tot.al laryngect.omy, PL: Partial laryngectomy, LE: Local excision, RND: Radical neck dissect.ion, DOD: Died of disease, DOC: Died of ot.her cause, NED : No evidence of disease
82 M
Odynophagia (4.5yrs) Neck mass (3wks) Hoarseness
Odynophagia Int.ermittent. loss of voice (6mos) Aryepiglottic Dysphagia fold(L) Odynophagia Hoarseness (2mos) Epig1ot.t.is Neck mass (3wks) Arytenoid(R) Hemopt.ysis (lmo) Ventricular Odynophagia fold(L) (4mos) Ventricular Hoarseness fold(R) (4mos) Ventricular Odynophagia fold (R) (lOmos)
Arytenoid(L)
25)Sato et al 82 M Arytenoid(L) (l990)
21)Patterson et al(1987) 22)Tanaka et al (1987) 23)Koshii et al (1989) 24)Miyahara et al(1988)
47 F
50 F
20)Baugh et 53 M al (l987)
(J )-
\0
~
><
Z
-<
;:tI
)-
t'""'
::r: rn
-l
o 'T]
;:tI
o
c::: 3::
-l
Z o S
;:tI (J
50
K. SA TO Table 2.
et. al(1969) 2)Horikawa et. al(1972) 3) Ferlit.o (1976) 4) Kamimura et. al(1980) 5)Markel et. al(1980) 6)Tach1 et. al(198l) 7)GapanyGapanavicius et. al(1981) 8)Tamai et. al(1981) 9)Capper et. al(1981) 10)Paladugu et. al (1982)
II} Nonomura
et. al(1983) 12) Duvall et. al(1983)
13)M1lls et. al(1984) 14)Blok et. al(1985)
15) Goldman et. al(1985) 16)Guerrier et. al(1985) l7)We1gh1l1 et. al(1986) 18) Snyderman et. al(l986) 19)5t.anley et. al(1986)
20)Baugh et. al(1987)
Serot.onin Init.ial 5 HIAA d1~~ NR Carcinoma
Argyrophil Argentaffin NeurosecreLory reactl on_~a ctiQn granUles in TEM
NR
Neg
NR
NR
NR
NR
NR
Nil
NR
NR
NR
NR
NR
Normal range NR
Undifferentialed carcinoma Carcinoid tumor
Pos
Neg
NR
Pos
NR
Pos
Normal range Normal range
Undifferent.1at.ed carcinoma AnaplasLlc carcinoma
Pos
Neg
Pas
NR
Undifferent.1at.ed carcinoma Undifferent.iat.ed carcinoma Well different.iat.ed adenocarcinoma Undifferent.iat.ed carcinoma .Undifferent iated carcinoma Carcinoid t.umor Poorly different.iat.ed carcinoma Carcinoid lumor
NR NR
Normal range Normal range
NR
Normal range
Normal range
NR NR
Carcinoid tumor
Undifferentiated
(Primary les10n) Neg Neg (Met.ast.at.1c les10n) Pos Pos Pos Neg
Pas
NR
Neg
Pos
Neg
Neg
Pos
Pos
Neg
Pas
Pos
Neg
Pos
Pos Pos
Neg NR
Pas Pos
Pos
NR
Pos
Pos Pos
NR NR
Pos Pos
Pas
Neg
Pas
NR
NR
Pos
NR
Carcinoid t.umor
Pas
NR
Pos
Normal
Carcinoid Lumor
Pos
Neg
Pos
Normal range
Adenocarcinoma
Pas
Nil
Pos
Poorly different.iat.ed carcinoma Adenocarcinoma
Pos
Neg
Pos
Pas
Neg
Pos
Oxyphilic carcinoma
Pos
Neg
Pos
Oxyph i lic neuroendocrine carcinoma Carcinoid lumor Undifferenliat.ed carcinoma Squamous cell carcinoma Carcinoid tumor
Pos
Neg
Pos
NR NR
NR NR
NR NR
NR
NR
NR
Pas
NR
Pos
CarcinOid t.umor
Pas
NR
POs
Poorly Differentiat.ed squamous cell carcinoma Poorly different.iated squamous cell carcinoma CarcinOid t.umor
Pas
NR
NR
Pos
NR
Pos
Normal
range
Normal range
range
Normal range Normal range Normal range Normal range NR Normal range NR
Normal range Normal range
24) Miyahara
NR
NR
Normal Pas range Normal Carcinoid t.umor Pas range NR: NOt. reported, Pes: Positive, Neg: Negative
25)sat.o et. al(1990)
Pos
squamous cell carcinoma Poorly DlfferenLiaLed s quamous cell carcinoma Carcinoid t.umor
21) Pat.t.erson et. al(1987) 22)Tanaka et. al(1987) 23)Koshii et. al(1987) et. al(1988)
al.
Summary of laboratory tests and histopathological findings of 35 cases.
