Frozen section diagnosis is often critically important for
surgical decision-making, therefore the pathologist must be aware of the question being asked. How one
should approach the intra-operative consultation depends on the history, clinical findings, the operation
being performed and the specimen submitted. The following is an outline of the scope of this topic,
however, only selected areas will be discussed.
- For primary diagnosis of disease
- Pre-operative diagnosis/biopsy not possible
- Unexpected intra-operative findings or second disease process
- Benign versus malignant mass
- Determine extent/type of procedure
- Margins of excision
- Lymph node
- Major resection eg of lung, only if nodes are negative
- Rarely, sentinal nodes in pediatric melanoma, but not for frozen
Extent of disease
- In Hirschsprung's disease - to place colostomy or in primary
endorectal pull-through, to determine level of normal ganglion cells
- Local resectability and metastasis or not
- Triage of
- First obtain diagnostic tissue
- Tumor protocols (touch preparations, frozen tissue, electron
microscopy, tissue culture for cytogenetics etc.)
A. Pediatric Cases:
Commonly seen frozen sections can be grouped
according to organ system and/or clinical question. Only the first three of the following will be
- Hirschsprung's disease
- Lymph nodes (reactive vs. lymphoma)
- Primary (Wilms [not for diagnosis but
occasionally for extent of disease], neuroblastoma vs. ganglioneuroma, sarcoma vs. nodular fasciitis,
ovarian malignancy vs. torsion)
- Metastatic (resection for cure eg in
osteosarcoma, Wilms, may need to confirm tumor and determine margins, if first diagnosis eg in
neuroblastoma, triage tissue for ploidy and n-myc)
- Brain and cord
- Bone lesions
- Transplant related
- Recipient (infection, recurrence of primary disease, post-transplant
- Donor, evaluation of organ suitability (kidney, liver, lung etc.)
Reference: Coffin CM et al. Frozen section diagnosis in pediatric surgical pathology: a decades
experience in a children's hospital. Arch Pathol Lab Med 2005;129(12):1619-25.
Case 1. History: One month-old male with Hirschsprung's disease
diagnosed clinically and on suction rectal biopsy, now undergoing endorectal pull-through. Both
specimens were labeled "rectal biopsy".
FS1: Full thickness biopsy: no ganglion cells
FS2: Full thickness biopsy: ganglion cells present
Final diagnosis: same
Notes: The first frozen was done to confirm diagnosis of Hirschsprung's
disease since suction rectal biopsy is not the gold standard for diagnosis (but full thickness biopsy
is). The second frozen was done to determine level of pull-through.
Case 2. History: 16 day-old male with Hirschsprung's
disease diagnosed clinically and on suction rectal biopsy, now undergoing endorectal pull-through. One
frozen section was submitted, labeled "rectum".
FS1: Full thickness biopsy: ganglion cells present
Final diagnosis: same
Notes: The first section cut was too thin making it
difficult to recognize ganglion cells. 6-8 micron sections, over-stained in hematoxylin by 30 seconds,
make recognition of ganglion cells easier. Also, one would have expected the first specimen to be from
the aganglionic zone and an error could easily have been made. In this case, the surgeon decided that
the diagnosis was obvious and sent only the normal colon to confirm the level. It is the responsibility
of the pathologist to clarify site and purpose of the frozen.
Case 3. History: 7 year-old
male with large pelvic mass, exploratory laparotomy done for open biopsy.
FS1: Favor lymphoma, but other small round blue cell tumors to be
Final diagnosis: Burkitt's lymphoma
Notes: Specimen was triaged appropriately for
Case 4. History: 9 year-old
male with abdominal mass, who on exploratory laparotomy was found to have enlarged lymph nodes
compressing the cecum. First frozen was sent, labeled "pericecal mass" followed by two additional
frozens "pericecal lymph node" and "pericolonic mass".
FS1: Edematous connective tissue, fat and focal lymphocytic
FS2 and 3: Reactive lymph nodes (not shown)
Final diagnosis: Organizing peritonitis and reactive lymph
Notes: In children, masses around the cecum/appendix
are often inflammatory, since the first line of treatment for appendicitis is medical management with
Case 5. History: 10 year-old female with left
posterior thigh mass, which is biopsied and sent for frozen section.
FS1: Small blue cell tumor
Final diagnosis: Primitive neuroectodermal tumor, metastatic
Notes: This patient did have a history of PNET
involving cranium (primary site), chest wall and right lung with multiple resections over the past 3
years. The current frozen was done to determine the nature of a new mass in the thigh. Tissue was
appropriately sent for electron microscopy and was frozen for tissue bank.
