Diagnosis in Oncology
tic agents is largely supportive, and most reports recommend the use
Fig 4.
Hypoxic lung injury during cancer therapy poses a serious problem.
Multiple agents can be implicated. In this patient, vinorelbine most
likely was the causative agent of the pulmonary findings. While filgras-
tim has been associated with hypoxemia during neutrophil recov-
ery,1,2 the lack of temporal association, leukocytosis, or positive
rechallenge during subsequent chemotherapy makes it an unlikely
offender in this case. No other causes could be elucidated after exten-
sive work-up, though remote history of radiotherapy to the chest wall
may have been a sensitizing factor. In a pooled analysis of three large
multicenter trials conducted in North America with vinorelbine
(n ⫽ 327), dyspnea was reported in 5% of patients; in 3% it was
severe.3 This complication may occur after either the first or subse-
quent treatments. In fact, it may manifest as late as on the tenth cycle of
treatment.4,5 Potential risk factors include concomitant use of
mitomycin-C and history of dyspnea from a previous infusion.5,6
Two types of respiratory distress associated with vinorelbine
have been reported: acute and subacute. The acute form, typically
associated with acute dyspnea, bronchospasm, fever, hypotension,
and alveolar infiltrates, usually occurs within minutes after vinorel-
bine infusion.3,6 The subacute form, occurring hours to days after
infusion, is marked by progressive dyspnea, diffuse interstitial infil-
trates, and in rare cases, acute respiratory distress syndrome.7 Vinorel-
bine, a semisynthetic vinca alkaloid, interacts with tubulin. It causes
imbalance between polymerization and depolymerization and leads
to a disruption of microtubule assembly—an essential component of
vascular permeability regulation.8 Microtubule inhibitors cause a dys-
functional actomyosin cytoskeleton, leading to endothelial cell barrier
dysfunction, which is similar to the pathogenesis of many conditions
such as sepsis and acute lung injury.8 After infusion, vinorelbine
achieves much higher concentration in heart and lung tissues than in
serum.9 In fact, rare cases of myocardial infarction have also been
reported in association with vinorelbine.10,11 Treatment of acute lung
injury associated with vinorelbine or other suspected chemotherapeu-
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of corticosteroids. Typically, respiratory distress associated with
single-agent vinorelbine is followed by full recovery. This syndrome,
as with other vinca alkaloids such as vinblastine, may result in chronic
lung disease, especially when mitomycin-C was concurrently admin-
istered.12 After one episode of respiratory distress, re-treatment with
vinorelbine may lead to a more severe reaction, though some investi-
gators re-treated patients, noting only a mild reaction, using premed-
ication with corticosteroids.3,6 Vinorelbine most likely was the
causative agent in this patient, and while resulting in a critical situa-
tion, was associated with a full recovery. As the role for vinorelbine in
solid tumors, including breast cancer, continues to expand, clinicians
must be aware of this possible severe, albeit uncommon, pulmonary
complication, and query patients regularly regarding dyspnea during
chronic vinorelbine dosing.