Authors 1) Goldman
el
Neg
Nil
Neg
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therapy. Irradiation of metastatic skin lesions was performed in 3 cases, but no effect was evident. Postoperative radiotherapy was conducted in 4 cases. Thus, radiotherapy has not been shown to control laryngeal carcinoids. Chemotherapy was administered in 6 cases at some point in their course but this treatment was not effective. Local excision was carried out in 8 cases and 3 of these developed a primary recurrence. Partial laryngectomy was performed in 9 cases, none of which had recurrence. Total laryngectomy was performed in 12 cases and again no recurrence was found. Therefore, neck metastasis was well controlled by neck dissection. Thirteen cases died of the disease, and 5 cases died from other causes. Distant metastasis was the most common cause of death. Carcinoid tumor of the larynx is agressive, malignant, and unresponsive to radiotherapy or chemotherapy. Therefore, adequate surgical excision is currently the only effective treatment. Metastasis. Among the 35 patients with laryngeal carcinoid tumors, metastasis was observed in 24 at some point in their course. The cervicallymphnodes were the most common site of metastasis and were involved in 19 cases. Thirteen cases presented with distant metastases: subcutaneous metastasis in 6, lung metastasis in 5, liver metastasis in 5, and bone metastasis in 2. Multiple organ metastasis (heart, pancreas, etc.) were found in 3 cases. Interestingly, 4 of 6 cases suffering from skin metastasis complained of pain. Metastasis to skin and bone are common with foregut and hindgut carcinoids (WILLIAMS and SANDLER, 1963), and laryngeal carcinoid shows a similar tendency. Distant metastasis occurred frequently and was the most common cause of death. Laboratory tests. Serum levels of serotonin and urinary levels of its metabolite, 5-hydroxy indoleacetic acid, were examined in 20 cases. All cases were within the normal range. After LEMBECK (1953) reported that carcinoid tumors contained high levels of serotonin, excessive secretion serotonin by the tumor was taken to indicate the carcinoid syndrome. Laryngeal carcinoid tumors did not contain large amounts of serotonin. Initial histological diagnosis. Eight cases were diagnosed as undifferentiated carcinoma, and 5 cases were termed poorly differentiated carcinoma on the basis of biopsy specimens. Laryngeal carcinoid tumors frequently have atypical histological features and may be misdiagnosed as undifferentiated or poorly differentiated carcinoma. Argyrophil or argentaffin reaction. Among the 27 cases for which an argyrophil reaction was reported, 26 were Grimelius stain positive. One case was Grimelius negative in the primary lesion but positive in the metastatic lesion. Almost all of the cases reporting an argentaffin reaction were Fontana-Masson stain negative. WILLIAMS and SANDLER (1963) have pointed out that carcinoid tumors arising from the foregut are usually argyrophil positive and argentaffin
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negative. Our review of the literature indicates that laryngeal carcinoid tumors appear to show a similar tendency. Transmission electron microscopy (TEM). All of the tumors subjected to TEM showed neurosecretory granules. If the histological findings revealed no typical carcinoid tumor cell arrangement, or if the argyrophil reaction was negative, neurosecretory granules identified by TEM provided the final diagnosis. The term carcinoid tumor was introduced by OBERNDORFER (1907), to describe tumors of the small intestine which were less agressive than most carcinomas. However, carcinoid tumors of non-appendiceal sites are most often malignant and metastasize more frequently than those of appendiceal origin (PEARSON and FITZGERALD, 1949). Our literature review showed that all laryngeal carcinoid tumors had a high degree of malignancy and a grave prognosis.