Case 6. History: 6 year-old female with right renal
mass. Nephrectomy specimen (134 g) sent for frozen. A 2.5 cm cystic lesion filled with grey tan
granular tissue admixed with blood, which was readily separable from the cystic wall, was
FS1: Most consistent with cystic nephroma
Final diagnosis: Papillary renal cell carcinoma, metastatic to one
Notes: The tumor consisted of a cystic and solid
component; only the former was present on the frozen slide since the latter became separated. The
pathologist, who made the interpretation based only on the cystic portion, did not realize that the tumor
had a solid component as well. In this case, the intra-operative management was not changed (nephrectomy
had already been performed), but one can see how critical it is to correlate the gross and microscopic
findings. Comment: This is a very unusual case since renal cell carcinoma is rare in children and
papillary carcinoma is even rarer.
Case 7. History: 7 year-old male with history of
dermatofibrosarcoma protuberans on left upper back, status post biopsy. Now undergoes wide local
excision, which is sent for frozen to evaluate the deep margin.
FS1: Deep margin suspicious for residual dermatofibrosarcoma
Final diagnosis: Margin free (area of scarring)
Notes: Even though the tumor was present on the
frozen section and could be compared, sometimes it is just not possible to be sure of margins, as in this
case. This situation should be discussed with the surgeon, who is in a position to decide whether to
take additional margin or wait for the permanent section.
Case 8. History: 7 year-old male with left forearm
nodule, which is excised and sent for frozen. The specimen consists of soft tissue with a firm 0.6 cm
FS1: Benign, rule out granuloma annulare
Final diagnosis: Necrotizing palisaded granuloma
Notes: The clinical differential diagnosis included
nodular fasciitis, soft tissue tumor. As long as the diagnosis was benign, the exact nature of the
lesion did not matter for surgical management in this case.
Case 9. History: 5 year-old female with cervical
FS1: Consistent with Rosai-Dorfman disease
Final diagnosis: Rosai-Dorfman disease
Notes: This patient did have a history of
Rosai-Dorfman disease almost 3 years ago, in the same location (history was provided to the pathologist
at the time of frozen section). Although some cases are recurrent and more aggressive, this is rare.
The biopsy was done to rule out lymphoma or other disease.
2. Lung and Pleura:
The most commonly asked questions are:
Peripheral lung nodule
- Benign or malignant
- If malignant, small or non-small
- If malignant, primary or metastatic
- If malignant, resectable or not
Mediastinal lymph nodes - positive or negative
- Benign or malignant
- Mesothelioma or metastatic carcinoma
- Immunocompromised host
- Opportunistic infection
Case 10a. History: 68 year-old male with right lung
mass. Endobronchial biopsy (EBBx) of distal trachea was sent for frozen.
FS1: Carcinoma (probably squamous)
Final diagnosis: Poorly differentiated squamous cell carcinoma
Case 10b. History: 60 year-old female with mediastinal
mass. Left main stem bronchus EBBx sent for frozen.
FS1: Small cell carcinoma
Final diagnosis: Small cell carcinoma
Notes: In these two cases, the tumors were unresectable, but the purpose
of the frozens was to document that diagnostic tissue had been obtained. More often, the surgeon wants
to know whether it is a small or non-small cell carcinoma.
Case 11. History: 61 year-old female with lung mass.
Needle biopsy sent for frozen.
FS7: Carcinoma, non-small cell type
Final diagnosis: Adenocarcinoma, poorly differentiated
Notes: The first six specimens were various
mediastinal lymph nodes, which were all benign on frozen section (all lymph node tissue should be frozen,
since further surgery is dependent on benign lymph nodes). The needle biopsy was sent to make the tissue
diagnosis of carcinoma before proceeding with the lobectomy.
Case 12. History: 73 year-old male with left upper
lobe nodule. Wedge resection containing a 1.1 cm mass sent for frozen.
FS1: Positive for malignancy
Final diagnosis: Small cell carcinoma
Notes: Multiple mediastinal nodes were benign on
frozen and a lobectomy was performed. The general understanding is that small cell carcinomas need not
be resected, since they are so frequently metastatic, but for the rare patient who presents with a Stage
I or II tumor, resection is indicated. Thus in this patient, the appropriate procedure was done.
Whenever possible, one should say whether the tumor is small or non-small cell carcinoma on frozen
section. The differential diagnosis of carcinoid tumor should be kept in mind, for which a limited
resection may be adequate. Also, when sectioning a peripheral lung nodule for frozen, don't cut where
the tumor is closest to pleura (since pleural involvement in tumors less than 3 cm is important for
staging). That section should be submitted for permanent section.
Case 13. History: 72 year-old male with lung nodule.
Level 7 lymph node sent for frozen.
FS1: Metastatic carcinoma
Final diagnosis: Metastatic poorly differentiated
Notes: The lung nodule was wedged and frozen
(adenocarcinoma). No further surgery was undertaken.
Case 14. History: 64 year-old female with right upper
lobe nodule and history of chronic lymphocytic leukemia. A 1.5 cm wedge biopsy (specimen #1) was
entirely submitted for frozen.