Tawee Tanvetyanon, Edward R. Garrity, and
Kathy S. Albain
Division of Hematology/Oncology, and Lung Transplantation Program, Division
of Pulmonary and Critical Care Medicine, Loyola University Chicago Stritch
School of Medicine, Maywood, IL
© 2006 by American Society of Clinical Oncology
REFERENCES
1. Schilero GJ, Oropello J, Benjamin E: Impairment in gas exchange after
granulocyte colony stimulating factor (G-CSF) in a patient with the adult respira-
tory distress syndrome. Chest 107:276-278, 1995
2. White K, Cebon J: Transient hypoxaemia during neutrophil recovery in
febrile patients. Lancet 345:1022-1024, 1995
3. Hohneker JA: A summary of vinorelbine (Navelbine) safety data from North
American clinical trials. Semin Oncol 21:42-47, 1994 (suppl 10)
4. Tassinari D, Sartori S, Gianni L, et al: Is acute dyspnoea a rare side effect
of vinorelbine? Ann Oncol 8:503-504, 1997
5. Raderer M, Kornek G, Hejna M, et al: Acute pulmonary toxicity associated
with high-dose vinorelbine and mitomycin C. Ann Oncol 7:973-975, 1996
6. Cattan CE, Oberg KC: Vinorelbine tartrate-induced pulmonary edema
confirmed on rechallenge. Pharmacotherapy 19:992-994, 1999
7. Kouroukis C, Hings I: Respiratory failure following vinorelbine tar-
trate infusion in a patient with non-small cell lung cancer. Chest 112:846-848,
1997
8. Birukova AA, Smurova K, Birukov KG, et al: Microtubule disassembly
induces cytoskeletal remodeling and lung vascular barrier dysfunction: Role of
Rho-dependent mechanisms. J Cell Physiol 201:55-70, 2004
9. Leveque D, Quoix E, Dumont P, et al: Pulmonary distribution of vinorelbine
in patients with non-small-cell lung cancer. Cancer Chemother Pharmacol 33:176-178,
1993
10. Bergeron A, Raffy O, Vannetzel JM: Myocardial ischemia and infarction
associated with vinorelbine. J Clin Oncol 13:531-532, 1995
11. Karminsky N, Merimsky O, Kovner F, et al: Vinorelbine-related acute
cardiopulmonary toxicity. Cancer Chemother Pharmacol 43:180-182, 1999
12. Rivera MP, Kris MG, Gralla RJ, et al: Syndrome of acute dyspnea related to
combined mitomycin plus vinca alkaloid chemotherapy. Am J Clin Oncol 18:245-
250, 1995
DOI: 10.1200/JCO.2005.03.0023
■ ■ ■
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Laryngeal Obstruction and Hoarseness
Associated With Rosai-Dorfman Disease
A 54-year-old African American man presented with pro-
gressive hoarseness and shortness of breath of more than 4
weeks’ duration. Medical history was significant for a diagnosis
of Rosai-Dorfman disease (RDD) of the right nasal sinus 9 years
1953
 Cossor et al
earlier, which was surgically removed. He had a 40 pack-year
history of smoking. Except for swelling of the superior aspect of
his right nostril his physical examination was unremarkable.
Computed tomography scan of the head and neck was limited
secondary to artifacts, but revealed opacification of the frontal
and right and left maxillary sinuses. The ethmoidal septae and
nasal septum were destroyed (Fig 1, arrow). Direct laryngoscopy
disclosed a polypoid mass below the right true vocal cord, encompass-
ing approximately 80% of the proximal trachea in the subglottic area,
obstructing the airway. A biopsy of the mass was done. Pathologic
examination showed RDD (Fig 2A and B), with the classic RDD
histiocytes and emperipolesis. Immunohistochemistry was positive
for the S-100 protein. Because of airway obstruction and increased
breathing difficulty, a tracheostomy was required. He was treated with
radiation therapy with complete amelioration of his symptoms, and at
16 months follow-up he had no evidence of recurrence.
In 1969, Rosai and Dorfman described the disease entity as
sinus histiocytosis with massive lymphadenopathy, later re-
ferred to as RDD.1,2 RDD occurs worldwide and is primarily a
disease of childhood and early adulthood, although it can affect
all age groups. Males are more commonly affected than females
and there may be an increased incidence in black patients. Most
patients (83% to 95%) present with massive, painless, bilateral
cervical lymphadenopathy; however, other nodal sites includ-
ing axillary, inguinal, para-aortic, and mediastinal lymph nodes
may be involved.1,2 Approximately 43% of patients have at least
Fig 1.