REFERENCES BAUGH, R. F., WOLF, G. T ., LLOYD, R. V., MCCLATCHEY, K. D ., and EVANS, D. A.: Carcinoid (neuroendocrine carcinoma) of the larynx. Ann. 0101. Rhinol. Laryngol. 96: 315-321, 1987. BLOK, P. H. H. M., MANNI, J. J ., VAN DEN BROEK, P., VAN HAELST, U. J. G . M ., and SLOOH, J. L.: Carcinoid of the larynx. A report of three cases and a review of the literature. Laryngoscope 95: 715-719,1985. CAPPER, J. W. R., MICHAELS, L., and GREGOR, T.: A malignant carcinoid tumor of the supraglottic larynx. l. Laryngol. 0101.95: 963-971, 1981. DUVALL, E., JOHNSTON, A., McLAY, K., and PIRIS, J.: Carcinoid tumor of the larynx. J. Laryngol. 0101.97: 1073-1080, 1983. FERLITO, A.: Histological classification of larynx and hypopharynx cancers. Acla Ololaryngol. 342: 9-88, 1976. GAPANY-GAPANAVICIUS, B., and KENAN, S.: Carcinoid tumor of the larynx. Ann. 0101. Rhinol. Laryngol. 90: 42--47, 1981. GOLDMAN, N . c., HOOD, C. 1., and SINGLETON, G. T . : Carcinoid of the larynx. Arch. 010laryngol. 90: 90-93, 1969. GOLDMAN, N. c., KATIBAH, G. M ., and MEDINA, J.: Carcinoid tumor of the larynx. Ear Nose Throal l. 64: 130-134, 1985. GUERRIER, Y., LALLEMANT, J. G., CHARLIN, B., and PAGES, A . : A carcinoid tumor of the larynx. ORL 47: 113-118, 1985. HIRANO, M., and KURITA, S.: Transepiglottic pharyngolaryngotomy. l. Ololaryngol. 87: 603606, 1984. HORIKAWA, T., and MATSUBARA, H.: A carcinoid tumor of the epiglottis. Ololaryngology (Tokyo) 44: 437-440, 1972. KAMIMURA, R., MIYATA, S., MATSUI, 0., TAKASHIMA, T ., and NONOMURA, A.: Carcinoid of the larynx. lpn. l . Cancel' Clin. 26 : 1255-1258, 1980. KOSHII, K., HIRABAYASHI, H ., UNO, K., OHGAKI, H., AKIYAMA, K ., SOEDA, H., and HINOHARA, T. : A case of carcinoid tumor of the larynx. J. lpn. Bronchoesophagol. Soc. 38: 452-456, 1987. LEMBECK, F . : 5-Hydroxytryptamine in a carcinoid tumor. Nalure 172 : 910-911,1953 . MARKEL, S. F., MAGIELSKI, J. E ., and BEALS, T. F.: Carcinoid tumor of the larynx. Arch. Ololaryngol. 106: 777-778, 1980. MILLS, S. E., and JOHNS, M. E.: Atypical carcinoid tumor of the larynx. Arch. Ololaryngol. 110: 58-62, 1984.
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MIYAHARA, H., SATO, T., YOSHINO, K., UMATANI, K., and TSURUTA, Y.: Carcinoid tumor of the larynx. Pract. Otol. (Kyoto) 81: 1761-1767, 1988. NONOMURA, A., SHINTANI, T., KONO, N., KAMIMURA, R., and OHTA, G.: Primary carcinoid tumor of the larynx and review of the literature. Acta PatllOl. lpn. 33: 1041-1049, 1983. OBERNDORFER, S.: Karzinoide Tumoren des Dlinndarms. Frank! Zschr. PatllOl. 1: 426-432,
1907. PALADUGU, R. R., NATHWANI , B. N., GOODSTEIN, J., DARDI, L. E ., MEMOLI, V. E., and GOULD, V. E.: Carcinoma of the larynx with mucosubstance production and neuroendocrine differentiation . An ultra structural and immunohistochemical study. Cancer 49: 343-349,
1982. PATTERSON. S. D., and YARINGTON, CT.: Carcinoid tumor of the larynx. The role of conservative therapy. AI/I/. Otol. Rhinal. Laryngol. 96: 12-14, 1987. PEARSON, C. M., and FITZGERALD, P. J.: Carcinoid tumors. A reemphasis of their malignant nature. Cancer 2: 1005-1026, 1949. SNYDERMAN, C, JOHNSON, J . T., and BARNES, L.: Carcinoid tumor of the larynx: Case report and review of the world literature. Otolaryngol. Head Neck Surg. 95: 158-164, 1986. STANLEY, R. J., DESANTO, L. W., and WEILAND, L. H .: Oncocytic and oncocytoid carcinoid tumors (well-differentiated neuroendocrine carcinomas) of the larynx. Arch. Otolaryngo .1
Head Neck Surg. 112: 529-535, 1986. TACHI, T., TAMORI, M., KAMIMURA, R ., SHINTANI, T., and FUKUSHlRO, R.: Laryngeal carcinoid tumor with skin metastasis. lpn. l. Clil1. Dermatol. 35 : 581-586, 1981. TAMAI, S. , 1RI, H ., MARUYAMA, T., KASAHARA, M ., AKATSUKA , S., SAKURAI, S., and MURAKAMI, Y.: Laryngeal carcinoid tumor. Light and electron microscopic studies. Callcer 48: 2256-
2259, 1981. TANAKA, M., HASEGAWA, T., KIN, S., TAMAOKI, H., KOTOU, K., and YOSHIDA, J.: A case of atypical carcinoid of the larynx. Otolaryngology (Tokyo) 59: 663-669, 1987. WEIGHILL, J. S., TANKEL, J. W ., and MENE, A.: Carcinoid tumour of the larynx (A case report and review of the literature). l. LarYlIgol. Otol. 100: 1421-1426,1986. WILLIAMS, E. D., and SANDLER, M.: The classification of carcinoid tumors. Lancet 1: 238-239,
1963.
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Dr. K. Sato, Department of Otolaryngology-Head and Neck Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830, Japan