FS1: Fibrosis, no evidence of tumor
Final diagnosis: Well-differentiated adenocarcinoma with acinar and
Notes: The remaining nodule was wedged (specimen #2)
and sent for permanents (1.4 cm area of firmness was noted in this specimen). At the time of the frozen,
the surgeon did not indicate that only a part of the nodule had been sent for frozen section. On
comparison with the non-frozen tumor, it was clear that the first specimen also represented tumor. This
case illustrates the difficulty of making a definite diagnosis of malignancy in a small peripheral lung
nodule. When in doubt, one should be conservative on frozen section, since this would avoid unnecessary
surgery. Four weeks later, the patient underwent mediastinal lymph node biopsies (negative on frozen)
and lobectomy (no residual malignancy).
Case 15. History: 64 year-old female with right lung
nodules. Wedge biopsy sent for frozen.
FS1: Inflammatory lesion, no tumor
Final diagnosis: Acute and organizing pneumonia
Notes: Organizing pneumonia (formerly called
bronchiolitis obliterans organizing pneumonia or BOOP) can often present as a mass lesion.
Case 16. History: 82 year-old female with left lung
nodule, S/P treatment for head and neck carcinoma. Wedge biopsy of lung containing a 0.9 cm nodule is
sent for frozen. Two blocks cut for frozen (FS1a and FS1b).
FS1a: Organizing pneumonia
FS1b: Poorly differentiated carcinoma, probably squamous
Final diagnosis: Poorly differentiated squamous cell carcinoma
Notes: At first only one block was frozen. When this
showed only organizing pneumonia, the pathologist froze the remaining nodule, since, on gross
examination, it was suspicious for tumor. This case illustrates the importance of gross examination by
the pathologist and adequate sampling on frozen section.
Case 17. History: 80 year-old male with spontaneous
pneumothorax who undergoes VATS (video-assisted thoracoscopic surgery) pleural biopsy.
FS1: Pleural fibrosis with chronic inflammation and mesothelial
Final diagnosis: Same
Notes: Although mesothelial cells can appear atypical
on frozen section, without definite evidence of invasion, a diagnosis of malignancy should not be made
unless there is a large amount of tumor tissue present. Other helpful clues are zone effect or layering
of changes (fibrin or mesothelial cells at one surface and granulation tissue or fibrosis at the other)
in reactive hyperplasia. When in doubt, look for fat or skeletal muscle invasion.
Case 18. History: 63 year-old male with recurrent
pleural effusions undergoes thoracoscopic pleural biopsy, which is submitted for frozen section.
FS1: Rule out mesothelioma
Final diagnosis: Malignant mesothelioma, epithelial type
Notes: The first biopsy consisted of small fragments of
tissue (largest 4mm) all of which was frozen. The purpose of this frozen was to decide if additional
(non-frozen) tissue should be obtained for definite diagnosis. A second biopsy was sent for electron
microscopy and permanent sections. Whenever possible, some tissue should be kept unfrozen, since frozen
artifact can make definite diagnosis difficult. Discuss with the surgeon the pros and cons of
Case 19. History: 67 year-old female with CML, in
blast crisis who presented with a nasal "polyp".
FS1: Large non-branching hyphae in necrotic tissue
Final diagnosis: Septate fungal hyphae, invading necrotic tissue
(culture result: Aspergillus flavus)
Notes: Fungus can be identified on FS, the key is to
stain longer in hematoxylin by 15-30 sec. The frozen can be reported as fungal hyphae present.
Pediatric frozen sections
- Coffin CM, Spilker K, Zhou H, et al. Frozen section diagnosis in
pediatric surgical pathology: a decades experience in a children's hospital. Arch Pathol Lab Med
- Fisher JE, Burger PC, Perlman EJ, et al. The frozen section
yesterday and today: Pediatric solid tumors-crucial issues. Ped Dev Pathol 2001;4:252-66.
- Cozzi DA, Schiavetti A, Morini F, at al. Nephron-sparing surgery
for unilateral primary renal tumor in children. J Pediatr Surg 2001;36(2):362-5.
Lung frozen sections
- Sienko A, Allen TC, Zander DS, et
al. Frozen section of lung specimens. Arch Pathol Lab Med 2005;129(12):1602-09.
- Yoshida J, Nagai K, Yokose T, et al. Limited resection trial for
pulmonary ground-glass opacity nodules: fifty-case experience. J Thoracic Cardiovasc Surg
- Kutla CA, Urer N, Olgac. Carcinoma in situ from the view of
complete resection. Lung Cancer 2004;46(3):383-5.
- Marchevsky AM, Changsri C, Gupta I, et al. Frozen section diagnoses
of small pulmonary nodules: accuracy and clinical implications. Ann Thoracic Surg 2004;78(5):1755-9.
- Maygarden SJ, Detterbeck FC, Funkhouser WK. Bronchial margins in
lung cancer resection specimens: utility of frozen section and gross evaluation. Mod Path