1954
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Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
one site of extranodal involvement. Such sites typically include
the upper respiratory tract, skin, salivary glands, bone, CNS,
and soft tissue.1,2 The head and neck are common sites of
extranodal involvement, with the nasal cavity and paranasal
sinuses most frequently affected, followed by the major salivary
glands.3-6 Less commonly, the larynx and trachea may be in-
volved, usually manifested as tissue infiltration and edema,
which may cause circumferential narrowing or a polypoid-
appearing lesion. Vocal cord lesions may cause impaired mobil-
ity and hoarseness. Such lesions may cause life-threatening
dyspnea or marked stridor.3-6 Surgically excised lymph nodes
are yellow-white, often matted together by perinodal and cap-
sular fibrosis. Lymph node sinuses are expanded by a prolifera-
tion of histiocytes with round or vesicular nuclei with delicate
membranes and a centrally located nucleolus.7 The hallmark of
the histiocyte is its presence within the cytoplasm of variable
numbers of intact lymphocytes, a phenomenon referred to as
lymphophagocytosis or emperipolesis.7 The most useful immu-
nohistologic marker for RDD histiocytes is the expression of
S-100 protein.8 Although precise treatment for RDD is un-
known, multiple modalities have been utilized, including
surgery, radiotherapy, chemotherapy, corticosteroids, and in-
terferon.9,10 In the majority of cases, no treatment is necessary
since the disease is usually self limited. Only in patients in whom
massive nodal or extranodal involvement threatens organ func-
tion is therapy indicated. In a review of 80 patients with RDD,
40 did not require any treatment.10 Corticosteroids reduced
lymphadenopathy and ameliorated fevers. Radiation therapy
was associated with three patients with complete remissions,
three with partial remissions, and three patients who died of
disease. Of 12 patients treated with chemotherapy (vinca alka-
loids, alkylating agents, and anthracyclines), 10 showed no
response, while two achieved complete remission with metho-
trexate and 6-mercaptopurine. In summary, RDD is a rare
atypical cellular proliferation of histiocytes of unknown etiol-
ogy. Laryngeal involvement associated with obstruction and
hoarseness is an uncommon complication but potentially life
threatening, as demonstrated in the present case. Although the
precise treatment for RDD is undefined, radiotherapy may be
efficacious in some patients.
Furha Cossor, Al-Hareth M. Al-Khater, and Donald C. Doll
Ellis Fischel Cancer Center, University of Missouri–Columbia School of
Medicine, Columbia, MO
© 2006 by American Society of Clinical Oncology
REFERENCES
1. Rosai J, Dorfman RF: Sinus histiocytosis with massive lymphadenopathy:
A newly diagnosed benign clinicopathologic entity. Arch Pathol 87:63-70, 1969
2. Rosai J, Dorfman RF: Sinus histiocytosis with massive lymphadenopathy:
A pseudolymphomatous benign disorder with massive lymphadenopathy—
Analysis of 34 cases. Cancer 30:1174-1188, 1972
3. Carbone A, Passannante A, Gloghini K, et al: Review of sinus histiocytosis
with massive lymphadenopathy (Rosai-Dorfman disease) of head and neck. Ann
Otol Rhinol Laryngol 108:1095-1104, 1999
4. Chang LY, Kuo T, Chan HL: Extranodal Rosai-Dorfman disease with
cutaneous, ophthalmic and laryngeal involvement: Report of a case treated with
isoretinoin. Int J Dermatol 41:888-891, 2002
5. Aluffi P, Prestinari A, Ramponi A, et al: Rosai-Dorfman disease of the
larynx. J Laryngol Otol 114:565-567, 2000
6. Hazarika P, Nayak D, Balakrishnan R, et al: Rosai-Dorfman disease of the
subglottis. J Laryngol Otol 114:970-973, 2000
JOURNAL OF CLINICAL ONCOLOGY
 Diagnosis in Oncology

Fig 2.

7. Foucar E, Rosai J, Dorfman R: Sinus histiocytosis with massive lymphad- months of combination therapy revealed marked regression of
enopathy (Rosai-Dorfman disease): Review of the entity. Semin Diagn Pathol
the liver lesions and normalization of her LFTs. She was subse-
7:19-73, 1990
8. Eisen RN, Buckley PJ, Rosai J: Immunophenotypic characterization of quently monitored on goserelin acetate and tamoxifen, which
sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). she tolerated well. She remained asymptomatic and enjoyed a
Semin Diagn Pathol 7:74-82, 1990 good quality of life. Remarkably, the patient’s disease continued
9. Komp DM: The treatment of sinus histiocytosis with massive lymphade-
nopathy (Rosai-Dorfman disease). Semin Diagn Pathol 7:83-86, 1990
in a sustained partial remission on combination therapy for
10. Pulsoni A, Anghel G, Falcucci P, et al: Treatment of sinus histiocytosis with almost 4 years, when she was found to have a local recurrence of
massive lymphadenopathy (Rosai-Dorfman disease): Report of a case and her breast cancer at the surgical scar site. Imaging studies at that
literature review. Am J Hematol 69:67-71, 2002 time demonstrated a new bony metastasis in her sternum and
DOI: 10.1200/JCO.2005.02.1378 increased size of the liver lesions. Her LFTs were noted to have
■ ■ ■
risen. Goserelin acetate was continued, and tamoxifen was
Authors’ Disclosures of Potential Conflicts of Interest switched to the nonsteroidal aromatase inhibitor letrozole (2.5
The authors indicated no potential conflicts of interest.
mg/d by mouth). Three months later, despite remaining asymp-
tomatic, staging CT scans revealed progressive disease with
Aromatase Inhibitor Withdrawal Response prominent liver lesions. A representative liver lesion is shown in
in Metastatic Breast Cancer Figure 1. At this time, a decision was made to stop all therapy (both
goserelin acetate and letrozole), allow her to resume normal menses
A 31-year-old premenopausal woman was diagnosed with (which occurred within one cycle), and monitor her for a response to
left-sided invasive breast cancer when she presented with breast withdrawal of estrogen-suppressing therapy. Three months later, on
discomfort and a palpable mass. The patient was in good general no treatment, her LFTs decreased, and imaging studies revealed im-
health without any medical problems. She had no symptoms provement in the sternal lesion and impressive decreases in the size of
and had an excellent performance status. She underwent men- the hepatic lesions. An example of a regressed liver lesion is seen in
arche at 12 years of age and had never been pregnant. She had no Figure 2. To date, 14 months later, the patient continues to feel well,
family history of breast, ovarian, or other cancers. She had without new symptoms. Her scans continue to reveal a sustained
emigrated from Romania, where in 1985, at 16 years of age, she
lived 700 miles from the nuclear accident at Chernobyl. She
underwent a lumpectomy with axillary node dissection, reveal-
ing a 1.7-cm, Bloom-Richardson grade 3 invasive ductal carci-
noma, with one of 16 sampled nodes positive for metastatic
disease. The tumor stained estrogen receptor–positive, interme-
diate for progesterone receptor, and did not overexpress Her2-
neu. At presentation to the medical oncology team, the patient
was noted to have mildly elevated liver function tests (LFTs),
with an AST of 83 U/L and an ALT of 243 U/L. Staging evalua-
tions revealed three suspicious liver lesions measuring 1.8 cm,
1.3 cm, and 0.8 cm, which were confirmed as liver metastases on
liver biopsy. The patient was initiated on tamoxifen 20 mg/d.
After approximately 6 weeks, her LFTs had normalized, but her
computed tomography (CT) scan demonstrated slight increase
in the size of the liver lesions. She was still menstruating regu-
larly, and luteinizing hormone-releasing hormone agonist ther-
apy (goserelin acetate 3.6 ␮g intramuscularly monthly) was
added to tamoxifen. A repeat CT scan after approximately 2 Fig 1.

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Copyright © 2006 American Society of Clinical Oncology. All rights reserved.